The Autonomic Nervous System in Health and Disease [1st ed.] 0824704088, 9780824704087, 9780585426686

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The Autonomic Nervous System in Healthand Disease

NEUROLOGICAL DISEASE AND THERAPY Series Editor WILLIAM C. KOILER Department of Nmrologv University of Kansas Medical Center

Kansas City, Karlsos

1. Handbook of Parkinson's Disease, edited by William C. Koller 2. Medical Therapyof Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer'sDisease:Molecular Genetics and Clinical Perspectives, edited by Gary D. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimer's Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinson's Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thorpy 7. Epilepsy and SuddenDeath, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Researchand Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen I O . The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. CognitiveDisorders:PathophysiologyandTreatment, edited byLeon J. R. Gamzu Thal, Walter H. Moos, and Elkan 12.Handbook of AmyotrophicLateralSclerosis, edited by Richard Alan Smith 13. Handbook of Parkinson'sDisease: Second Edition, Revised and Expanded, edited by Wilham C. Koller 14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15.Handbook of Tourette'sSyndrome and Related Tic and Behavioral Disorders, edited by Roger Kurlan 16. Handbook of Cerebellar Diseases,edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases,edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew B. Stern and William C. Koller 19. Handbook of Head and Spine Trauma,edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robert A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. WarrenOlanow, Moussa B. H. Youdim, and Keith Tipton

22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak 24. Handbook of Neurorehabilitation,edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology, edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robert R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology, edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller 31. Neuro-Ophthalmological Disorders: Diagnostic Work-up and Management, edited by RonaldJ. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33.Handbook of Neurological SpeechandLanguage Disorders, edited by Howard S. Kirshner 34.Therapyof Parkinson's Disease:Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35.EvaluationandManagement of GaitDisorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robert S. Dyer 37. Neurological Complications of Cancer, edited by Ronald G. Wiley 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne 40. Etiology of Parkinson's Disease, edited by Jonas H. Ellenberg, William C. Koller, and J. William Langston 41. Practical Neurology of the Elderly, edited by Jacob 1. Sage and Margery H. Mark 42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by StuartD. Cook 44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos 45.SubarachnoidHemorrhage: Clinical Management, edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson 46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta 47.SpinalCord Diseases: Diagnosis andTreatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48.Management of AcuteStroke, edited by Ashfaq Shuaib and Larry B. Goldstein

49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgefher 51. TheAutonomicNervous System in HealthandDisease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. lngoglia and Marion Munay

Additional Volutnes in Preparation Handbook of Multiple Sclerosis: Third Edition, edited by Stuart D. Cook

The Autonomic Nervous System in Health and Disease David S. Goldstein National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, Maryland

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Preface Thisbook presents principlesof neurocardiology,by applying homeostatic concepts about the functlonand dysfunction of the body’s “autonomic” systems-especially those that use the catecholamines, norepinephrine, epinephrine, and dopamine. Thinking homeostatically about autonomic function and dysfunction helps understand neurocardiologic disorders, test mechanistlc and experimental therapeutic hypotheses, teach integrative physiology, and manage patients with dysautonomias. For centuries, clinicians and writers have appreciated the importance of the nervous system in regulating the heart and circulation. Neurocardiology is a new term for a classical discipline in medicine. Giants of physiology, cardiology, neurology, endocrinology, andpsychiatryintroduced its foundingconcepts. Physicians todayacceptthe“autonomic nervoussystem,”the“sympathicoadrenal” and “parasympathetic nervous” systems, “stress,” and “homeostasis” as keymedicalsclentific terms that enhance understanding ofmechanisms and treatments for many diseases of modemhumanity. Yet all these concepts have required rethinking and revision, for neurocardiology as presented in this book to maintain currency. The phrase “autonomic nervous system,” first used by Langley about the turn of the 20th century,implies an independence from the centralnervous system that one can nolongeraccept. Instead,effector systems that largely unconsciously, reflexively, and involuntarily regulate smooth muscle and glands worktogetherwith those thatlargelyconsciously and voluntarilyregulate skeletal muscle, to maintain the apparent steady-states that characterize all living higher organisms. The definition of “stress” has incited debate ever since Selye popularized stressasamedicalsclentificidea in the 1930s. Selye’s doctrineof nonspecificity, definingstressasthe non-specific responseofthebody to any demand imposed upon it, hasbeenshowntobe untestable and therefore of limitedscientificvalue; andbecauseof circularity,his distinctionbetween “distress” and “eustress” haslittle scientlfic worth. Even the well-known “homeostasis,” coined by Cannon early in the 20th century, may not suffice, because it suggestsasingle setof steady-state conditions, whereas organisms survive by dynamically re-defining what homeostasis is-“homeodynamics,” as it were. iii

iv

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In many places mthis book, thediscussionleads to modificationsthat help modernize neurocardiology as medical a discipline. For instance, consideration of Cannon’s and Selye’s views about the meaning of stress leads to the proposltion here of a “homeostat theory,”whichmelds the psychological concept of “intervening variables,” cybernetic views about feedback-regulated systems, and principles operation of of effector systems, including catecholarmnergic systems. According to the homeostat theory, derangements of homeostatic regulation cause or contribute importantly to many clinical manifestations of neurocardiologic disorders. Thechaptersof this bookintroduce neurocardiology, vla historical vignettes about major discoveries in the field and via brief presentations of novel modem concepts; present an overview of the autonomic nervous system; depict central neuralpathwaysdeterrmning autonomic outflows;analyzestress and distressfrom ascientific perspectiveand introduce the homeostattheory; consider the variousroles ofautonomic systems in stress responses;provide schemas for clinical evaluation of patients with known or suspected neurocardiologic disorders; consider the roles of catecholaminergic systems in worseningindependentneurocardiologic disease states; describesyndromes whereabnormalities ofcatecholaminergichnctionare primarily etiologic; discuss mysterious or controverslal entities; and predict future trends in the area. The introductory chapter provides both historlcal and conceptual perspective. Historical aspects include Galen’s ironic ancient description of the sympathetic system; Abel’s and Takamine’s Identification of adrenaline as the active product of the adrenal glands-the firstidentified hormone;Bernard’s conceptof the “nrilieu itkrierrr,” theinternalenvironment;Elliot’sidea of chemical neurotransmission; Cannon’s teachings about homeostasis, the emergency functions of the “sympathico-adrenal” system, and “fight-or-flight’’ responses;vonEuler’sidentification of norepinephrine as the sympathetic neurotransmitter; Axelrod’sdiscoveriesabout mechanisms of inactivation of catecholamines; Ahlquist’s proposal about the existence of adrenoceptors; the discoveryby Vogt of catecholaminerglcsystemsin the brain;andLeviMontalcini’s andCohen’sdiscoveryofnerve growthfactor. Newconcepts include: the homeostat theory of stress and principles of homeostat operation; defining characteristics of stress and distress; “pnmitive specificity” of stress responses; separate regulation of the sympathetic nervous and adrenomedullary hormonalsystems; the third peripheral catecholamlne system;distinct sources and meanings of plasma levels of catechols; pathophysiology-based treatment of neurocardiologic disorders;and“homeostatism”as basis a of integrative physiology and medicine. Thesecondchapterprovidesanoverviewof theautonomic nervous system, including the cranial and sacral divisions of the parasympathetic system, cholinergic neurotransmission andacetylcholine receptors, the sympathetic

Preface

V

nervous system, noradrenergic neurotransmission, adrenomedullary the hormonal system, adrenoceptors, co-transmission, embryology and development, effectsofagingonautonomc function, and non-cholinergic,non-adrenergic neurotransmission. Because of the importance of catecholamines in mediating key autonomic functions and in clinical autonomic function testing, pathways of catecholamine synthesis,release, reuptake,metabolism, andturnoverreceive intensive treatment. The third chapterdescribescentral neuralregulation of autonomic outflows-especially the central neuroanatomy of sympathoneural outflow to the cardiovascular system-and the roles of catecholamines in the brain. This is a long, difficult chapter, mainly because the abundance of research literature about connections among cardiovascular regulatory ”centers” and about catecholaminergic chemical neuroanatomy contrasts withalack of organizing concepts about the relationship between activities of catecholaminergic neurons in the brainand sympathetically-mediatedrelease of catecholamines in the periphery. Little is known aboutpatterned alterations in theactivity of those centers in stress or neurocardiologic disorders, or about how their functions reset during distress or in dysautonomias. Despite rapidly expanding literature about centralcatecholamnergic pathways andadrenoceptors, the roles ofcentral catecholamines specifically in regulation of autonomic outflows remains incompletely understood. These roles probably will proveto beindirect and complex,suchas bygatingafferentinformation fromexteroceptorsand interoceptors, modulatinghypothalamic secretionof releasing hormonesand elaborationof neuroendocrineresponsepatterns, and facilitatinglong-term memory ofdistressing events, vigilance, and initiation of motorbehaviors. The fourth chapterconsidersstressand distress as medical scientific ideas. The discussion analyzes the stress theory of Selye and then proposes a new definition, in which stress is a condition where expectations do not match perceptions of the internal or external environment, and this discrepancy elicits “primitivelyspecific” compensatory responses. To sense and respond to such discrepancies, the bodydependsonhomeostaticcomparators,“homeostats,” whichregulate effector systemresponses. Homeostatic physiologicalsystems operate according to several principles, including negative feedback regulation, multiple effectors, effectorsharing by differenthomeostats,andhomeostat resetting. Distress is presented as a form of stress that is conscious, aversive, produces observable signs, and causes homeostat resetting. The chapter describes several of the body’s stress effector systems, including the pituitaryadrenocortical system, renin-angiotensin-aldosterone system, endogenous opioid system, and vasopressin system; and notes direct and indirect interactions among these effectors. The fifth chapter describes the roles of the parasympathetic and sympathetic nervous systems and the adrenomedullary hormonal system in stress

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responses.Afternotingthe dominanceof the parasympathetic system in mediating “vegetative” behaviors, the presentation distinguishes stresses associated withmainly sympathoneuralactivation(e.g., orthostasis, exercise, cold, post-prandialstate) from those associated mainly with adrenomedullary and pituitary-adrenocortical activation (e.g., glucoprivation, distress). Discussion of parasympathetic-sympathetic interactions moves beyond the traditional view that the twosystemsalways antagonizeeachotherto the view that in many situations (e.g., hypoglycemia, altered environmental temperature, hemorrhage, neurally mediated syncope), parasympathetic, sympathetic, and adrenomedullary responsesoccur in stressor-specific,differentiatedpatterns. Thepresentation pays close attention to the role of the sympathetic nervous system in maintaining blood pressure during orthostasis and conversely to orthostatic hypotension as a cardinal sign of sympathetic neurocirculatory failure. This chapter also considers in detail the adrenomedullary hormonal systemin glucose counter-regulation. The sixth chapterpresents a schema forevaluation ofpatients with neurocardiologic disorders. Sections in the chapter follow a classical approach that begins withthemedicalhistory and physicalexamination,then discusses routine clinicallaboratorytesting, and then specialized testing. Beat-to-beat blood pressure responses associated with the Valsalva maneuver receive considerable attention because of their importance in the diagnosis of sympathetic neurocirculatory failure. Topics in clinical neurochemistry related to clinical diagnosis and management include the sources and meanings of plasma levels of catechols andthe remarkable sensitivlty of plasma metanephrines in the diagnosisofpheochromocytoma.Plasma levels of different catechols reflect different aspectsof sympathoneural hnction,and simultaneous estimatesof regional spillover rates of DOPA, norepinephrine, and its metabolites into the bloodstream provide a comprehensive picture of local synthesis, release, uptake, and metabolism norepinephrine of in sympathetic nerve terminals. Neuropharmacological tests include clonidine suppression and glucagon stimulationtesting,yohimbine challenge testing,isoproterenolinfusion, and ganglion blockade.Theprinciples underlyingtheuse of positron-emitting analogsof catecholamines orsympathomimeticamines for positronemission tomographic (PET) scanning of cardiac sympathetic innervation and function are presented, along with initial clinical findings fromthe use of this new technology in humans. The chapter closes withadiscussionabout cardiac PET scanning after administration of 6-[18F]fluorodopamine in the evaluation of sympathetic innervation and hnction in patients with dysautonomias. The seventh chapter considers some of the ways by which catecholamines participate in pathological processes by worsening an independent disease state. Examples are myocardial infarction, emotional distress-induced sudden death in the setting of underlying coronary heart disease, and chronic heart failure.

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vi i

The eighth chapter deals with disorders where abnormalities of catecholammerglc hnction play a primary pathophysiologic or etiologic role. Hypo-catecholaminergic statesinclude several sympathetic neurocirculatory failure syndromes. Hyper-catecholaminergic states include pheochromocytoma. Some neurogeneticdiseasesresult from mutationsthatinterferewith the synthesis or metabolism of catecholamines. Several mysterious or controversial entities in neurocardiology have been thought to involve dysautonomia, as noted in the ninth chapter. These include neurally mediated syncope, chronic fatigue syndrome, reflex sympathetic dystrophy, mitralvalve prolapsesyndrome, poshIra1 tachycardia syndrome, humanessentialhypertension, and the “Type A coronary prone”behavior pattern. The tenthandfinal chapterdiscusses futuretrends in neurocardiology research and more generally in integrativemedicine, with anemphasison bndging molecular genetics and molecular biology with integrative physiology. Such bridging constitutes the basis for a new type of medical discipline. This chapter considers the concepts of teleology vs. apparent purposiveness, genetic directions vs. algorithms,the evolutionof consciousness,and diseasesof senescence (e.g., neurodegeneration, cardiovascular hypertrophy) in evolutionary perspective. Thelackof a wordtodescribe the conceptual foundation of integrative physiology and medicine leads to the proposition of a neologism, ”homeostatism,” where organisms maintain their internal environment by the operation in parallelof feedback-regulatedsystems. The chapterpredicts redirection ofmolecular genetics,molecularbiology, and integrativephysiology to focus on apotential“first cause” of manymodem diseases of adults: the loss of “wellness,” where both health and disease depend on geneticalgorithms determining the development, structure, andadaptive regulation of homeostatic systems.Theconcept of diseases of regulation, development, andsenescence, andthe notions of wellness and holism, will become more and more important subject matters for medical scientific research and incorporated into clinical practice. Conveyingprinciples ofneurocardiology, comprehensivelybut also comprehensibly, culminates more than a quarter century of thinking, researching, teaching,and writing aboutbrain regulation of thecardiovascular system in stressanddisease.This interest datesfrom my collegedays. In this book I develop hrther severalideas, originally published in Srress, Catecholamines. ancl Cardiovascular Diseases, andapplythem indiscussing the diagnosis, pathogenesis, and treatment of neurocardiologic disorders. Writing this book has posed a daunting challenge. It also, however, has offeredthesatisfaction that comes from the sense of contributing to medical scientific understanding. The experience has confirmed for me that the pursuit of knowledgenever ends; that science refinesignorancemorethan eliminates it;

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that command of a subject requires awareness of what is not known more than understanding of what is known; that advances depend on attempting to answer incisive questions; that discoveries outweigh ideas; that patient-oriented clinical researchersenjoy aunique advantageover theirbasic and disease-oriented colleagues, which is that patients point us to the truth, if we pay attention; and that the joy of scientific effort comes from sparkles of insight. As an ancient prayer states, “Blessed are you, God, Lord of the Universe, who endows insight to a frail mortal.” The mostworthwhilescientific ideas I have hadhave comefrom conversations wlthknowledgeable peersabout unexpectedobservations. The intramural research programs of the National Institutes of Health, both in the NationalHeart, Lung, andBlood Institute and the National Institute of Neurological Disorders and Stroke, have afforded me the privilege and opportunity not only to pursue ideas but also to work, learn, and discover with many fine colleagues, including (inalphabeticalorder) InesArmando, Simon Bruce, Richard 0. Cannon, 111, Peter Chang, Carol Joan Folio, Anna Golczynska,Graeme Eisenhofer, Giora Feuerstein, Steven M. Frank, Ehud Grossman,Moshe Garty, CourtneyHolmes,DavidHonvitz,Harry R. Keiser, Irwin J. Kopin, Richard Kvetnansky, Jacques Lenders, Paul Levinson, Shengting Li, KarelPacak, Arshed Quyyumi, JohnStuhlmuller, RobinStull, Katalin Szemeredi, Cees Tack, Efrat Wolfovitz, Gal Yadid, Reuven Zimlichman, and Zofia Zukowska. Dr. Steven M. Frank read the entire text of thls book in draft form, and I appreciated his comments and suggestions. Finally,Ithank my wife, Minka, and our familyfortheir support and encouragement over the years and for the sacrifices they have made that allowed me the time to write this book. David S. Goldstein

Contents

Preface

1.

2.

Introduction Historical Perspective: ConceptsAbout the Autonomic Nervous Systemand Their Originators New Concepts and Topicsin this Book References

Overview of theAutonomicNervousSystem Parasympathetic Nervous System Sympathetic Nervous System Adrenomedullary Hormonal System Non-Neuronal Catecholamine Systems Non-Cholinergic, Non-Adrenergic Neurotransmission Adrenoceptors Autonomic Pharmacology Embryology and Development Circadian Rhythms Aging Cholinergic-Catecholamine Interactions Summary and Conclusions References

...

111

1 1 10 20

23 25 35 61 62 66 70 78 96 100 101 103 105 109 ix

Contents

X

3.CentralNeuralRegulation of AutonomicOutflows Historical and Conceptual Introduction Spinal Cord Medulla Pons Midbrain Hypothalamus HACER AV3V Limbic System Circumventricular Organs Cerebral Cortex Central CatecholamineNeuroanatomy Functions of Catecholamines in the Brain Centrally Acting Drugs Affecting Sympathoneural or Adrenomedullary Outflows Cardiac Parasympathetic Outflows Summary and Conclusions References

137 137 142 144 154 157 158 162 163 163 165 165 166 170

4.

Stress and Distress Theories of Stress A HomeostaticTheory of Stress and Distress Non-Autonomic Stress Systems and Their Interactions with Catecholamine Systems Distress Stress in Evolutionary Perspective Summary and Conclusions References

199 199 208

AutonomicSystemsinStress Vegetative Functions andthe Parasympathetic System Stresses Associated with Sympathoneural Activation

279 280 283

5.

176 182 183 185

227 239 25 1 26 1 262

Contents

6.

7.

8.

xi

Stresses Associated with Adrenomedullary Activation Summary and Conclusions References

299 319 322

Clinical Evaluationof Neurocardiologic Disorders Medical History Physical Examination Physiological Tests Neuropharmacological Tests Neurophysiological Tests Neurochemical Tests Sympathetic Neuroimaging Summary and Conclusions References

335

Diseases in Which Activation of Catecholamine Systems Worsens an Independent Pathologic State Cardiovascular Psychiatric Endocrine/Metabolic Summary and Conclusions References

421

Disorders in Which Abnormal Catecholaminergic Function Is Etiologic Sympathetic Neurocirculatory Failure Autonomic Failurewithout Central Neurodegeneration Autonomic Failurewith Central Neurodegeneration Hypertension Cardiac Necrosisand Cardiomyopathy Neurogenetic Diseases Other Summary and Conclusions References

455

335 340 345 357 365 368 396 399 40 1

422 438 441 444 445

455 458 469 480 490 493 502 502 503

Contents

xii

9.Controversial Entities Mysterious or 525 Postural Tachycardia Syndrome (POTS), Chronic Orthostatic Intolerance(COI) / Hyperdynamic Circulation Syndrome, Neurasthenia,and Hyperadrenergic Orthostatic Intolerance 526 Mitral Valve Prolapse-Dysautonomia Syndrome 529 Neurocardiogenic Syncope/ Neurally Mediated Syncope / ndrome Fatigue Chronic Reflex Sympathetic Dystrophy, Fibromyalgia, and Complex Regional 533 Pain Syndrome Stress Post-Traumatic Disorder 535 Catecholamines and Human Essential Hypertension 536 Stress and Cardiovascular Disease 546 Summary 553 and Conclusions References

s

10.

Index

Future Clinical Neurocardiology and Integrative Medicine 575 Toward a New Medical Science References

575

577

587

555

Introduction HISTORICAL PERSPECTIVE: CONCEPTS ABOUT THE AUTONOMIC NERVOUS SYSTEM AND THEIR ORIGINATORS Galen and the Sympathetic Nervous System

Thenotionthatthenervoussystemregulatesandcoordinatesbody functions originated in ancient times. The 2nd Century Greek physician, Galen, whose concepts dominated most of the history of western medicine, taught that the body contains “spirits”-natural, vital, and animal. He considered nerves emanating from the brain to function as conduits for distributing the animal spirits in the body, fostering consent, or “sympathy,” among the body parts. Galen’s view that the nerves coordinate activities of body organs was essentially, ironically, correct, and the idea of the sympathetic nervous system antedated the discovery of the circulation of the blood by fourteen centuries. Winslowre-introducedtheancientterm in 1732, to describe the chains of ganglia and associated nerves connected to the thoracic and lumbar spinal cord (1).

Much of this book presents concepts and describes clinical experiments that, perhaps surprisingly, fit in general with Galen’s view that the sympathetic nervous system coordinates body functions. These concepts help to understand thepathophysiologyofseveralneurocardiologicdisordersandprovidea rationale for pathophysiology-based treatments. Harvey and the Circulationof the Blood

The birth of modem medical science took place in 1628. In that year, William Harvey published his thin book, On the Circulation of the Blood. The elegantlysimpleexperimentaldemonstrations in it setasidekeyGalenic teachings, such as that blood warmed by the “vital spirit” passes through pores in the septum dividing theleft and right ventricular chambersof the heart. These refutations led to abandonment of Galen’s theory of natural and vital spiritsbutnottothedemiseofvitalism,tracesofwhichpersist in modern-day “alternative” or holistic medicine. 1

2

Chapter 1

One can argue that the medical discipline of neurocardiology came into being at the same time, in the same book, when Harvey noted the effects of emotions on the heart-something neither the ancient Hebrews and Greeks nor Galen’s disciples had realized: Foreveryaffectionofthemindthatis attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the hea rt...( Harvey, 1894, p. 74). Bernard, Sympathetic Vasoconstriction, and Scientific Determinism

About two centuries later, in 185 1, Claude Bernard first demonstrated regulation of vascular “tone” by the sympathetic nervous system. He showed that cutting the “sympathetic nerve” in the rabbit neck produced flushing and warmth of the ear and enlargement of the regional network blood of vessels on that side. From this experiment Bernard concluded that cutting the sympathetic nerve directly increased local generation of heat. This deduction illustrates a common,albeitunintended,sideeffectofmedicalscientificenterprisesseeminglynecessarybutactuallyerroneousinferencesdrawnfromcorrect experimental observations. Bernard’s creed was that by scientific observation, one can grasp the laws governing and so predict the activities of body systems. The foundation of what hecalled“scientificdeterminism”wasthecriterionofdeductionfrom experiment. If the experimental conditions were identical, then the experimental results would be the same-i.e., the results would be determined. This belief is so basic to modern biology, it seems intuitively obvious. As noted above, however, for most of medical history, Galen’s 2nd Century vitalist doctrine dominated medical thought. Vitalism holds that life processes differ uniquely from physicochemical phenomena and transcend understanding by physicochemicallaws.Vitalist explanations always have offered a pleasing sense of order and purpose. For instance, according to Galen, blood entering the right side of the heart contacts air flowing from the lungs via the pulmonary veins to the heart, the mixture imbuing the blood with the vital spirit, igniting a biological flame that literally heats the blood and so warms the body. This explains simply why living things contain warm blood. For 1,400 years, the heart was viewed as a furnace, not a pump (2). How ironic that Bernard concluded that cutting the sympathetic nerve supplying a rabbit’s ear generated local heat!

Introduction

3

In 1852, Bernard and Brown-Sequard reported skin cooling and pallor during electrical stimulation of the proximal end of the sectioned sympathetic nerve. Brown-Sequard correctly attributed the fall in skin temperature to the constriction of the blood vessels (3). Bernard and Brown-Sequard disagreed aboutpriority in this work-another commontheme in thehistoryof experimental science. The French Academy of Sciences settled the issue in 1853, awarding Bernard, for the fourth and last time in his career, its prize for experimental physiology. The same year, Bernard described the main signs of interference with sympathetic neurotransmission to the head-decreased sweating, constriction of the pupil, drooping of the eyelid (ptosis), and recession of the eye into the orbit-a syndromethat in Europestillbearshisname,“Horner-Bernard syndrome.” Americans refer to this as “Horner’s syndrome,” since in 1869, Homer described this syndrome for the first timein humans. In 1863, Bernard reported that transection of the cervical spinal cord produced immediate, marked hypotension-probably the first evidence that the brain regulates overall cardiovascular “tone.” Oliver, Schafer, Abel, Takarnine, and Discovery of the “Active Principle” of the Adrenal Gland

The contribution of the adrenal medulla to circulatory function remained unknown until about a century ago. According to the story relatedby Sir Henry Dale (4) and by Barcroft and Talbot (5), Dr. George Oliver, a physician in Harrogate, England, used his son to test a device for measuring the caliber of peripheralarteries.Afteradministeringanextractofadrenalgland,Oliver observed constriction of his son’s radial artery. Meanwhile, Dr. E. A. Schafer, a notedProfessorofPhysiologyattheUniversityCollege in London,was demonstrating measurement of blood pressure by the height of a column of mercury in a tube. Oliver visited Schafer’s laboratory, bringing a vial of the adrenalextractwithhim.Injectionofthematerialintotheveinofadog produced an immediate, startling increase in the animal’s blood pressure. This led to publication in 1895 of the first report ( 6 ) about the cardiovascular effects of what was identified soon afterward as epinephrine. Versions of the story differ about the mode of administration of the extract. According to Dale, the extract was injected; according to Barcroft and Talbot, based on the writings of both Oliver and Schafer themselves, the extract was given orally. This seemingly minor point actually relates to a prominent concept in this book, which is that of an enzymatic “gut-blood barrier” for catecholamines. Considering humankind’s omnivorous nature, the potency of epinephrineas a hormone,andthepresenceofhighconcentrationsof epinephrine in the adrenal glands, one might have predicted as an evolutionary

4

Chapter 1

necessity that the gastrointestinal tract would possess impressively efficient means for detoxifying ingested catecholamines; and it does, using multiple, redundant enzymes present in the stomach, intestine, and liver. Thus, after swallowing an epinephrine solution, circulating levels of epinephrine hardly increase at all (7). Indeed, today one can purchase adrenal concentrate as a “dietary supplement” in health food stores. Oral ingestion of adrenal extract by Oliver’s son probably would have elicited little if any arterial constriction, because of the extremely efficient metabolic degradation of epinephrine in the gastrointestinal tract. If Oliver had injected the adrenal extract intravenously, he could well have killed his son. Soon after Oliver and SchSifer’s report, researchers rapidly joined a hunt for the “active principle” of the adrenal extract.In 1897, Abel and Crawford (8) purified the substance, and in 1901 Takamine (9) andin 1902 Abel(l0) isolated it in crystalline form and reported its structure. Epinephrine therefore was the first identified hormone (the term, “hormone,” was used firstto describe secretin by BaylissandStarling in 1902).Abel’s1902reportwasalsothefirstto describe the synthesis of a hormone. American medical literature uses Abel’s appellation for the adrenomedullary hormone, “epinephrine,” whereas English medical literature uses Takamine’s term, “adrenaline.” “Adrenalin” is a registered trademark of Parke-Davis. Langley and the Autonomic and Parasympathetic Nervous Systems

AlsosoonafterOliverand SchSifer’s report, J.N. Langley,ofthe University of Cambridge, coined the term, “autonomic nervous system,” to describe the portion of the nervous system regulating largely involuntary, visceral functions by nerve fibers, the cell bodies of which lie outside the central nervous system (1 1-14). Salivation, lacrimation, contraction of gastrointestinal sphincters, piloerection, sweating, blood pressure, heart rate, penile erection, and urinary bladder contraction and relaxation exemplify these functions. Langley contrasted them with voluntary or reflexive regulation of skeletal muscle by nerve fibers, the cell bodies of which lie within the central nervous system. He viewed the autonomic nervous system to include thoraco-lumbar, cranial, sacral, andentericcomponents.SupplementingWinslow’sdefinitionofthe sympathetic nervous system, Langley defined the “parasympathetic” nervous system as the cranial and sacral components of the autonomic nervous system. According to Langley, most internal organs have a dual nerve supply, one excitatory (sympathetic) and the other inhibitory (parasympathetic), with the two systems antagonizing each other.

5

Introduction

Of relevance to the issue of the existence of a “sympathico-adrenal” system, Langley’s conception of the autonomic nervous system did not include the adrenal gland as a component, Elliott, Loewi, and the Theory of Chemical Neurotransmission

Aspointedout by Bard ( l ) , thedistinctionbetweenanautonomic, vegetative, involuntary nervous system for internal changes mediated by smooth muscle, and a voluntary, reflexive nervous system for behaviors mediated by skeletalmuscle,haslostmuchof its usefulness.Autonomically-mediated, involuntary changes virtually always accompany skeletal muscle behaviors, in coordinated responses to stressors, as discussed in detail in the chapter about stress as a scientific idea. Indeed, one can modify visceral functions relatively easily voluntarily-blood pressure and pulse rate by clenching a fist, lacrimation by cutting an onion, salivation by thinking of a lemon, sweating by public speaking,penileerection by readingpornographicliterature,and so forth. Conversely, alterations in autonomic function, such as sweating, piloerection, and forceful heart contractions, can markedly affect the performance of voluntary behaviors, exemplified in Cannon’s notion of “reservoirs of power,” discussed below in thesectionaboutbiologicaleffectsofcatecholamines.Finally, Langley’s “autonomic nervous system” implies a functional independence from the central nervous system that simply does not exist and which ignores the adrenocortical, adrenomedullary, and other neuroendocrine effector systems organisms use to maintain homeostasis. Thus, at the beginning of the 20th Century, physiologists considered the nervous and endocrine systems as distinct, with nervous impulses to and from skeletal muscle mediating interactions with the external environment and with theautonomicnervoussystemandchemicalsubstancestransported in the bloodstream-hormones-determining the states of activity of internal organs. The work and ideas of Elliott and Loewi blended the neural and endocrine traditions in medicine.Elliott (15), Langley’sstudent,notedthesimilarity between the effects of adrenal extracts and those produced by stimulating sympathetic nerves. In 1904, Elliott proposed a revolutionary idea:

...a mechanism developed out of the muscle cell, in responsetoitsunionwiththe synapsing sympathetic fibre, the function of which is toreceiveandtransformthe nervous impulse. Adrenalin(e) might then be a chemicalstimulantliberatedoneach occasionwhentheimpulsearrivesatthe periphery ((19, p. xxi).

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Sir Henry Dale (16) credited the idea of chemical neurotransmission, a foundingprincipleofneuropharmacology,toElliott’sexplanationforthe similarity between the effects of adrenaline and those of stimulating sympathetic nerves. In the 1920s, Otto Loewi proposed that a chemical messenger substance, acetylcholine, produced the physiological effects of vagal stimulation. His experiment was a milestone, because it identified a new type of endogenous substance-a neurotransmitter-and for this work he shared with Sir Henry Dale the Nobel Prize in Physiology or Medicine in 1936. Loewi stimulated the vagus nerve of the perfused heart of a donor frog. During the stimulation, the perfusate was applied to the heart of a recipient frog. Stimulation of the vagus nerve of the donor frog produced the expected decrease in the rate of contraction of the donor frog’s heart; application of the perfisate to the recipient’s heart decreased the rate of contraction of the recipient’s heart as well. Loewi called the substance thatwasreleasedbythefirstheartandslowedtherateofthesecond, “Vagusstoff,” or the “substance of the vagus.” Using bioassay preparations, wherethesubstanceproducedidenticalresponsestothoseproducedby acetylcholine, in 1926LoewiandNavratilidentifiedtheVagusstoffas acetylcholine (1 7). Somewhat ironically, Loewi used virtually the same bioassay preparation to demonstrate that in the frog heart, epinephrine is the sympathetic neurotransmitter (1 8). Cannon, von Euler, and Identification of the Sympathetic Neurotransmitter

Confirmation of epinephrine as both the adrenomedullary hormone and the sympathetic neurotransmitter in mammals would have led to complete merging conceptually of the neural and hormonal components of a single neuroendocrine, “sympathico-adrenal” system. AfterLoewidemonstratedchemicalneurotransmissionbyboth acetylcholine and epinephrine in the frog heart, Cannon and Rosenblueth (19) obtained evidence for either release of a substance other than epinephrine during stimulation of sympathetic nerves, or else conversion of epinephrine to a different substance in the effector cells. Cannon erroneously backed the latter view. In anesthetizedcats“sensitized”withcocaineandpre-treatedwith ergotoxine, hepatic or lower abdominal sympathetic nerve stimulation increased blood pressure, whereas administration of epinephrine decreased blood pressure. Cannon proposed two forms of the released transmitter, excitatory “sympathin E” andinhibitory“sympathin I.” In1939,heandLissak (20) proposed epinephrine formally as the sympathetic neurotransmitter, with differences in organ responses to epinephrine and to “sympathin” due to conversion of the latter to another substance in activated effector cells:

7

Introduction

...sympathetic neurones liberate adrenaline at their terminals and ...this agent, when it escapesintothebloodstream,hasbeen modified in suchmannerthatithasthe peculiaractionsofsympathin on remote organs in thebody.Thedesignation, “adrenergicnervefibers,”wouldthusbe quiteexact(Cannon & Lissak,1939,p. 774). We now know that inhibition of a-adrenoceptors by ergotoxine and the greateraffinityforepinephrinethanfornorepinephrineatvascular B2adrenoceptors can explain the results, but the report of Cannon and Rosenblueth appeared 15 years before introduction of the idea of adrenergic receptors. Based onthesuggestionofBacq(21),vonEulersubsequentlyidentifiedthe sympathetic neurotransmitter in mammals as norepinephrine, the precursor of epinephrine (22,23). Peart (24) confirmed von Euler’s results. Loewi shared the Nobel Prize with Dale in 1936, and von Euler shared the Nobel Prize with Axelrod in 1970,butCannon,despitehisseminalworkandideasabout catecholaminergic function and homeostasis, never received a Nobel Prize. His failure to identify the sympathetic neurotransmitter correctly may have been the reason. Muscarinic and Nicotinic Neurotransmission

The early 20th Century also witnessed, especially through the work of Dale, discovery of the two main mechanisms of parasympathetic effects on involuntary smooth muscle-nicotinic and muscarinic (25). Administration of thetobaccoconstituent,nicotine,increasestherateandforceofcardiac contraction, by stimulating ganglionic neurotransmission, although as noted by Langley and others, at high doses nicotine blocks ganglionic neurotransmission. Nicotine also exerts well-known, pronounced central stimulatory effects and decreases appetite. Administration of muscarine (a toxin in the Amanita species of poisonous mushrooms) decreases the heart rate and evokes nausea, vomiting, abdominal cramps, and diarrhea. In contrast, curare (obtained from an aqueous extract of the South American woody vine, Strychnos toxfera, which as the name implies is also a source of the poisonous alkaloid, strychnine) paralyzes skeletal muscle but leaves smooth muscle unaffected. Hexamethonium and structurally related compounds block nicotinic effects, and atropine (from the plants, deadly nightshade, Atropa belladonna, and the henbane, Hyoscyamus niger) blocks muscarinic effects. Physiologists already were acquainted with the

Chapter 1

8

very different agonist effects (nicotinic autonomic, muscarinic autonomic, and skeletalmusclevoluntary)beforetherealizationthatthesamechemical messenger, acetylcholine, mediated all of them. Catecholamines: The Nobel Chemicals

Discoveries about norepinephrine and epinephrine, the effector chemicals of the sympathetic nervous and adrenomedullary hormonal systems, have led to several Nobel Prizes. These discoveries relate directly to the physiology and pathophysiology of the autonomic nervous system and to the development of successfulpathophysiology-basedtreatments.Thissectionpresentsthese discoveries together, to introduce briefly concepts that receive much more detailed attention later in this book and to affirm the continuing importance of these compounds in medical research. About the same time that von Euler identified norepinephrine as the sympathetic neurotransmitter, disproving Cannon’s notions about sympathin E and sympathin I, Ahlquist (26) proposed a different explanation for the disparate cardiovasculareffectsofnorepinephrineandepinephrine-thatthese catecholamines differentially stimulate specific receptors-adrenergic receptors, or adrenoceptors. In 1948, Ahlquist proposed two types of adrenoceptors, a and R. Numerous pharmacological and molecular biological studies have by now not only confirmed this suggestion but also elucidated the molecular structures of adrenoceptors and described in detail the mechanisms that link occupation of the receptors in the cell membrane to processes inside the effector cells. The discovery of adrenoceptors led to the development of novel, highly successful drugs to treat common cardiologic disorders. For the development of R-adrenoceptorblockers,whichremainkeyagents in thetreatmentof hypertension, angina pectoris, and arrhythmias, Sir James Black shared the Nobel Prize for Physiology of Medicine in 1988. Adrenoceptors such as R-adrenoceptors in the cell membrane transmit information via signal-transducing “G-proteins” (guanine-nucleotide regulatory proteins), located near the receptors on the inner portion of the cell membrane. For the discovery of G-proteins and their significance in cellular activation by epinephrine, Alfred G. Gilman and Martin Rodbell shared the Nobel Prize in Medicine in 1994. Describing to an audience of colleagues his reaction to the news that he had won a Nobel Prize, Gilman joked ironically, First, I secreted a hell of a lot of adrenaline andthenthatreachedmyadrenergic receptorsandtheyrespondedviatheG proteins(WashingtonPost,October 1 1, 1994, p. A4).

Introduction

9

In the liver, epinephrine and glucagon liberate glucose by stimulating the catabolismofglycogenviatheenzymephosphorylase.Activationof phophorylase by epinephrine, after binding of epinephrine to D2-adrenoceptors on liver cells, depends on formation of cyclic adenosine monophophate (CAMP) insidethecells.ThediscoveryofCAMP,thefirstidentifiedintracellular messenger (“second messenger,” the first being the hormone) depended on studies of the fractions of cell homogenates that were required for the hormonal effects of epinephrine and glucagonin the liver. For the discovery of CAMP, E. W. Sutherland received the 1971 Nobel Prize for Physiology or Medicine. TheNobelPrize-winningdiscoveryofcellularactivationby phosphorylation also depended on hormonal effects of epinephrine in the liver. CAMP activates protein kinase A (PKA), which catalyzes the production of activated phosphorylase B kinase from inactive phosphorylase B kinase and adenosinetriphosphate(ATP).Activatedphosphorylase B kinase in turn catalyzes the production of phosphorylase A from inactive phosphorylaseB and ATP. Finally, phosphorylase A catalyzes the breakdown of glycogen to glucose l-phosphate and the generation of energy in the form of ATP (27-3 1). For the discovery of phosphorylation as a key step in the activation or inactivation of cellular processes, Edmond H. Fischer and Edwin G. Krebs shared the 1992 Nobel Prize. After release of norepinephrine from sympathetic nerves, the chemical transmitter undergoes inactivation mainly by a conservative recycling process, where sympathetic terminals take up norepinephrine from the extracellular fluid-a processcalledUptake-l.Onceinsidetheaxoplasm,mostofthe norepinephrine undergoes uptake into storage vesicles. Julius Axelrod’s studies about the disposition of catecholamines introduced the idea that termination of the actions of some neurotransmitters depends on neuronal reuptake. Axelrod shared with U. S. von Euler the 1970 Nobel Prize for Physiology or Medicine. Asnotedabove,vonEulerreceivedtheNobelPrizeforidentifying norepinephrine as the sympathetic neurotransmitter. Releaseofnorepinephrine in responsetosympatheticnervetraffic dependsontheexistenceoffunctionalsympatheticterminals,andthe developmentandcontinuedexistenceofsympatheticterminalinnervation depends on nerve growth factor. The discovery of nerve growth factor arose from observations of effects of mouse sarcomas on the growth of sensory and sympatheticganglia.Fordiscoveringthefirstknownneurotrophicfactor, StanleyCohenandRitaLevi-Montalcinisharedthe1986NobelPrizefor Physiology or Medicine.

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NEW CONCEPTS AND TOPICS IN THISBOOK

Each chapter of this book includes new concepts relevant to the etiology, pathophysiology, diagnosis, and treatment of neurocardiologic disorders. These provide frameworks for clinical thinking. The results of numerous studies using novel physiological, neurochemical, and nuclear scanning techniques led to most of these concepts. A Homeostatic Theory of Stress and Distress

Comprehending the physiology and pathophysiology of the autonomic nervous system depends on understanding the roles of the sympathoneural and adrenomedullarysystems in stressanddistress.This in turndependson defining stress and distress in scientific terms. The current presentation builds uponBernard’snotionofthemilieu inte‘rieur andCannon’snotionof homeostasis to propose a “homeostatic theory” of stress and distress (32). According to this theory, stress is not a noxious environmental stimulus, nor a stereotyped organismic response, but a condition or state, in which the individual’s expectations do not match perceptions of the internal or external environment, and the discrepancy elicits patterned, compensatory responses. Distress is a form of stress with additional defining features-consciousness, aversiveness, observable signs, and pituitary-adrenocortical and adrenomedullary activation. In stress the organism senses a disruption or a threat of disruption of homeostasis. The experience of stress therefore requires a comparative process, where the brain compares available information with set-points for responding. The body has many such comparators-here they are called “homeostats.” Each homeostat compares information with criteria for responding, determined by a regulator. The homeostat uses one or more effectors to change values for the controlledvariable.Accordingtotheseconstructs,theimportanceofthe sympathoneural and adrenomedullary systems arises from their roles as effectors for stress responses. Homeostaticsystemsoperateaccordingtoafewprinciples,which, despite their simplicity, can explain complex physiological phenomena and can helptoresolvepersistentlycontroversialissues in theareaofstressand cardiovascular disease. The discussion includes several clinical demonstrations of the principles of multiple effectors, compensatory activation, effector sharing, and homeostat resetting. Thenotionofstressor-specificresponsepatternsdisagreeswiththe theories of both Cannon and Selye. Cannon, largely ignoring other systems, asserted that sympathico-adrenal activation meets most or all important threats to the internal environment. Selye also overemphasized a single system-the

Introduction

11

pituitary-adrenocortical system. Differential regulation of stress effector systems argues against Selye’s doctrine of non-specificity, according to which stress is defined as the non-specific responseof the body to any demand uponit. Separate Regulation of Sympathoneural and Adrenomedullary Function

A major thesis of this book is that activities of stress effectors are coordinated in relatively specific patterns, including neuroendocrine patterns. These patterns, produced by the actions of different homeostats, serve different homeostatic needs. The sympathetic nervous and adrenomedullary hormonal systems operate attheintangibleinterfacebetweenthemindandthebody.Thisbook emphasizes the separate regulation of sympathoneural and adrenomedullary responses, the latter often tied with responses of the pituitary-adrenocortical system. Differential regulation of the sympathoneural and adrenomedullary systems during different forms of stress supports the concept of primitive specificity. The Third Peripheral Catecholamine System, Non-Neuronal Catecholamines Synthesis, and the “Gut-Blood Barrier”

In mammals, the sympathetic neurotransmitter is norepinephrine, and the main adrenomedullary hormone is epinephrine. The sources and physiological roles of the third endogenous catecholamine, dopamine, outside the brain have been obscure. Several lines of evidence suggest thatin the periphery, rather than dopamine serving only as the precursor for the active compounds, released from sympathetic nerves and the adrenal medulla, dopamine may also act as an autocrine/paracrine regulator of local organ function (33). Thus, in the kidneys, most of dopamine formation appears to result from uptake of plasma L-DOPA by proximal tubular cells. Binding of locally formed dopamine to dopaminergic receptors then inhibits N d K ATPase activity and augments excretion of sodium. Recent clinical and laboratory animal studies have also indicated that the mesentericorganscontributesubstantiallytototalbodyproductionand metabolism of dopamine. Generation of dopamine in non-noradrenergic, nonadrenergic cells can explain why human urine contains higher concentrations of dopamine and its metabolites than of norepinephrine and its metabolites. The vast preponderance of plasma dopamine in humans is sulfoconjugated. Since patients with sympathoneural failure have normal plasma levels of dopamine sulfate,onemayhypothesizethatthesulfoconjugatingmechanismacts relatively independently of sympathetic nerves to localize dopamine effects and prevent dopamine generated in the gut from entering the circulation. These

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considerations lead to the concept of a third peripheral catecholaminergic system, where dopamine, derived at least partly from plasma L-DOPA, acts as an autocrine/paracrine substance in several parenchymal organs; and that cells of the gastrointestinal tract detoxify ingested catecholamines and catecholamine precursors by enzymatic O-methylation, oxidative deamination, and sulfoconjugation-a “gut-blood barrier.” Separate Sources and Meanings of Levels of L-DOPA, Catecholamines, and Their Metabolites: Novel Applicationsof Clinical Neurochemistry

Clinicans and clinical researchers often have presumed that measurement of levels of any catecholamine or metabolite of a catecholamine provides an index of sympathico-adrenal “tone.” Instead, this book highlights the related but distinct sources and meanings of catecholamines and their metabolites in body fluids and the usefulness of combined neurochemical measurements in the evaluation of different aspects of sympathoneural and adrenomedullary function. Since L-dihydroxyphenylalanine (L-DOPA) is the immediate product of therate-limitingenzymaticstep in catecholaminebiosynthesis-tyrosine hydroxylation-regional release of L-DOPA into the bloodstream appears to relate to the regional rate of catecholamine synthesis. Nevertheless, tissue concentrations of L-DOPA and tyrosine hydroxylase do not correlate well, meal ingestion increases plasma L-DOPA levels, and other enzymes besides tyrosine hydroxylase influence plasma L-DOPA levels. Sympathetic stimulation releases onlyasmallproportionofstorednorepinephrine, so thatnorepinephrine synthesis and release relate only weakly to each other, explaining why plasma LDOPA and norepinephrine levels also correlate only weakly. Plasma dihydroxyphenylglycol (DHPG), the predominant intraneuronal metabolite of norepinephrine, mainly reflects the turnoverof norepinephrine in sympathetic nerves. This turnover depends partly on release and reuptake of norepinephrineduringsympatheticstimulationbutmainlyonimperfect recycling of norepinephrine that leaks from storage vesicles in the axoplasm. AS a product of metabolism catalyzed by monoamine oxidase A (MAO-A) and aldehyde reductase, DHPG levels depend on and can indicate activities of these enzymes. Plasma normetanephrine (NMN) arises from extraneuronal metabolism of norepinephrine catalyzed by catechol-O-methyltransferase (COMT). Since most of released norepinephrine undergoes reuptake into sympathetic nerves, plasma NMN levelssubstantiallyunderestimatenorepinephrinereleasefrom sympathetic nerves. In the adrenal medulla, metabolism of norepinephrine and epinephrine by surprisingly abundant catechol-O-methyltransferase, before the catecholamines enter the bloodstream, appears to be a major determinant of

Introduction

13

plasma NMN and the main determinant of metanephrine (MN) levels. As a result, measurement of plasma levels of metanephrines (NMN and MN) provides anextraordinarilysensitivetesttodetectpheochromocytoma,ararebut clinically important tumor that synthesizes and releases catecholamines, since pheochromocytoma cells express COMT. Dopamine in thecirculationoccursmainlyasdopaminesulfate,the sources and physiological significance of which until recently were obscure. Plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesizedfromL-DOPA in thegastrointestinaltract.Bothdietaryand endogenousdeterminantsaffectplasmadopaminesulfatelevels,providing support for the existence of an enzymatic gut-blood barrier both for detoxifying exogenousdopamineandfordelimitingautocrine/paracrineeffectsof endogenous dopamine generatedin the third catecholamine system. One purpose of clinical neurochemistry has been to indicate “activities” of catecholamine systems, by assaying levels of the effector compounds or their metabolites in bodyfluidssuchasplasma,cerebrospinalfluid,urine,or microdialysate.Anotherpurposeistorelatespecificcatecholaminergic phenotypes to neurogenetic disorders. Distinctive patterns of catecholamines and their metabolites in several neurogenetic conditions reflect enzyme deficiencies as direct or indirect effects of gene mutations. These neurochemical patterns can providepotentiallyimportantcluestothediagnosis,treatment,and pathophysiology of neurogenetic disorders. Linking genetic abnormalities with molecular mechanisms and clinical manifestations of disease represents a useful new direction in clinical neurochemistry.

Neurocardiology: A New Medical Discipline Neurocardiology is evolving as a discipline in clinical medicine (34-37). Several academic medical centers have initiated neurocardiology or autonomic function testing services. The focus of research in neurocardiology has shifted over the years, from sympathetic hyperfunction in hypertension and behavior patterns in coronary artery disease to primary or secondary autonomic failure. Table 1-1 providesalistingofseveralneurocardiologicdisorderswhere catecholamines participate either primarily or secondarily. Catecholamines contribute to every known risk factor and epidemiological feature of coronary heart disease, including hyperlipidemia, hypertension,nicotiniceffectsofsmoking,obesity,theTypeAbehavior pattern, and insulin resistance, and catecholamines can precipitate acute events in patientswithcoronaryarterydisease.Nevertheless,theroleofchronically repeated episodes of stress in the development of coronary disease remains controversial. The putative catecholaminergiclink remains unproven. According to the theory of the “Type A coronary prone behavior pattern,” the Type A

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Table 1-1 Neurocardiologic Disorders That Feature Abnormal Catecholaminergic Function

Disorders Where Physiologic Changes in Catecholaminergic Function Worsen an Independent Pathologic State Cardiovascular

Myocardial Ischemia and Infarction Arrhythmias Anginapectoris Coronaryspasm Heart failure Generalized and cardiac sympathoneural activation Myocardial norepinephrine depletion Prognosis Arrhythmias and Sudden Death Psychiatric

Depression PanidAnxiety Endocrine/Metabolic

Hypothyroidism Obesity, Diabetes, and “Metabolic Syndrome” Disorders Where Abnormal Catecholaminergic Function Is Etiologic HypofunctionalStatesWithoutCentralNewodegeneration

Acute, Primary Neurocardiogenic Syncope Spinalcordtransection Acute pandysautonomia Sympathectomy Acute, Secondary Drug-related (e.g., alcohol, tricyclic anti-depressant, chemotherapy, opiate, barbiturates,benzodiazepines, sympatholytics, general anesthesia) Seizures Guillain-Barr6 syndrome Alcohol Chronic, Primary

Introduction Pure autonomic failure Horner’s syndrome Familial Dysautonomia Carotid sinus syncope Adie’s syndrome Dopamine-B-hydroxylasedeficiency Sympathectomy Chronic,Secondary Autonomicfailurewithperipheralneuropathy Amyloid polyneuropathy Hereditary amyloid polyneuropathy Diabetic neuropathy Diabetic autonomic neuropathy Painful diabetic neuropathy Quadriplegia Chagas disease Tabes dorsalis Hyperfunctional States Without CentralNeurodegeneration Acute, Primary Panidanxiety Acute, Secondary Drug-related (e.g., nicotine, caffeine, cocaine, amphetamine, Opiate withdrawal, tyramine “cheese effect”) Stroke-relatedmyocardialnecrosis Seizures Guillain-Barre syndrome Post-endarterectomy Tetanus Chronic,Primary Hypertension Neurogenic hypertension Baroreflex failure Pheochromocytoma Sporadic Familial Multiple Endocrine Neoplasia Type I1 vonHippel-Lindau disease Neurofibromatosis Type I Carotid body tumor HypojitnctionalStates with CentralNeurodegeneration Multiple System Atrophy (MSA)

15

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Chapter 1

Table 6-1 Neurocardiologic Disorders with Abnormal Catecholaminergic Function (Con ‘t.) MSA wlth sympathetic neurocirculatory failure (Shy-Drager Syndrome) MSA with Isolated parasympathetlc failure Parkinson’s Disease with Autonomic Failure Neurogenetic Diseases Genetic Diseases withSpeciJic Catecholaminergic Phenotypes: Synthesis

Tyrosine hydroxylase deficiency Dihydropterldinereductase deficiency L-DOPA-Responsive dystonia L-Aromatic-amino-acid decarboxylase deficiency Menkes disease Genetic Diseuses with Specific Cutecholutninergic Phenotypes: Metabolism

Monoamine oxidase deficiency Pseudopheochromocytoma Mysterious or Controversial Entities ChronicOrthstuticIntolerance

Postural Tachycardia Syndrome (POTS) HyperdynamicCirculationSyndrome HyperadrenergicOrthostaticIntolerance MitralValveProlapse-DysautonomiaSyndrome Chronic Fatigue Syndrome

Neurocardiogenic Syncope Neurasthenia Chronic Regionrrl Puin Svndrome

Reflex Sympathetic Dystrophy Fibromyalgia Post-Truurnutic StressDisorder Human Essential Hypertension “Type A“ Coronary-Prone Behavior Puttern

individual’s style of reaction to stress constitutes an independent coronary risk factor. The theory therefore shifts emphasis from stressors that may accelerate development of atherosclerosis to aspects of the individual’s personality that increasecoronaryrisk.AlthoughFriedmanandRosenmanintroducedand popularized the Type A theory, William Osler presaged it in his characterization of the typical coronary patient as “not the delicate neurotic but the robust, the vigorous In mind and body, the keen ambitious man, the indicator of whose

Introduction

17

engineisalwaysfullspeedahead”(38).Whetherhostility,lackofsocial support, or joyless striving constitute “toxic” components of the Typepattern A remains unresolved. Type A individuals have larger plasma norepinephrine and epinephrineresponsesduringexposuretovariouslaboratoryandclinical stressorsthandoType B individuals(39),suggestingthatabnormal catecholamine responses to stress underlie the increased risk. Although the neuroendocrine mediator hypothesis can explain increased coronary risk in peoplewiththehostileTypeApattern,thepathophysiologicmeaningof excessive catecholamine responses in the long-term development of coronary disease is unknown. Given the large number of factors regulating blood pressure, and the likely heterogeneity of clinical hypertension, the contribution of increased autonomic activity to essential hypertension varies widely across patients. About 60% to 80% of the observed difference from normotensives resultsfrom non-autonomic factors. Compensatory activation of other pressure-regulatory systemsleadstounderestimationofthecontributionoftheautonomic component. Compensatory activation acutely, and hypertrophic processes that produce “amplifier” effects chronically, compromise inferences from depressor or vasodilator responses during autonomic blockade in the estimation of autonomic cardiovascular “tone” in hypertension. After taking into account several possibly confounding factors, including body-mass index, individual maximum physical work capacity, urinary sodium excretion, and anxiety scores, relatively young patients with borderline hypertension have increased antecubital venous plasma norepinephrine concentrations and increased directly recorded skeletal muscle sympathetic nerve traffic, compared to values in age-matched normotensive subjects. The combination ofhigh baseline levels of norepinephrine and plasma renin activity, a large depressor response to clonidine, and a large pressor responsetoyohimbinemaythereforeidentifypatientswithanincreased sympathoneural contribution to blood pressure better than does any of these measures in isolation. The value of this profiling, both in therapeutic decisionmaking and in predicting cardiovascular morbidity, remains unknown. In congestive heart failure, the plasma norepinephrine level constitutesan independent prognostic factor and correlates with functional status. In contrast with a high rate of spillover of norepinephrine into cardiac venous blood, the myocardial tissue content of norepinephrine decreases. Of several possible causes for this depletion, the most likely is a combination of metabolic abnormalities leadingtodecreasedrecyclingofnorepinephrineafteritsreleasefrom sympathetic nerves. The situation would be much worse, if it were not for the large pool of stored norepinephrine available for release. The large turnover of stored norepinephrine under resting conditions is consistent with a “vesicular motor,” which is always “revved” and ready for emergency action. Since most of thedopamineproduced in thekidneysarisesfromrenaluptakeand

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Chapter 1

decarboxylation of circulating L-DOPA, and since dopamine acts locally in the kidneys to augment sodium excretion, L-DOPA may act as a renal dopaminergic pro-drug. Accordingly, oral L-DOPA produces a beneficial natriuretic response in patients with congestive heart failure who have responded to intravenous dopamine as emergency treatment for heart failure that remains symptomatic after treatment with digoxin, an inhibitor of angiotensin-converting enzyme, and the diuretic furosemide. Most physicians lump together all forms of autonomic failure, manifested by abnormal bowel and bladder function, decreased sweating, a constant pulse rate, impotence, and orthostatic or post-prandial hypotension. In contrast, the current presentation distinguishes orthostatic or post-prandial symptoms and hemodynamicabnormalitiesasmanifestationsspecificallyoffailureof sympatheticneurocirculatoryfunction.Erectiledysfunction,constipation, urinary retention, decreased thermoregulatory sweating, and a constant pulse rate indicateparasympatheticorcholinergicfailure.Onecannowdiagnose sympathetic neurocirculatory failure non-invasively, from analysis of beat-tobeat blood pressure during and after performance of the Valsalva maneuver. In patients who cannot perform a satisfactory Valsalva maneuver, the pattern of beat-to-beat blood pressure after a spontaneously occurring premature ventricular contraction can also indicate sympathetic neurocirculatory failure. Using thoracic 6-[18F]fluorodopamine positron emission tomographic scanning and assessments of the entry rate of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), one can now distinguish pathophysiological subtypes of autonomic failure. Patients with pure autonomic failureorwithParkinson’sdiseaseandautonomicfailurehavemarkedly decreasedmyocardial 6-[18F]fluorodopamine-derivedradioactivityand correspondingly decreased cardiac norepinephrine spillover, indicating loss of myocardial sympathetic nerve terminals. In contrast,patientswithmultiple systematrophywithsympatheticneurocirculatoryfailure(theShy-Drager syndrome) have increased 6-[18F]fluorodopamine-derivedradioactivity for a given amount of delivery by blood perfusion, indicating intact sympathetic terminalsanddecreasednervetraffic.Dysautonomiapatientswithout sympathetic neurocirculatory failure have normal myocardial 6[ 18F]fluorodopamine-derivedradioactivity and normal cardiac norepinephrine spillover. These findings have led to a clinical pathophysiological classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, on values for cardiac norepinephrine spillover, and on results of 6[18F]fluorodopamine positron emission tomographic scanning. The results also demonstrate that patients with sympathetic neurocirculatory failurein the setting of Parkinson’s disease have cardiac sympathetic denervation, leading to the suggestion that in Some patients,Parkinson’sdiseaseresultsfromnotonly central but also peripheral neurodegeneration.

Introduction

19

Acute, marked decreases in sympathetic neural outflows characterize noncardiac syncope (neurocardiogenic syncope, vasodepressor syncope, the common loss of consciousness in the faint), by far the most common cause of sudden generalpopulation.Sympathoinhibition,coupledwithincreasedcirculating epinephrine levels, decreases vascular resistance, especially in skeletal muscle, and decreased total peripheral resistance, without compensatorily increased cardiac output, causes the blood pressure to plummet. The patient feels faint (presyncope) or actually loses consciousness (syncope). Patients with a history of non-cardiac syncope or presyncope appear to have suppressed release of norepinephrine from intact sympathetic nerve terminals in the heart. Tonic suppression of cardiac sympathetic outflow could contribute to a tendency to faint, by limiting norepinephrine release in situations where maintenance of blood pressure depends on sympathetically-mediated increases in the rate and force of cardiac contraction. A neuroendocrine pattern combining adrenomedullary stimulation with more generalized sympathoinhibition appears to constitute the proximate cause of vasodepressor reactions in predisposed individuals. Clinicalsympatheticneuroimaging,using6-[18F]-fluorodopamine sympathoneural scanning, holds great promise for delineating not only anatomic butalsofunctionalabnormalities in avarietyofotherneurocardiologic disorders. integrative Medicine

The recent history of medical science has witnessed the ascendance of molecular genetics, which by now has outdistanced integrative physiology in theraceformoney,personnel,space,andprogrammaticpriorities.This competition actually continues an ancient dispute about what medical scientific knowledge is and about how one should go about acquiring it. The resolution will not be by victory for either side but by merging of the two disciplines into a new one. The lack of a word to describe the conceptual foundation of integrative medicine has led tothepropositionofaneologism:“homeostatism” (37). Homeostatism uses a feedback-dependent(i.e., circular) approach to the apparent steady-statesthatcharacterizealllivingthings.Theprincipleunderlying homeostatism is that organisms maintain their internal environment by the operation in parallel of adaptive, feedback-regulated systems. Via negative feedback regulation, comparator “homeostats,” and multiple effectors, adult organisms maintain levels of monitored variables within prespecified ranges. According to thehomeostaticconcept,growth,senescence,disease,and, ultimately,organismicdeathresultfrominstabilityintroducedbypositive feedback loops-upward and downward spirals rather than circles-leading to

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Chapter 1

new apparent steady-states. These considerations led to the homeostatic theory of stress (32), refined further in this book. Patient-oriented research based on catecholaminergic systems can bridge molecular genetics and molecular biology with integrative physiology and support a new type of medical discipline, where illness reflects disorders of homeostatic regulation. Discoveries in neurocardiology could spearhead this development. By learning about function and dysfunction of the autonomic nervous system, one can acquire principles of integrative medicine and apply them in clinical practice.

REFERENCES 1. Bard, P. Autonomic nervous system

or efferent pathways to visceral effectors. In: Mountcastle VB. ed. Medical Physiology. Saint Louis, MO: The C. V. Mosby Company, 1968:1811-1838. 2. Miller J. The Body in Question. New York:Vintage Books, 1978; 3 . Brown-Sequard CE. Experimental researches applied to physiology and pathology.MedExam(Philadelphia) 1852; 8:481-504. 4. Dale H. Accident and opportunism in medical research. Br Med J 1948; 2:451-455. 5 . Barcroft H, Talbot JF. Oliver and Schafer’s discovery of the cardiovascular action of suprarenal extract. Postgrad Med J 1968; 44:6-8. 6. Oliver G , Schafer EA. On the physiologicalactionofextractof the suprarenal capsules. JPhysiol 1895; 17:ix-xiv. 7. Richter D. Inactivation of adrenaline in vivo in man. J Physiol 1940; 98:361-374. of the suprarenal 8. Abel JJ, Crawford AC. On the blood-pressure-raising constituent capsule.Bull Johns HopkinsHosp 1897; 8:151-157. 9. Takamine J. The isolation of the active principle of the suprarenal gland. J Physiol 1901; 27130P-39P. IO. Abel JJ. On a simple methodofpreparingepinephrinandits Johns Hopkins Hosp 1902; 13:29-36.

compounds. Bull

11. Langley JN. The Autonomic Nerves. Amsterdam, The Netherlands: University of

Amsterdam, 1905. J N . The Autonomic Nervous System. Cambridge, England: W. Heffer and Sons, Ltd., 1921. 13. Langley JN. On the union of the cranial autonomic visceral fibres with the nerve cells of the superior cervical ganglion. J Physiol 1898; 23:240-270. 14. Langley JN. The autonomic nervous system. Brain 1903; 26:l-26. 15. Elliott TR. On the action of adrenalin. J Physiol 1904; 31:xx-xxi. 16. Dale H. Opening Addres. Ciba Foundation Symposium on Adrenergic Mechanisms.Boston:Little,BrownandCompany, 1960. 1

12. Langley

21

Introduction

17. Loewi 0, Navratil E.UberhumoraleUbertragbarkeit

Mitteilung.

der Herzenvenwirkung. X. Uber das Schicksal des Vagusstoffs. PflugersArch 1926;

214:678-688. 18. Loewi 0 . UberhumoraleUbertragbarkeit der Herzenvenwirkung. Pflugers Arch 192 1 ; 189:239-242. 19. CannonWB, Rosenblueth A. Studies on conditions of activity in endocrine organs. XXIX. SympathinEandSympathin I. Am J Physiol 1933; 104:557574. 20. CannonWB,Lissak K. Evidence for adrenaline in adrenergic neurones. Am J Physiol 1939; 125:765-777. systeme nerveux autonome, etparticulierement 21. BacqZM.Lapharmacologiedu

dusympathique,d’apreslatheorieneurhumorale. Annales de physiologieet de physiocochimie biologique 1934; 10:467-528. 22. vonEuler US. A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) anditsrelations to adrenalineandnor-adrenaline.ActaPhysiol Scand 1946; 12:73-96. 23. von Euler US. Identification of the sympathomimetic ergone in adrenergic nerves of cattle (sympathin N) withlaevo-noadrenaline.ActaPhysiolScand 1948; 16:63-74. 24. Peart WS. The nature of splenic sympathin. J Physiol 1949; 108:491-501. to 25. Dale HH. The action of certain esters and ethers of choline, and their relation muscarine. J Pharmacol Exp Ther 1914; 6:147-190. 26. AhlquistRP.Astudyof adrenotropic receptors. Am J Physiol 1948;153:586600. 27. Moratinos J, Olmedilla B, dePablosI, Vigueras MD. Alpha-adrenoceptor

involvement in catecholamine-induced hyperglycaemia in conscious fasted rabbits. Br J Pharmacol 1986; 89:55-66. A. Impairedprotein 28. Cipres G , Butta N, UrcelayE,ParrillaR,Martin-Requero kinase C activation is associated with decreased hepatic alpha 1adrenoreceptorresponsiveness in adrenalectomizedrats.Endocrinology 1995; 1361468-475. 29. Exton JH. Mechanismsofhormonalregulationof hepatic glucose metabolism. DiabetesMetabRev 1987; 3:163-183. 30. Bouscarel B, Exton JH. Regulation of hepatic glycogen phosphorylase and

glycogen synthase by calcium and diacylglycerol. Biochim Biophys Acta 1986; 8881126-134. 3 1. Blackmore PF, Strickland WG,BocckinoSB,Exton

JH. Mechanism of hepatic glycogen synthase inactivation induced by Ca2+- mobilizing hormones. Studies using phospholipase C and phorbol myristate acetate. Biochem J

1986; 237:235-242. 32. Goldstein DS. Stress as a scientific idea:A homeostatic theory of stress and distress. Homeostasis 1995: 4:177-215.

22

Chapter 1

33. Goldstein DS, Mezey E, Yamamoto T, Aneman A, Friberg P, Eisenhofer G. Is there athird peripheral catecholaminergic system? Endogenousdopamine as an autocrinelparacrine substance derived from plasma DOPA and inactivated by conjugation.HypertensRes 1995; 18Suppl I:S93-S99. 34. Johnson RH, Lambie DG, Spalding JMK. Neurocardiology: The Interrelationships between Dysfunction in theNervousand Cardiovascular Systems. Philadelphia, PA: WB Saunders Co., 1984. 35. Natelson BH. Neurocardiology: An interdisciplinary area for the 80s.Arch Neurol 1985; 421178-184. 36.Armour JA, Ardell JL. Neurocardiology. New York, NY: Oxford University Press, 1994. 37. Goldstein DS. On the dialectic between molecular genetics and integrative physiology: Toward a new medical science. Pers Biol Med 1997; 40505-515. 38. Osler W. The Lumleian lectures on angina pectoris. Lancet 1910; 1:697-699 and 83. 39. DeQuattro V, Loo R, Foti A. Sympathoadrenal responses to stress: the linking of type A behavior pattern to ischemic heart disease. CIinExpHyper 1985; 7:469-481.

Overview of the Autonomic Nervous System Abouttheturnof20thcentury,thegreatEnglishphysiologist J.N. Langley coined the term, “autonomic nervous system,” to denote the portion of the nervous system mediating largely involuntary, unconscious functions of internalorgans, in contrastwiththeportionmediatinglargelyvoluntary, conscious,externallyobservablebehaviorsmediated by skeletalmuscle. Supportingthisdistinction,cellbodiesofautonomicnervesprojectingto internal organs occur in ganglia outside the central nervous system, whereas cell bodies of nerves projecting to skeletal muscle occur in the anterior horns of the spinal cord. Soonafterward,Walter B. Cannon,SirHenryDale,andtheir contemporaries conceptualized the autonomic nervous system as also containing two components-parasympatheticandsympathico-adrenal(Figure2-1). Cannon considered the parasympathetic component to subserve vegetative, energy-producing processes such as digestion, during periods of quiescence, withacetylcholinetheeffectorcompound;andthesympathico-adrenal component to subserve energy-consuming processes such as “fight-or-flight’’ behaviors,duringemergencies,withepinephrine(adrenaline)theeffector compound. The two components would antagonize each other in maintaining “homeostasis,” a word Cannon coined (1-3) to describe the stability of the internal environment. Subsequent findings have forced re-considerationof these distinctionsand concepts. First, as subsequent discussion in this and other chapters will make evident, different stressors evoke patterned, closely coordinated, dynamically interacting autonomic and locomotor changes, and this questions the usefulness of the notion of independent central and autonomic nervous systems (Figure 22). Second, the sympathetic nervous system contributes importantly to values for key internal variables, such as arterial blood pressure, even under “resting” conditions, with compensatory activation of alternative effectors obscuring those contributions. This means that the sympathetic nervous system functions as much more than an “emergency” system. Third, stressors can elicit directionally opposite responses of the sympathetic nervous and adrenomedullary hormonal effectors or can elicit parallel changes in parasympathetic and adrenomedullary 23

24

Chapter 2

Langley

NeNOUS System

n I

J

Central Nervous System AutonomlcNervousSystem Voluntary Somatlc Involuntary Vlsceral Non-Cardlac Strlated Muscle Cardlac & Smooth Muscle Cell BOdleS Central Nervous System Cell Eodles Outslde Central Nervous System

Cranial & Sacral Thoraclc Vegetatlve Parasyrnpathetlc

Cannon

Adrenerglc

e,

Lumbat

Non-Vegetative

Syrnpathetlc

AutonomlcNervousSvstem

Vegetatlve Parasympathetlc Cholmerglc

Emergencles Sympathlco-Adrenal System

Syrnpathetlc NervousSystem

Adrenal Medulla

Non-SDecihc Acbvatlon

Figure 2-1 Langley’s and Cannon’sconceptions of theautonomicnervous system. Notethat Cannon combined the adrenalglandand sympathetic nervous system into a“sympathico-adrenalsystem.”Langley’s schema did not include the adrenal gland, although it did include the “enteric” system of the mesenteric organs (not shown above).

outflows.Thiscontrastswiththenotionofantagonismbetweenthe parasympathetic and sympathico-adrenal systems. In fact, in some situations, adrenomedullary and parasympathetic or adrenomedullary and hypothalamopituitary-adrenocortical changes correlate better than do adrenomedullary and sympathoneuralchanges.Fourth,non-neuronalornon-cholinergic,nonnoradrenergic neuronal effectors influence the performance of internal organs. Indeed, a large and somewhat bewildering group of peptides, purines, steroids, and gases has over the last few decades attracted so much of the attention of basic researchers that studying the classical cholinergic and catecholamine systemshasfdlensomewhatoutofvogue.Andfifth,numerousinternal processesvar)overtimeandadjusttochangingconditions, in essence redefining h o ~ ~ l e i ~ t acontinually sis in life. The internal steady-states Bernard and Cannon conceptualized are not staticideals.

25

Overview of the A.N.S. Hlgher NeNOUS System

F

4 4 t

Hypothalamus

Lower Bramstem

G Feedback

T

Splnal Cord

t

Responses

1:":I 2-*

Local

Monitored

Patterned Effector

Varlables

Visceral Internal Sympathoneural Adrenomedullary Parasympathetic Pituitary-Adrenocortical Rentn-Angiotensin-Aldosterone Vasopressin Insulin-Glucagon Local (NO. Endothelin) etc.

Figure 2-2 Current conception of the autonomic nervous system. The sympathetic nervous system, adrenomedullary hormonal system, and parasympathetic nervous systemareeffectors,along with severalothers, that determine the visceral components of patternedresponses by theorganismthathelptomaintain homeostasis.

Theorganizationofthischaptertakesintoaccountsomeofthese developments, by considering separately the parasympathetic nervous system, sympathetic nervous system, adrenomedullary hormonal system, non-neuronal catecholamine systems, and non-cholinergic, non-noradrenergic systems. PARASYMPATHETIC NERVOUS SYSTEM

The parasympathetic nervous system consists of two sets of nerves, one derived from the brainstem, constituting the cranial parasympathetic outflow, and the other derived from the intermediolateral columns of the sacral spinal cord, constituting the sacral parasympathetic outflow (Figure 2-3). In contrast, sympathetic nerves emanate from the intermediolateral columns of the thoracic and lumbar spinal cord. As one would predict from the teleological view that the parasympathetic system regulates mainly vegetative, conservative processes, parasympathetic stimulation stimulates digestion, by increasing release of gastrin and insulin and increasing gut motility. Conversely, parasympathetic activity decreases during many but by no means all situations involving emotional distress. In general,

26

Chapter 2

Cranlal

Head & Neck Glands e . g . , Puplls, Salwary

0-

ThoracoLumbar

A

Mesentertc Organs

0. Sacral

-

ACL(

Genltal Organs L o w e r GI T r a c t

J

Figure 2-3Parasympathetic neurotransmission. Acetylcholine (ACh)is the main neurotransmitter of the parasympatheticnervoussystem.Thepre-ganglionic neurons(opencircles) are inthebrainstemandin the sacralspinal cord. Thepostganglionic neurons (black circles) lie near or in the target organs.

when sympathoneural activity increases, parasympathetic activity decreases, but itwillbecomeclear in discussionsofphysiologicalresponsessuchasto hypoglycemia and pathophysiological responses such as neurally mediated vasodepression that exceptions to this generalization occur. Cell bodies of the parasympathetic preganglionic neurons are located in brainstem nuclei for the third, seventh, ninth, and tenth cranial nerves and in the intermediolateral columns of the sacral spinal cord (Figure 2-4). The Edinger-Westphal nucleus, in the rostral portion of the nucleus of the third (oculomotor) cranial nerve in the midbrain, projects to the ciliary ganglion. The post-ganglionic fibers supply the ciliary muscle and sphincter muscleof the iris and also enter the globe of the eye. Oculomotor nerve lesions include

Overview of the A.N.S.

27

dilationofthepupil(mydriasis),becauseofunopposedsympatheticallymediated radial muscle contraction. Pre-ganglionicparasympatheticfibers in thenervusintermedius,a division of the seventh (facial) cranial nerve, arise from the superior salivatory nucleus and synapse in the pterygopalatine and submandibular ganglia. Fibers emanating from the pterygopalatine ganglion innervate the lacrimal glands; mucosaofthepalate,pharynx,andposteriornasopharynx;andthe submandibular and sublingual salivary glands. Pre-ganglionic parasympathetic fibers in the ninth (glossopharyngeal) cranial nerve, arising from the inferior salivatory nucleus, synapse in the otic ganglion, the post-ganglionic fibers innervating the parotid gland. The main parasympathetic nerve in the body, the vagus nerve, emanates fromthemedullaofthebrainstemasthetenthcranialnerve.Thevagus innervates the heart, bronchioles, skin, and mesenteric organs up to the splenic flexure of the colon. Vagal ganglia generally lie near or within the innervated organs, and so the vagus consists of pre-ganglionic fibers. Vagal stimulation contracts bronchial smooth muscle cells, increases bronchial secretion of mucus, augments gastrointestinal peristalsis, evokes gastric and pancretic secretion, and relaxes the pyloric and ileocolic sphincters. Stimulation of the right vagus nerve slows the discharge rate of the sinus node, while stimulation of the left vagus induces less slowing of the sinus rate but more interference with atrioventricular conduction. Vagal stimulation also promotes vasodilation, via generation of nitric oxide and inhibition of norepinephrine release from sympathetic nerve terminals. Parasympathetic fibers originating in the intermediolateral columns of the sacral spinal cord participate importantly in penileerectionandmicturition (Figure 2-5). Parasympatheticpre-ganglionicefferents in the pelvic nerves stimulate the bladder detrusor and relax the urethral internal sphincter muscles, promoting bladder emptying. Parasympathetic Neurotransmission

In the 1920s, Otto Loewi proposed that a chemical messenger substance, acetylcholine, produces the physiological effects of vagal stimulation. Loewi’s experiment was a milestone, because it identified a new type of endogenous substance-a neurotransmitter. As noted in the introductory chapter, Loewi called the substance released by the frog heart during vagal nerve stimulation, “Vagusstoff,” or the substance of the vagus. In 1926, he and Navratil identified the Vagusstoff as acetylcholine. All parasympathetic nerves release acetylcholine as the neurotransmitter. Acetylcholine is synthesized from the choline acetyltransferase-catalyzed transfer

28

Chapter 2

Oculomotor Nerve

Facial Nwve

Porn

7 . Glossopharyngeal Nerve

Pelvu Nerve

J Figure 2 4 Overview of parasympathetic nervous systemoutflows.These arise from cranial nerves 111, VII, IX, and X and from the sacral spinal cord. Vagal outflows to the heart derive from the dorsal motor nucleus @MN) and the nucleus ambiguus (NA) in the medulla.

of acetyl-coenzyme A to choline and is inactivated by acetylcholinesterase almost immediately after release of the transmitter from nerve endings. Other cholinergic nerves participate in neuromuscular transmission, adrenomedullary and sweat gland secretion, and, in some species, sympathetic vasodilation. Acetylcholine released from parasympathetic terminals exerts several effects in different organs. In the heart, cholinergic stimulation decreases the cardiac rate, inhibits atrioventricular conduction, and decreases the inotropic state (in the atria more than the ventricles). All these effects depend to some

Overview of the A.N.S.

29

extent on the concurrent sympathetic tone. Preganglionic vagal fibers from the nucleus ambiguus to the heart fire in synchrony with the pulse and do not appear to possess intrinsic pacemaker activity (4).The rate of cardiac vagal efferent traffic generally decreases during inspiration and peaks just after inspiration, accounting in large measure for “respiratory sinus arrhythmia,” wherethepulserateincreasesduringinspirationanddeclinesabruptly afterwards. Acetylcholine acts as a vasodilator, probably at least partly via occupation In the of M3 receptors and local generation of nitric oxide, as noted below. gastrointestinal tract, acetylcholine stimulates secretory activity and peristalsis, the enhanced motility producing symptoms such as nausea, cramps, and an urge to defecate. Cholinergic agonists act by a variety of mechanisms to stimulate bladdercontractionandurination.Acetylcholinealsostimulatessecretory activity by most glands receiving parasympathetic innervation, including the salivary glands (eliciting watery secretion), lacrimal glands, and sweat glands. In the eye, acetylcholine induces miosis of the pupil. Acetylcholine itself is not used as a drug in clinical medicine, because of the diverse toxic effects and susceptibility to rapid degradation. Exogenously administered cholinergic agonists (e.g., bethanecol) are used to treat nonobstructive urinary retention and gastric atony. These drugs stimulate digestive processes and intestinal motility, increase salivation, and increase sweating, with relatively little change in heart rate. Drugs that inhibit acetylcholinesterase and cross the blood-brain barrier (e.g., physostigmine) reverse central nervous depression due to overdose of anticholinergics. Edrophonium, which does not cross the blood-brain barrer, rapidly stimulates cardiac cholinergic receptors and is used to treat paroxysmal supraventricular tachycardia; and neostigmine, which also does not cross the blood-brain barrier, is used in the diagnostic evaluation ofmyasthenicsyndromes.Anticholinergicsareusedclinically in several conditions, including bladder atony, paralytic ileus, myasthenia gravis, asthma, insomnia, peptic ulcer disease, symptomatic bradycardia or heart block, diarrhea, hyperhidrosis,Parkinson’sdisease,Alzheimer’sdisease,andmushroom poisoning. Cholinergic Receptors

Specific receptors mediate the effects of acetylcholine. Classically they have been divided into nicotinic and muscarinic ( 5 ) . Agonist occupation of nicotinic receptors increases entry of Ca”, and agonist occupation of muscarinic receptors leads to complex effects mediated by G-proteins (Table 2-1).

30

Chapter 2 Pyramlda! Tract

Pudendal Nerve

Internal Sphincter

External Sphtnct er

" PARASYMPATHETIC SYMPATHETIC

Figure 2-5 Sympathetic and parasympathetic nervous system outflows to the Urinary Bladder. The sympathetic outflow derives from the L2-4 sympathetic ganglia and the parasympathetic outflow from the sacral spinal cord. Muscarinic Muscarinicagonistsstimulategutsmoothmusclecontractionand glandular secretion and inhibit norepinephrine release from sympathetic nerve terminals. Atropine blocks muscarinic receptors selectively. Molecular cloning studies have identified five subtypes of muscarinic receptors, designated M1-M5. All have the typical structure of G-proteincoupledreceptors,including 7 trans-membranedomains.Identification of subtype-specificdrugs-especiallysubtype-specificagonists-haslagged behind.

31

Overview of the A.N.S.

57

M1. M3. OR M5 AGONIST

n

CS-

ca"

ENDOPLASMIC RETICULUM

M2 or M4 AGONIST

G,

GTP

ADENYL CYCLASE

&ATP

CA'MP

I

PKITEIN KINASE A

57

M1. M2, M3. M4. M5 AGONIST

4

Figure 2-6 Intracellularmechanismsupon occupation of subtypes of muscarinic receptors.G-proteinsconsisting of a, R, and y subunits bind toguanosine triphosphate (GTP), catalyzing production ofguanosine diphosphate (GDP) and adenosinetriphosphate(ATP) and activating enzymes leading to formation of secondmessengerssuchascyclicadenosinemonophosphate(CAMP), inositol triphosphate (IP3), and diacylglycerol (DG). Production of nitric oxide (NO) leads to generation of cyclic guanosine monophosphate (cGMP).

32

Chaoter 2

Choline

+

Vasodilation

A c e tCyO l -A

* $ f

Choline Acetyltransferase

t 0

II

IAcetylcholinet

‘U Citrulline

Acetylcholinesterase

Vascular Smooth

Muscle Cell

Choline

+ Acetate

Cholinergic Terminal

Figure 2-7 Mechanism of acetylcholine-induced vasodilation via formation of nitric oxide (NO). Note that tetrahydrobiopterin (BH4) is a requiredco-factor for nitric oxidesynthase (NOS). NO elicits vasodilation via generation of cyclic guanosine monophosphate(cGMP).

Stimulationof M1, M3, and M5 receptorsleadstohydrolysisof phosphoinositides and increased intracellular mobilization of Ca++, via the Gprotein, Gq (Figure 2-6). Stimulation of M2 and M4 receptors inhibits adenyl cyclase, via the pertussis toxin-sensitive G-proteins, Gi and Go. The vasodilator effect of acetylcholine depends at least partly on intact endothelium (6). Acetylcholine increases local generation of the endotheliumderived relaxing factor, nitric oxide (NO, Figure 2-7). Blockade of nitric oxide production therefore prevents acetylcholine-induced vasodilation, and denudation of endothelium not only unmasks a vasoconstrictor effect of acetylcholine but also potentiates responses to norepinephrine (7). Non-adrenergic, non-cholinergic neuronal mechanisms mediating penile erection may also depend on local generation of NO(8).

Overview of the A.N.S.

33

Activation of muscarinic cholinergic receptors increases generationNO, of with subsequent cellular functional changes by activation of cyclic GMPdependent protein kinase, altered potassium channel function, and diffusion of NO into the extracellular fluid. The subtypes of muscarinic receptors mediating N O production, and the intracellular mechanisms of NO production, remain unsettled. Evidence has accrued in different studies for NO production after occupation of all five subtypes (9- 15). Accordingtocurrentthinking,M1receptorsmediateinhibitionof norepinephrine release from sympathetic nerves; M2 receptors mediate vagal bradycardiaanddecreasedcardiacinotropy;andM3receptorsmediate contraction of gastrointestinal smooth muscle and increased glandular secretion (16). About muscarinic inhibition of norepinephrine release, the situation in reality may be more complex. In human papillary muscle, atropine and the M3 subtype-selective antagonist 4-DAMP augment release of 3H-norepinephrine (17), indicating that muscarinic receptors of the M3 subtype tonically inhibit release of norepinephrine from cardiac sympathetic nerves. In the human irisciliary body, M2 receptors appear to inhibit local norepinephrine release(18). In isolated superior cervical ganglion neurons, the subtype-nonspecific agonist oxotremorine M inhibits norepinephrine release, as measured by carbon fiber amperometry, and methoctramine and tropicamine but not pirenzipine attenuate thiseffect,suggestingparticipationofM2orM4receptorsinmuscarinic inhibitionofnorepinephrinereleasefromthepost-ganglionicsympathetic terminals (19).

Nicotinic Hexamethonium and structurally related drugs block nicotinic receptorsin autonomicgangliaselectivelyandbydoing so inhibitsympatheticpostganglionicnervetraffic.Nicotinicreceptorsalsomediatecholinergic transmission in parasympatheticgangliaandcholinergicstimulationof adrenomedullary secretion. At skeletal neuromuscular junctions, acetylcholine bindstonicotinicreceptorsdistinctfromthose in theautonomicnervous system. Nicotinic receptors are acetylcholine-gated cation channels (Figure 2-8). The receptors consist of subunits, a and R, arranged in pentamers in the cell membrane. Additional subunits, 6 and y, exist in post-synaptic receptors on skeletal muscle cells. In the mammalian nervous system, 8 a and 4 R subunit genes have been cloned so far. Pharmacological tools have allowed partial identificationofsubunits in native nicotinic receptors. Alpha-bungaratoxin blocks a7,a 8 , or a9 subunits;cytisineactivates a 7 or R4 subunits;and neuronal bungaratoxin blocks a R2 subunit.

34

Chapter 2

TABLE 2-1 Cholinergic Receptors

Channel

Agonist

Antagonist

Na' Ca++

Nicotine Cytisine RJR-2403

Erysodine

GTS-21

Methylaconitine

DMPP

Hexamethonium Trimethaphan Chlorisondamine

TMA

Succinylcholine Tubocurarine

Agonist

Antagonist

Muscarine Pilocarpine

Atropine Scopolamine

Nicotinic

Neuronal a-BG Insensitive

K+

Neuronal Ca++Sensitivea-BG

Na+ K+

Autonomic Ganglionic

Na' Ca++ K+

Skeletal Muscular

Na' Ca++ K+

G-Pr. 2d Msg. Channel Muscarinic

M1

Pirenzepine

Gq Caw IP3/DG No

M2CAMP Gi M3

Ca++

Gallamine Methoctramine 4-DAMP Tropicamide

K+

IP~DG

No M4 M5

Gi

CAMP

K+

Gq

IP3/DG No

Ca*

Overview of the A.N.S.

35

= G-protein; 2d Msg. = Second messenger; a-BG = a Bungaratoxin; DMPP = 1 , l ,-Dimethyl-4-phenylpiperazinium; TMA = Tetramethylammonium; IP3= Inositoltriphosphate; DG = Diacylglycerol; CAMP = Cyclic adenosine monophosphate; NO = Nitric oxide; 4-DAMP = 4Diphenylacetoxy-N-methylpiperidine.

Abbreviations: G-Pr.

Epibatidine,afrogalkaloidthatstimulatesthe a4R2 site,exertsan extraordinary analgesic effect about 200-fold stronger that that of morphine (20). This drug, however, also affects ganglionic and neuromuscular neurotransmissionandhasanunacceptabletoxic:therapeuticratio.Other agonists at the a4R2 site are under development as analgesics 1,22). (2 Nicotinic agonists such as those active at the a4132 site stimulate trans-membrane entry of Ca++ via N-type calcium channels. N-Type-specific calcium channel blockers appear to exert analgesic(23) but also sympatholytic (24) effects. No study to date has identified all the components of any native nicotinic receptor. SYMPATHETIC NERVOUS SYSTEM

The sympathetic nervous system, the neuronal component of what Walter B. Cannonconsideredthesympathico-adrenalsystem,consistsofnerve networks. Since sympathetic nerves derive from cells in ganglia, rather than from cells in the spinal cord or brainstem, sympathetic nerves consist mainly of post-ganglionic neurons (Figure 2-9). Peripheral nerves contain sympathetic fibers that supply the vasculature of the skeletal muscle and skin, innervate sweat glands, and carry afferent traffic from nociceptors. The fibers enmesh the adventitial and adventitial-medial layer of arteries and form lattice-like networks in the myocardium and in glands. Sympathetic nerve stimulation constricts arterioles almost instantaneously,increasingregionalresistancetobloodflowandthereby diverting blood flow to other regions with less resistance. Diffuse sympathetic stimulationincreasestotalarteriolarresistancetobloodflow,andsince sympathetic activation in theheartincreasestheforceandrateofcardiac contraction, blood pressure increases from both increased peripheral resistance and increased cardiac output. Stimulation of sympathetic nerves to the salivary glandsincreasessalivation(elicitingthick,viscoussecretionvia aladrenoceptors and amylase secretion via R-adrenoceptors), to the eyes dilates the pupils, to sweat glands increases sweating, to hair follicles evokes piloerection, tothekidneysinhibitssodiumexcretion,andtoskeletalmusclecauses trembling.

36

Chapter 2

Figure 2-8 Diagram of a nicotinic acetylcholine receptor in the lipid bilayer cell membrane. Cations enter the cell through the pore surrounded by the pentameric array of receptor components.

The most well known chemical transmitter at sympathetic nerve endings is norepinephrine. Sympathetic stimulation releases norepinephrine, and binding of norepinephrine to adrenoceptors on cardiovascular smooth muscle cells causes the cells to contract. Noradrenergic Neurotransmission

The spinal cord is the most distal site of the central nervous system that generates patterns of sympathetic activity. The final common pathway for sympathetic outflow is the preganglionic neuron. Cell bodies of the sympathetic preganglionic neurons are located mainlyin the intermediolateral columns of the thoracolumbar spinal cord. The sympathelic preganglionic neurons discharge spontaneously at a slow rate. Their tonic activity depends mainly on input from chemoreceptor, somatic, and visceral afferent nerve trafficto the spinal cord and importantly on descending input from supraspinal structures. Whereas feedback from the periphery contributes relatively little to direct regulation of sympathetic preganglionic neuron activity, feedback becomes a

Overview of the A.N.S.

Cranial

37

Glands

ThoracoLumbar

Sacral

Figure 2-9 Sympathetic neuronal outflows. Sympathetic pre-ganglionic outflows emanate from the thoracolumbar spinal cord, with the bodies of the post-ganglionic cells in the chain of sympathetic ganglia, in contrast with the craniosacral origin of parasympathetic outflows.

prominent feature at thelevel of the medulla, where most visceral afferent fibers synapse. Medullary cardiovascular centers therefore subserve simple homeostatic reflexes and also provide ascendinginput to centers higherin the neuraxis.

Ganglionic and post-ganglionic neurotransmission After exiting the spinal cord, axons of sympathetic preganglionic neurons travel via myelinated branches(“white rami“) to the preaortic and paravertebral chains of sympathetic ganglia. Some fibers pass through the splanchnic ganglia without synapsing, providing innervation to the adrenal medulla. Most synapse on cell bodies of post-ganglionic neurons, which supply the heart, vasculature, viscera, kidneys, and glands. Adrenal nerve activity therefore at least partly

Chapter 2

38

reflects preganglionic sympathetic outflow, whereas renal nerve activity reflects postganglionic sympathetic outflow. Adrenomedullary chromaffin cells resemble post-ganglionic sympathetic neurons in some respects; for instance, the adrenomedullary nerves release acetylcholine as the neurotransmitter, as do sympathetic preganglionic neurons synapsing in ganglia. Sympathetic post-ganglionic activity, whether to the heart, blood vessels, or sweat glands, occurs in bursts in groups of fibers, driven mainly by preganglioniccellfiring (24). Drugsthatblockganglionicneurotransmission decrease the rate of bursts of post-ganglionic sympathetic traffic to virtually zero. Loss ofsympatheticvasoconstrictortoneduringganglionblockade explains decreased total and forearm vascular resistance, dilation of conjunctival blood vessels, and nasal congestion. Drugs that block ganglionic neurotransmission (e.g., trimethaphan, hexamethonium, pentolinium) concurrentlyproducesymptomsandsignsofparasympatheticinhibition, including dry mouth and decreased gastrointestinal and urinary bladder motility. Conversely, parasympathetic stimulation plays an important role in the “cephalic phase” of digestion, increasing salivation, secretion of insulin and gastrin, and gastrointestinal motility. The effects of acute administration of nicotine, which augments ganglionic neurotransmission, result mainly from increased adrenomedullary secretion of epinephrine. Norepinephrine synthesis Enzymatic steps in norepinephrine synthesis have been characterized in moredetailthanthoseforanyotherneurotransmitter.Norepinephrine biosynthesis begins with uptake of the neutral L-amino acid, tyrosine, into the cytoplasm of sympathetic neurons, adrenomedullary cells, possibly para-aortic enterochromaffin cells, and specific centers in the brain. Other neutral L-amino acids compete with tyrosine for transport into the brain and presumably into sympathetic terminals. In contrast with norepinephrine biosynthesis, dopamine biosynthesis in non-neuronal cells such as in the kidneys depends on uptake of the catechol amino acid, L-dihydroxyphenylalanine(L-DOPA).

Tyrosine hydroxylase Tyrosine hydroxylase catalyzes the conversion of tyrosine to L-DOPA (Figure 2-10). This is theenzymaticrate-limitingstep in norepinephrine synthesis. The enzyme is almost saturated under normal conditions. Thus, although alterations in dietary tyrosine intake normally should not affect the rate of catecholamine biosynthesis under baseline conditions, after prolonged rapid

39

Overview of the A.N.S.

TY ROSlNE

Dihydroblopterin ATP

DOPA

F

Z

O

H

H0

I

H0

+ CO2 Figure 2-10 Enzymatic steps in the biosynthesisofL-DOPAfrom tyrosine and dopamine from DOPA. Tyrosine hydroxylase (TH) catalyzes the first step and Laromatic-amino-acid decarboxylase (LAAAD, also known as L-DOPA decarboxylase, DDC) the second.

40

Chapter 2 Tyroslne

L-Dlhydroxyphenylalanlne L-DOPA

I

Dihydroptendine

A

/

reductase

dehydratase

OHPR

2 NADP+

HCOOH

T Y

Recycling 6-Pyruvoyl

tetrahydropterm synthase

GTP-Cyclohydrolase

I

GTP

De Novo Synthesls

Figure 2-1 1 Synthesis and recycling of tetrahydrobiopterin (BH4). turnover of catecholamines, tyrosine availability may become a limiting factor. The enzyme is stereospecific for L-tyrosine. Concentrationsoftetrahydrobiopterin,Feff,andmolecularoxygen regulate tyrosine hydroxylase activity. The reducedpteridine,tetrahydrobiopterin, is a key co-factor for tyrosine hydroxylase and therefore for the synthesis of biogenic amines (Figures 2-1 1, 2-12). Dihydropteridine reductase catalyzes the reduction of dihydropterin, produced during the hydroxylation of tyrosine, regenerating tetrahydrobiopterin. Dihydropteridine reductase deficiency decrease theamountoftyrosinehydroxylationforagivenamountoftyrosine hydroxylase enzyme. Not only tyrosine hydroxylase but also phenylalanine hydroxylase and tryptophan hydroxylase (as well as another important enzyme, nitric oxide synthase, discussed later) require tetrahydrobiopterin as a co-factor (Figure 2-12). Becausepatientswithdihydropteridinereductasedeficiencyhave decreased ability to metabolize phenylalanine, the disease presents clinically as a form of phenylketonuria. Specific clinical consequences, if any, of decreased tryptophan hydroxylase and nitric oxide synthase activities in dihydropteridine reductase deficiency have not beenidentified. Exposure to stressors that increase sympathetic outflows augments the synthesis and concentration of tyrosine hydroxylase in sympathetic ganglia,

41

Overview of the A.N.S.

5-HTP LAAAO

BH4

HVA4---"OPAC COMT

DHPG

/ 'lA

MAO

Tyr

5-,HT

'

r,

Figure 2-12 Roles of tetrahydrobiopterin (BH4) in the synthesis of the amino acids tyrosine (Tyr) from phenylalanine (Phe), 5-hydroxtryptophan (5-HTP) from tryptophan (Trp), and L-dihydroxyphenylalanine(L-DOPA) from Tyr. BH4 is a required co-factor for tryptophan hydroxylase (TRH), phenylalanine hydroxylase(PAH),andtyrosinehydroxylase (TH). 5-HTPundergoes conversion to serotonin (5-hydroxytryptamine, 5-HT) and L-DOPA conversion to dopamine (DA) via L-aromatic amino acid decarboxylase (LAAAD). DA, norepinephrine (NE), and epinephrine (EPI) are the endogenous catecholamines. 5-HT and catecholamines undergo catabolism by monoamine oxidase (MAO) and catecholamines also by catechol-O-methyltransferase (COMT), to yield several metabolites.

sympathetically innervated organs, the adrenal gland, and the locus ceruleus of the pons (Figure 2-13). Sincetyrosinehydroxylasecatalyzestherate-limitingstep in catecholamine synthesis, homeostasis of norepinephrine stores during such exposuredependsimportantly on feedbackcontrols.Long-termregulation involving production of new tyrosine hydroxylase enzyme occurs at the levels of

42

Chapter 2 SWPAJHETIC NERM TERMINAL

SWPATHETIC NERM ERUINAL

Figure 2-13 Factors influencing activity and synthesis of tyrosine hydroxylase (TH) in response to stressors.Thesefactorsinclude membrane depolarization, intracellular ionized calcium, tetrahydrobiopterin (BHq), catecholproductsofthe tyrosine hydroxylation, and inhibitory modulation by a2-adrenoceptors on the cell membrane. transcription and translation (25,26). Short-term regulation includes negative feedback by the products of the enzymatic reaction (27,28) and on positive feedback in response to increased nerve traffic (28,29). Both short-term controls depend on phosphorylation of the enzyme under control of specific kinases(28). Catecholamines and L-DOPA feedback-inhibit tyrosine hydroxylase, and amethyl-para-tyrosine inhibits the enzyme competitively. These processes enable sympathetic neurons to respond appropriately in situations involving changes in the rate of loss of the transmitter, maintaining norepinephrine stores by regulating synthesis of new neurotransmitter to match loss from the tissue (turnover) following release from nerves or leakage from storage vesicles. Thus, situations associated with decreased sympathoneural outflows decrease tyrosine hydroxylase activity and L-DOPA production (30), and those associated with increased sympathoneural outflows increase tyrosine hydroxylase activity and L-DOPA production (3 1-33). Immediately after administration of reserpine, which blocks translocation of catecholamines into storagevesicles,netleakage of norepinephrinefromthestoresincreases axoplasmic norepinephrine concentrations, inhibiting tyrosine hydroxylase activity and decreasing production of DOPA; however, once the vesicular stores become depleted, both tyrosine hydroxylase activity and L-DOPA production increase (3 1).

Overview of the A.N.S.

43

L-aromatic-amino-acid decarboxylase (LAAAD)

L-aromatic-amino-acid decarboxylase (also called DOPA decarboxylase, DDC) in the cytoplasm catalyzes the conversion of L-DOPA to dopamine (Figure 2-10). Many types of tissue contain this enzyme-especially the kidneys, gut, liver,andbrain.Activityoftheenzymedependsonpyridoxalphosphate. Although L-aromatic-amino-acid decarboxylase metabolizes most of the LDOPA formed in catecholamine-synthesizing tissues, some of the L-DOPA enters the circulation unchanged. This provides the basis for using high plasma L-DOPAlevelstoexaminecatecholaminesynthesis(30,34-36)anddetect increasedhydroxylationoftyrosine in malignant pheochromocytoma (37), malignant melanoma (38,39), and neuroblastoma (37,40). a-MethylDOPA, aneffectivedrug in thetreatmentofhighblood pressure,inhibitsL-aromatic-amino-aciddecarboxylaseandtherefore norepinephrine synthesis. This inhibition does not explain the anti-hypertensive action of the drug, however. Instead, a-methylnorepinephrine, formed from amethylDOPA in catecholamine-synthesizing tissues, stimulates a2adrenoceptors in thebrain,andthea2-adrenoceptorstimulationinhibits sympatheticnervousoutflows.OtherinhibitorsofL-aromatic-amino-acid decarboxylaseincludecarbidopaandbenserazide.Thesecatecholsdonot penetrate the blood-brain barrier, and by inhibiting conversion of L-DOPA to dopamine in the periphery they enhance the efficacy of L-DOPAin the treatment of Parkinson’s disease. Dopamine-R-hydroxylase (DBH)

Dopamine-B-hydroxylasecatalyzestheconversionofdopamineto norepinephrine(Figure2-14).Liketyrosinehydroxylase,dopamine-Bhydroxylase is localized in tissues that synthesize catecholamines, such as noradrenergic neurons and chromaffin cells. Unlike tyrosine hydroxylase, which is present in the cytoplasm, dopamine-B-hydroxylase is confined to the vesicles. Dopamine-B-hydroxylase contains, and its activity depends on, copper. Because of this dependence, children with Menkes disease, a rare, X-linked recessive disorder of copper metabolism, have decreased conversion of dopamine tonorepinephrineandneurochemicalevidenceofconcurrentlyincreased catecholamine biosynthesis. Thus, patients with Menkes disease characteristically have highratios of D0PA:dihydroxyphenylglycol (DHPG), the neuronal metabolite of norepinephrine, in plasma and cerebrospinal fluid (41). Patients with congenital absence of dopamine-&hydroxylase have virtually undetectablelevelsofbothnorepinephrineandDHPGandhighlevelsof dopamine and its deaminated metabolite, dihydroxyphenylacetic acid (42).

44

Chapter 2

DOPAMINE

Ascorbate

Vesicular uptake (Mg ++, ATP)

NOREPINEPHRINE

Figure 2-14 Metabolic conversion of dopaminetoNorepinephrine, via the enzyme dopamine-B-hydroxylase (DBH). Note that DBH is a copper enzyme that also requires ascorbate and molecular oxygen.

Dopamine-&hydroxylase activity also requires ascorbic acid, which provides the electrons for the hydroxylation. Each molecule of norepinephrine synthesized from dopamine by the actions ofdopamine-l3-hydroxylase consumes a molecule of intragranular ascorbic acid. Loss of granular ascorbic acid therefore stops norepinephrine synthesis. Norepinephrine release Adrenomedullary chromaffin cells, much easier to study than sympathetic nerves,haveprovidedthemostcommonlyusedpreparationforstudying mechanisms of catecholaminerelease.Agonistoccupationofmembrane cholinergic nicotinic receptors releases catecholamines from the cells. Since nicotinic receptors mediate ganglionic neurotransmission, the results obtained in adrenomedullary cells might apply to post-ganglionic sympathoneural cells.

Overview of the A.N.S.

45

Exocytosis Accordingtotheexocytotictheoryofnorepinephrinerelease, acetylcholine depolarizes the terminal membranes by increasing membrane permeability to Na’ (Figure 2-15) The increase in intracellular Na’ directly or indirectly enhances transmembrane influx of Ca++ via voltage-gated Ca++ channels. The increased cytoplasmic Ca++concentration evokes a cascade of as yetincompletelydefinedbiomechanicaleventsresulting in fusionofthe vesicular and axoplasmic membranes. The interior of the vesicle exchanges briefly with the extracellular compartment, and the soluble contents of the vesicles diffuse into the extracellular space. Aspredictedfromthismodel,manipulationsbesidesapplicationof acetylcholine that depolarize the cell, such as electrical stimulation or increased extracellular K+ concentrations, also activate the voltage-gated Ca++channels and trigger exocytosis. Exactly how increased intracellular Ca*concentrations evoke exocytosis in sympathetic nerves is unknown, but, as noted below, the process appears to include coordinated, complex actions of several membrane and vesicular proteins. Simultaneous, stoichiometric release of norepinephrine with the soluble constituents of the vesicles-ATP, enkephalins, chromogranins, neuropeptide Y, anddopamine-R-hydroxylase-withoutsimilarreleaseofcytoplasmic macromoleculessupportstheexocytosistheory.Electronmicrographs occasionally show an “omega sign,” where an apparent gap in the cell membrane occurs at the site of fusion of vesicle with the axoplasmic membrane. At least two storage pools of norepinephrine may exist in sympathetic nerveterminals-asmall,readilyreleasablepoolofnewlysynthesized norepinephrine and a large reserve pool in long-term storage. Ultrastructural evidence has suggested release from two types of vesicles-large and small dense-core vesicles. The relationship between the pools of norepinephrine and the two forms of vesicles remains obscure. Severalproteinsinteracttoregulatedocking,fusion,poration, endocytosis, and regeneration of synaptic vesicles in sympathetic terminals. According to one model (Figure 2-1 S), protein kinases activated by second messengers catalyze conversion of dephosphorylated to phosphorylated synapsin I, promoting tethering of the vesicle by actin filaments. The vesicle-associated docking proteins, synaptobrevin (also called VAMP) and synaptotagmin (also called p65), interact with the membrane docking proteins, syntaxin, and SNAP25, rab3,synaptoporin,andsynaptophysin,tofusethevesiclewiththe membrane and porate the vesicle-cell membrane junction, resulting in release of the soluble contents of the vesicles. The protein, rab3, appears to identify appropriate destination sites. A key stepin the function of this “fusion machine” takesplacewhenthevesicle-associatedprotein,synaptotagmin,senses

46

Chapter 2

ReceptorOccupatlon or M e m b r a n e Depolarlzatlon

Secona Messengers

/

Dephosphorylated

\

Act In Tethermg

Docklng Protelns V A M P (=Synaptobrevln) Synaptotagmln

NPY ATPChr A

NL

MEMBFM Docklng Protetns rab3 Synapfoporln Synaptophysln Synt a x l n

Figure 2-15 Release of norepinephrine by exocytosis afterdepolarization of the cell membrane of a sympathetic nerve terminal. intracellular Ca", fostering interaction with the cell membrane regulatory protein, syntaxin. Knockout of syntaxin is lethal; however, knockout of other proteinsofthefusionmachine,includingtheputativeCa++sensor, synaptotagmin, has little effect on neurotransmitter secretion. This has led to the suggestionthatthemembraneprotein,synexin(alsocalledannexin VII), transduces the Ca++ signal to mediate fusion of the vesicle with the cell membrane (43). Catecholamine release, both in the brain and periphery, appears to occur importantlynon-synaptically.Thus,thevesicularmonoaminetransporter, VMAT-2, and dense core vesicles are localized ultrastructurally at sites distant from synaptic junctions(44).

Overview of the A.N.S.

47

Modulation In primary cultures of postganglionic sympathetic neurons and other ex vivo preparations, drugs acting at multiple receptors modulate norepinephrine release. Compounds that evoke or facilitate norepinephrine release include acetylcholine(atnicotinicreceptors),epinephrine(at82-adrenoceptors), angiotensin 11, corticotropin, pituitary adenylate cyclase-activating polypeptide (PACAP),y-aminobutyricacid(aty-aminobutyricacidAreceptors),and vasoactive intestinal peptide. Compounds that inhibit norepinephrine release include y-aminobutyric acid (at y-aminobutyric acidg receptors), acetylcholine Y (at muscarinic M1 receptors), adenosine (at A1 purinoceptors), neuropeptide (at Y2 receptors),somatostatin(atSRIFlreceptors),opioids(at 6 and K receptors),prostaglandinsofthe E series,nitricoxide,dopamine(atD2 receptors), and norepinephrine itself(at 1x2-adrenoceptors. In general, whether in vivo these compounds exert modulatory effects on release of endogenous norepinephrine remains untested or unproven, especially in humans (45,46).

a2-Adrenoceptors Substantialevidence,however,hasestablishedthatendogenous norepinephrinecanregulateitsownrelease, by stimulating inhibitory a2adrenoceptors on sympathetic nerves. This modulatory action is prominent in skeletal muscle beds such as the forearm, relatively weak in the kidneys, and virtually absent in the adrenals. In humans, systemic administration of the a2adrenoceptor blocker, yohimbine, produces much larger proportionate increases in forearm norepinephrine spillover than in directly recorded skeletal muscle sympathoneuralactivity,supportingtheviewthata2-adrenoceptorson sympathetic nerve endings in human limbs tonically inhibit norepinephrine release (47,48).

Co-transmission Compoundsbesidesnorepinephrinereleasedduringsympathetic stimulation may function as co-transmitters, amplifying norepinephrine effects at post-synaptic cells or modulating releaseof norepinephrine by binding to presynapticreceptors.ATP,adenosine,neuropeptide Y, acetylcholine,and epinephrine have received the most attention.

48

Chapter 2

Purinergic neurotransmission Thepurinenucleotide,adenosinetriphosphate(ATP)existsathigh concentrations in vesicles in sympathetic nerve terminals and in the adrenal medulla (49). Sympathetic stimulation releases ATP (50,5 l), which produces excitatory electrical responses in post-synaptic cells (52). Burnstock (53) has proposed that ATP acts asco-transmitter a (Figure 2-16). In the rat tail artery, the post-synaptic excitatory junction current (EJC) to released ATP occurs extremely rapidly. Neuronal release of norepinephrine takes much longer but nevertheless is an order of magnitude faster than the contractile response of the smooth muscle(53). Given the marked inhibitionof contraction by a-adrenoceptor blockade, norepinephrine acts as the main effector compound in this preparation (52). In the rat mesentery, purinergic receptor blockade with suramin inhibits nerve stimulation-induced vasoconstriction, supporting a role for released ATP in sympathetically-mediated vasoconstriction at least in that vascular bed (54). At least four receptors bind ATP-P~u, P ~ x P2y, , and P2z. Of these, P2u and P2y activate phospholipase C, via G-proteins, and P2x and P2z are ligand-gated ion channels. Administration of the P2x inhibitor, a,&methylene ATP, abolishes the early phase of neurogenic contraction but enhances later neurogenic contraction, without affecting the nerve stimulation-induced overflow of 3H-noradrenaline, consistent with a co-transmitter role of ATP at P2x receptors in the early phase of vasoconstriction (55); however, in humans, brachial intra-arterial infusion of ATP elicits vasodilation more pronounced than that during equimolar administration of adenosine, the effect unchanged by blockade of nitric oxide production or of P2x receptors (56). Stimulation of P2y receptors can release endothelial vascular relaxing factors and thereby induce vasodilation (57). ATP in the extracellular fluid undergoes rapid catabolism to adenosine diphosphate, adenosine monophosphate, and finally adenosine, especially during ischemic anoxia. In the brain, adenosine acts generally as a depressant, and inhibitionofitsactionsbycaffeineandtheophyllinshelptoexplainthe excitatory effects of drinking caffeinated beverages. In the periphery, adenosine dilates blood vessels (58-60), via both endothelium-dependent and endotheliumindependent mechanisms. This phenomenon has led to the use of adenosine as a pharmacological challenge test in the diagnostic evaluation of coronary ischemia in patients who cannot undergo treadmill exercise testing -64). (61 Brachial intra-arterial infusion of adenosine increases peroneal muscle sympathetic nerve traffic (58,65) and total body spillover of norepinephrine (66), consistentwithstimulationbyadenosineofmusclechemoreceptors (“metaboreceptors”) and reflexive sympathoneural excitation. Increased formation of adenosine in ischemic tissue and stimulation by adenosine of metaboreceptors

49

Overview of the A.N.S.

SYMPATHETIC

SMOOTH MUSCLE

ENDING

CELL

NE

ATP

a1 Vasoconstnctron

P2 VasoconsfrIctron?

Vasodilstron

Adenosme

BLOODSTREAM

Figure 2-16 Purinergicandnoradrenergic co-transmission.Accordingtothis model,adenosine triphosphate (ATP) andnorepinephrine (NE) in vesicles are released togetherby exocytosis. Adenosine, producedfromATP, feedback-inhibits further NE release.

may also provide a mechanistic explanation for ischemia-induced visceral pain. Thus, brachial intra-arterial infusion of adenosine evokes forearm discomfort (65), and coronaryintra-arterial injection of adenosine can induce typical anginal pain without evidenceof coronary ischemia (67). Adenosine binds to four receptors-A1, A2A, A2B, and A3. All are coupled to G-proteins. Occupation of A2A and A2B receptors increases and of A1 and A3 receptors decreases generation of CAMP. AI receptors exist on sympathetic nerve terminals(68), and a variety of clinical studies have indicated that adenosine, by occupying A1 receptors on sympathetic terminals, inhibits norepinephrine release and thereby attenuates sympathetically-mediated reflexive vasoconstriction.Duringbrachialintra-arterialinfusionofadenosine, norepinephrine spillover in the contralateral arm exceeds that in the arm receiving the infusion, despite locally increased blood flow, supporting the view thatcirculatingadenosineinhibitssympatheticallymediatedreleaseof norepinephrine from local sympathetic terminals (66). Brachial intra-arterial administration of the specific nucleoside transport inhibitor, draflazine, used as a

Chapter 2

50

pharmacologicaltooltopromoteaccumulationofendogenousadenosine, virtually abolishes the increase in forearm norepinephrine spillover normally attendinglowerbodynegativepressure(LBNP)(69),andintra-arterial administration of adenosine attenuates forearm vasoconstrictor responses to LBNP(59,69),suggestingthatendogenousadenosineattenuatesreflexive releaseofnorepinephrine in humans.Conversely,blockadeofadenosine receptors with theophylline, which attenuates adenosine-induced vasodilation (60), augments sympathetically mediated vasoconstrictor responses, even in the setting of a-adrenoceptor blockade (70). Neuropeptide Y Vesicles in chromaffin cells contain at least three types of polypeptides: enkephalins;neuropeptide Y (NPY);andchromogranin A, an acidic glycoprotein. Extracellular fluid levels of NPY and chromogranin A have been considered as indices of exocytosis (71-74). Physiological manipulations that enhanceendogenoussympatheticoutflowusuallyproducemuchsmaller proportionate increases in plasma levels of NPY (75-79) or chromograninA (7983) than of norepinephrine, although insulin-induced hypoglycemia produces rapid increases in plasma NPY levels (84). The results in intact organisms differ substantiallyfromthose in vitro or in isolatedorgansduringelectrical stimulation of sympathetic outflow (73,85,86), suggesting that only intense or prolongedincreases in sympatheticoutflowelicitexocytosisofvesicles containing these polypeptides. ThebestevidenceforaroleofNPY in sympathetically-mediated vasoconstriction comes from studies using NPY receptor blockers. BIBP 3226, thefirstselectiveNPYreceptorblocker(87),antagonizesY 1 receptors competitively. BIBP 3226 inhibits cold stress-induced and electrical field or nervestimulation-inducedvasoconstriction in ratmesentery(54,88-91). Analogously, administration of the Y 1 receptor antagonist, 1229U9 1, inhibits slow neurogenic contraction of vascular smooth muscle in rat hepatic mesentery (92). In the pithed rat preparation, administration of BIBP 3226 or 1229U91 does not affect the pressor response to electrical stimulation of the entire sympathetic outflow but does inhibit the sustained pressor effect after cessation of the stimulation (93). Thus, perhaps about 30% of sympathetically-mediated vasoconstriction in the rat mesenteric vasculature may result from released NPY, but the pressor response to generalized sympathetic stimulation depends mainly on released norepinephrine. In pigs, studies based on the Y 1 receptor antagonists, SR 120107A and BIBP 3226, have demonstrated that long-lasting vasoconstriction in response to sympathetic stimulation appears to depend at least partly on occupation of Y1 receptors (94,95). In humans, NPY administration produces sustained decreases

Overview of the A.N.S.

51

in the compliance of hand veins, and subconstrictor doses of NPY augmentaladrenoceptor-mediated vasoconstriction (96). In general,NPYappearstoplaylittlerole in tonicsympathetic neurocirculatorytoneor in acute sympathetically-mediated vasoconstrictor responses,whichdependmainlyonagonistoccupationofadrenoceptors; however, NPY, acting at Y 1 receptors, may prolong sympathetically-mediated vasoconstriction. NPYexertsinhibitorymodulationofnorepinephrinerelease, by stimulating inhibitory Y2 receptors. For instance, in human atrial appendage pre-incubated with 3H-norepinephrine, administration of subtype-selective NPY analogsthatbindselectivelytoY2receptorsinhibitselectricstimulationinduced release of radioactivity (97). In PC12 cells, NPY inhibits catecholamine (L-DOPAmine)release, by stimulatingY2receptorsthatexertinhibitory modulation of N-type calcium channels; and inhibits catecholamine synthesis, by stimulatingY3receptorsthatexertinhibitorymodulationoftyrosine hydroxylase by inhibitingL-typecalciumchannels(i.e.,calciumchannels blocked by 1,4-dyhydropyridines) (86,98). T4-[NPY(33-36)]4, competitively antagonizes presynaptic Y2 receptors modulating norepinephrine release ( 9 9 , and one can expect reports about effects of T4-[NPY(33-36)]4 on release of norepinephrine in vivo.

Chromogranin A Chromogranin A is co-localized with NPY and ATP in large dense-core vesicles in chromaffin cells. As for release of NPY, release of chromogranin A probably reflects exocytosis, but also as for NPY, chromogranin A levels in plasma change relatively little during stimuli that produce clear-cut changes in plasma norepinephrine levels (79,82,83). Pancreastatin, a 49-amino acid peptide originally isolated from pig pancreas, derives from chromogranin A. Venous plasma levels of pancreastatin-like immunoreactivity correlate positively with levelsofnorepinephrine(100).Whetherstimulithatincreasesympathetic neuronal outflows also increase plasma pancreastatin-like immunoreactivity is unknown. Afragmentofchromogranin A, calledcatestatin,inhibits invitro secretionofcatecholaminesfromchromaffincells(lOl),possibly by competitively blocking neuronal cholinergic nicotinic receptors (102). Injected in vivo into rats, catestatin inhibits pressor responses to electrical stimulation of sympatheticoutflowsortoadministrationofNPYreceptoragonistsand produces large-magnitude increases in plasma epinephrine and histamine levels. Since pretreatment with a histamine H1 receptor antagonist blocks both the depressor and adrenergic responses, these effects of catestatin appear to result from histamine release.

52

Chapter 2

Non-exocytotic release

Sympathetic nerve endings can also release norepinephrine by calciumindependent,non-exocytoticmechanisms.Onesuchmechanismisreverse transport through the neuronal uptake carrier (103,104). This probably occurs in vivoonly in extraordinarycircumstances,suchasduringanoxicischemia (105,106), where high axoplasmic concentrations of norepinephrine result from disruption of processes that maintain the normal axoplasmic-vesicular gradient in norepinephrine concentrations (107). The hydrophilic nature of catecholaminesandtheirionizationatphysiologicalpHprobablyprevent norepinephrine efflux by simple diffusion. Sympathomimetic amines release norepinephrine non-exocytotically, as discussed below. Increases in intracellular Na' concentrations, such as produced by digitalis glycosides, enhance carrier-mediated efflux of norepinephrine (108). Norepinephrine inactivation Unlikeacetylcholine,whichisinactivatedmainlybyextracellular enzymes,norepinephrineisinactivatedmainlybyuptakeintocellsand subsequent intracellular metabolism or vesicular sequestration (Figure 2- 17). Uptake-l

Reuptake into nerve terminals-Uptake-l-is the predominant means of terminating the actions of released norepinephrine. Uptake-is 1energy-requiring and carrier-mediated. The carrier can transport catecholamines against large concentration gradients. The only common structural feature of compounds that are substrates for Uptake-l is an aromatic amine, with the ionizable nitrogen moiety not incorporated in the aromatic ring. Uptake-l does not require that the compound have a catechol nucleus. Alkylation of the primary amino group decreases the effectiveness of the transport. This explains why sympathetic nerves take up norepinephrine more efficiently than they do epinephrine (109) andwhythey do nottakeupisoproterenol,anextensivelyalkylated catecholamine, at all (1 10,111). Methylation of the phenolic hydroxyl groups also markedly decreases susceptibility to Uptake-l , and so sympathetic nerves do not take up 0-methylated catecholamine metabolites suchas normetanephrine and methoxyhydroxyphenylglycol. Neuronaluptakebydopaminergicneuronsdiffersfromthatby noradrenergic neurons. The former actually take up dopamine more avidly than they do norepinephrine, whereas the latter take up both catecholamines about equally well. Recent molecular genetic findings demonstrating different genes

53

Overview of the A.N.S.

SMOOTH MUSCLE CELL

SYMPATHETIC NERVE EN DIN G Upt ake-l

DOPAC

DHFG

TYR

Upt ake-2

DOPA NMN NE

HVA MHFG

BLOODSTREAM

Figure 2-17 Fate of norepinephrine (NE) released from sympathetic nerve terminals. Most of released norepinephrine undergoes reuptake by Uptake-l. A small portion enters the bloodstream, and a smallportion enters non-neuronal cells by Uptake-2. In the nerve terminal, NE can be taken back up into storage vesicles or can undergo oxidative deamination by monoamine oxidase (MAO) to form dihydroxyphenylglycol (DHPG). Because extraneuronal of catechol-0methyltransferase (COMT), end-products of NE metabolism are 0-methylated, including methoxyhydroxyphenylglycol (MHPG) and normetanephrine(NMN). Dihydroxyphenylacetic acid (L-DOPAC) and homovanillic acid (HVA)are metabolites of dopamine (DA), formed in the axonal cytoplasm after hydroxylation of tyrosine (TYR) by tyrosine hydroxylase (TH) to form dihydroxyphenylalanine (LDOPA)anddecarboxylation of L-DOPAbyL-aromatic-amino-acid decarboxylase (LAAAD). The diagram does not include vanillylmandelic acid (VMA), an 0methylated, deaminated metabolite produced mainly in the liver.

encodingmembranetransporters for norepinephrineanddopaminehave confirmed this pharmacological distinction. Neuronal uptake absolutely requires intracellular K+ and extracellular Na' and functions most efficiently when Cl- accompanies Na'. The transport does

Chapter 2

54

notdirectlyrequireATP;however,maintainingionicgradientsacrosscell membranes depends on ATP, and the carrier uses the energy expended in maintaining the transmembrane Na' gradient to co-transport amines with Na+. Since Uptake-l functions as a first-order kinetic process, the rate of norepinephrine reuptake increases in parallel with increases in norepinephrine (1 12) or release, such as during electrical stimulation of sympathetic nerves exposure of the organism to stressors ( l 13,114). Probably 90% or more of released norepinephrine undergoes neuronal reuptake (33,112115), the efficiency of the reuptake varying among tissues, depending on the width of junctional gaps. In the heart, where about 92% of released norepinephrine is removed by neuronalreuptake(33),reductions in theefficiencyofthetransporter dramatically amplify the amount of norepinephrine delivery to adrenoceptors. This explains cocaine-induced cardiotoxicity. Uptake- 1 blockade also increases the amount of spillover of norepinephrine into the bloodstream for a given amount of release(1 16). Many drugs or in vitro conditions inhibit Uptake-l, including cocaine, tricyclic antidepressants, low extracellularNa' concentrations, Li', and ouabain. Cocaineincreasesnorepinephrineconcentrations in extracellularfluidand thereforeatpost-synapticadrenoceptors;tricyclicanti-depressantsdonot, because administration of tricyclic anti-depressants produces marked concurrent decreases in rates of post-ganglionic sympathetic nerve traffic(1 17- 121). Desipramine-induced blockade of neuronal uptake of norepinephrine augments pressor responses during sympathetic stimulation or administration of catecholamines. Desipramine and other tricyclic antidepressants block uptake by noradrenergic neurons more effectively than they block uptake by dopaminergic neurons. These pharmacological differences also imply distinct transporters for norepinephrineanddopamine.Thehumannorepinephrineanddopamine transporterproteinsinclude12-13hydrophobicandthereforeprobably membrane-spanning domains. This structure differs substantially from that of adrenoceptors and other receptors coupled with G-proteins but is very similar to that of the y-aminobutyric acid, serotonin, and vesicular transporters, suggesting a family of neurotransmitter transporter proteins.

Uptake-2 Non-neuronal cells remove norepinephrine actively by a process called Uptake-2, characterized by the ability to transport isoproterenol, susceptibility to blockade by 0-methylated catecholamines, steroids, and 8-haloalkylamines, and absence of susceptibility to blockade by the Uptake-l blockers cocaine and desipramine (1 22). In contrast with Uptake-1, Uptake-2 functions independently of extracellular Na+. The Uptake-2 carrier has little if any stereoselectivity and has low affinity and specificity for catecholamines. For instance, extraneuronal

Overview of the A.N.S.

55

cellsremoveimidazolinessuchasclonidinebyUptake-2.Theaffinityof Uptake-2 for dobutamine averages about 100 times that of dopamine. WhereasreversetransportviatheUptake-lcarrierrequiresspecial experimental conditions, one can readily demonstrate reverse transport via the Uptake-2 carrier. Thus, during infusion of a catecholamine at a high rate, the catecholamine can accumulatein extraneuronal cells and re-enter the extracellular fluid via the Uptake-2 carrier after the infusion ends. Intracellular metabolism

After neuronal reuptake, norepinephrine in the axoplasm can undergo metabolismcatalyzed by theenzymemonoamineoxidase(MAO)toform dihydroxyphenylglycol or translocation back into the storage vesicles via the vesicularmonoaminetransporter(123,124).Thelatterconstitutesthe predominant pathway. Monoamine oxidase MAOcatalyzestheoxidativedeaminationofdopaminetoform dihydroxyphenylaceticacid(L-DOPAC)andnorepinephrinetoform dihydroxyphenylglycol (DHPG, DOPEG). Because of the efficient uptake and reuptake of catecholamines into the axoplasm of catecholamine neurons, and because of the rapid exchange of amines between the vesicles and axoplasm, the neuronal pool of MAO, located in the outer mitochondrial membrane, figures prominently in the overall functioning of catecholamine systems. Two isozymes of MAO, MAO-A and MAO-B, have been described, based on pharmacological characteristics and subsequent genetic cloning. MAOA predominates in neural tissue, whereas both subtypes exist in non-neuronal tissue. Norepinephrine and epinephrine are substrates for MAO-A, and dopamine is a substrate for both MAO-A and MAO-B. The deaminated products are short-lived aldehydes (Figure 2-18). For dopamine, the aldehyde intermediate, dihydroxyphenylacetaldehyde(DOPAL, DOPALD) is converted rapidly to DOPAC by aldehyde dehydrogenase. For norepinephrine,thealdehydeintermediate, dihydroxyphenylglycoaldehyde (DOPGAL), is converted mainly to DHPGby an aldehyde reductase. The formation of the aldehydes reduces a flavine component of the enzyme. The reduced enzyme reacts with molecular oxygen, regenerating the enzyme but also producing hydrogen peroxide, which may be toxic to cells, because the peroxidation releases free radicals. The aldehyde intermediates may themselves produce toxicity by generating free radicals (125).

56

Chapter 2

MAO-Binhibitorsdelayneurologicaldegeneration in patientswith Parkinson’s disease, possibly by limiting oxidative injury resulting from toxic aldehydes (126,127). The combination of blockade of the vesicular monoamine transporter and of MAO-A leads to substantial buildup of axoplasmic catecholamines. In this setting, norepinephrine can exit sympathetic terminals via reverse transport through the membrane norepinephrine transporter. MAO inhibitors are effective anti-depressants. A phenomenon known as the “cheese effect” limits their clinical use. In patients taking MAO inhibitors, administration of sympathomimetic amines such as in many non-prescription decongestants, or ingestion of foods such as aged cheese, wine, or meat, which contain tyramine, can produce paroxysmal hypertension. Since tyramine and othersympathomimeticaminesdisplacenorepinephrinefromsympathetic vesicles into the axoplasm, blockade of MAO causes axoplasmic norepinephrine toaccumulate,andoutwardtransportofthenorepinephrinestimulates cardiovascular smooth muscle cells, producing intense vasoconstriction and hypertension.Whengivenalone,MAOinhibitorsusuallydecreaseblood pressure and produce orthostatic hypotension, by unknown mechanisms. Aldehyde dehydrogenase and reductase As noted above, the actions of MAO-A lead to formation of aldehyde intermediates, with the deaminated dopamine aldehyde DOPALD undergoing conversiontoDOPACviaaldehydedehydrogenaseandthedeaminated norepinephrinealdehydeDOPEGALconversiontoDHPGviaaldehyde reductase (Figure 2-18). Drugs that inhibit aldehyde reductase increase formation of dihydroxymandelicacid(DHMA),theproductoftheactionofaldehyde dehydrogenase on DOPEGAL (128). Normally DHMA constitutes only a minor neuronal metabolite of norepinephrine(1 28). Asdiscussedaboveand in thechapteraboutetiologicrolesof catecholamines in disease processes, the aldehyde intermediates producedby the actions of MAO on dopamine and norepinephrine are neurotoxic.

Catechol-0-methyltramfirase Catechol-0-methyltransferase (COMT)catalyzestheconversionof norepinephrine to normetanephrine and epinephrine to metanephrine (Figure 219).Uptake-2andCOMTprobablyact in seriestoremoveanddegrade circulating catecholamines. The methyl group donor for the reaction is Sadenosylmethionine.Immunohistochemicalstudieshaveindicatedmainly extraneuronal localization of COMT, which exists at high concentrationsin the

57

Overview of the A.N.S.

/

AldehydeIAldose Aldehyde Dehydrogenase Dehydrogenase Reductase NADH A l NADH d e ? : d z

DHPG DOPACDHMA

\zt:::Aldo=

DOPET

Figure 2-18 Pathways in metabolism of dopamine and norepinephrine after oxidative deamination catalyzed by monoamine oxidase (MAO).Thealdehyde intermediates are unstable.Thefourstableproductsare dihydroxyphenylacetic acid (L-DOPAC),dihydroxyphenylethanol(DOPET), dihydroxymandelic acid (DHMA), and dihydroxyphenylglycol(DHPG).

liver and kidney. 0-Methylation of norepinephrine therefore usually requires extraneuronal uptake. Adrenal chromaffin cells, however, express abundant COMT (129). This explains why a substantial proportion of normetanephrine and virtually all of metanephrine in plasma derives from 0-methylation of catecholamines within the adrenal medulla (130). One clinically important application based on this finding is the extraordinary sensitivity of plasma levels of free metanephrinesin the detection of pheochromocytomas, tumors that synthesize catecholamines and express COMT(1 3 1,132). Vanillylmandelicacid(VMA)and methoxyhydroxyphenylglycol (MHPG), the products of the combined 0-methylation and deamination of norepinephrine, are the two main end-products of norepinephrine metabolism. MHPG has complex origins (133). Most derives from 0-methylation of DHPG produced in sympatheticnerves,withsmallerportionsfromoxidative deaminationofnormetanephrinetakenupfromthecirculationandof normetanephrine produced from norepinephrine after uptake of neuronal or circulatingnorepinephrine by Uptake-2.VMAisformedmainlyifnot exclusively in the liver, including from dehydrogenation of MHPG.

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PhenylethanolammeN-Methvltransferase (PNMT)

Norepinephrine

Epinephrine

S-AdenosYlmethlOnlne S-AdenosylhomOcystelne

S-Adenosylmethlonlne Catechol0-Methyltransferase

Catechol0-Methyltransferase (COMT)

(COMT)

S-Adenowlhomocysteme

Normetanephrine (NMN)

Metanephrine ( W

Figure 2-19 Metabolism of norepinephrine by methylation. Norepinephrine is converted to epinephrine via phenylethanolamine-N-methyltransferase (PNMT)and to normetanephrinevia catechol-0-methyltransferase (COMT). Epinephrineis converted to metanephrine via COMT. The methyl group donor for both COMT and PNMT is S-adenosylmethionine (SAM).

Recycling In cardiac sympathetic nerves, over 90% of norepinephrine removed by neuronal uptake returns to storage vesicles(33,134). The high efficiency of the cell and vesicular membrane transporters ensures that a large proportion released norepinephrine undergoes recycling back into storage vesicles (Figure2- 19). Hightransporterefficiencycountersthehighrateofleakageof norepinephrine from storage vesicles into the sympathetic axoplasm and reduces the impact of transmitter release as a driving force for norepinephrine turnover and synthesis (Figure 2-20). In the cardiac sympathetic neuron, under resting conditions the rate of leakage of norepinephrine from vesicles exceeds by nearly 5-fold the rate of norepinephrine release or neuronal reuptake (33). Leakage of norepinephrine from vesicles presumably reflects a passive process resulting from the high concentration gradient of norepinephrine between the sympathetic axoplasm and the proton-rich interior of the vesicles. Thus, norepinephrine in

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Overview of the A.N.S.

BLOODSTFlEAM DHPG 705

DOPA 107

DOPAC 173

109

NE

DHPG-SO4 68

NMN 7

MHPG 292

-1

CARDIAC MYOCYTE

Figure 2-20 Overviewofthesynthesis,release,re-uptake,turnover, and metabolism of norepinephrine (NE) in cardiac sympathetic nerves. Thicknessof arrows corresponds roughly to the rate of the process, shown in units of pmol/min. Under resting conditions, loss ofmyocardial tissue stores of NE due to imperfect recycling of vesicular NE (reflected in the sum of DHPG, DHPG-S04, NMN, and MHPG production) exceeds by far that due to entry of NE into the cardiac venous drainage (NE spillover). COMT = catechol-0-methyltransferase; DHPG = dihydroxyphenylglycol; DHPG-SO4 = dihydroxyphenylglycol sulfate; DOPAC = dihydroxyphenylacetic acid; MAO = monoamine oxidase; MHPG = methoxyhydroxyphenylglycol; NMN = normetanephrine; TYR = tyrosine; U1 = Uptake-l; U2 = Uptake-2. Modifed from a diagram kindly provided by G. Eisenhofer.

storage vesicles exists in a highly dynamic rather than a static state, exchanging rapidly with norepinephrine in the axoplasm.

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MostoftheDHPGproducedunderrestingconditionscomesfrom norepinephrineleakingfromvesicles,withonlyafractionderivedfrom recaptured transmitter (123,124). Because of the impacts on norepinephrine turnover and synthesis, the high rate of vesicular leakage at first glance would seem inconsistent with cellulareconomy;however,onemayviewthisactuallyasanadaptive mechanism,whichenablesthesympatheticnervoussystemtorespond appropriately to stresses despite relatively limited capacity to increase tyrosine hydroxylase activity. During increased sympathetic outflows, such as during exercise,thecontributionofnorepinephrinereleasetoturnoverincreases, whereas leakage of transmitter remains unchanged(1 12). Thus, the proportionate increase in turnoverissmallerthan in exocytoticrelease.Tomaintain norepinephrinestores,tyrosinehydroxylaseactivityneedincreaseonly in proportion to the smaller increase in turnover than the larger increase in release (32-34). The ability to “gear down” increases in turnover and synthesis in relation to increases in release may provide sympathetic nerves with a capacity for a more extended range of sustainable release rates than otherwise possible. Vesicular monoamine transporter Varicosities in sympatheticnervescontaintwotypesofcytoplasmic vesicles: small dense-core (diameter 40-60 nm) and large dense-core (diameter 80-120 nm). Vesicles generated near the Golgi apparatus of the cell bodies travel by axonal transport to the nerve terminals. Noradrenergic vesicles may also form by endocytosis within the axons. Since reserpine eliminates the electron-dense cores of the small but not the large vesicles, the cores of the small vesicles may represent norepinephrine, whereas the electron-dense cores of the large vesicles may represent additional components. Vesicles in sympathetic nerves actively remove and trap axoplasmic amines. Vesicular uptake favors L- over D-norepinephrine, Mg++ and ATP accelerate the uptake, and reserpine effectively and irreversibly blocks it. The vesicular uptake carrier protein resembles the neuronal uptake carrier structurally. In the brain, mRNA for the vesicular transporter is expressed in monoaminecontainingcellsofthelocusceruleus,substantianigra,andraphenuclei, corresponding to noradrenergic,dopaminergic,andserotonergiccenters. Neurotransmitter specificity appears to depend on the transporter expressed in the cell membrane, rather than on the vesicular transporter expressed within the cell. Cloning studies have revealed the existence of two isoforms of the vesicular monoamine transporter (VMAT). Neurons, whether in the brain or periphery,expressonlytheVMAT-2isoform (135). Incontrast,adrenal

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61

chromaffin cells express both isoforms. Catecholamines are better substrates for 1. VMAT-2 than for VMATReserpine and tetrabenazine effectively block the vesicular transport of aminesfromtheaxoplasmintothevesicles.Thisnotonlyshutsdown conversion of dopamine to norepinephrine but also prevents the conservative recycling of norepinephrine. Reserpine therefore depletes norepinephrine stores. After reserpine injection, plasma dihydroxyphenylglycol levels increase rapidly, reflecting marked net leakage of norepinephrine from vesicular stores, and then decline to very low levels, reflecting the abolition of vesicular uptake and consequently abollition of 8-hydroxylation of dopamine(3 1). ADRENOMEDULLARY HORMONAL SYSTEM

Incontrastwithsympatheticnerves,adrenomedullarycellssecrete catecholamines-in humans mainly epinephrine-directly into the bloodstream. The adrenomedullary system therefore is hormonal. Epinephrine, an agonist at all subtypes of a- and 8-adrenoceptors, affects the function of most body organs. Exogenously administered epinephrine rapidly increases the rate and force of cardiac contraction; increases myocardial cell automaticity; dilates bronchioles and increases the rate of breathing; redistributes blood volume toward the heart, brain, and skeletal muscle and away from the skin, kidneys, and gut; enhances the aggregability of platelets; relaxes smooth muscle of the uterusandgut;increasesbloodglucosebyavarietyofmeansincluding glycogenolysis and antagonizing insulin; dilates pupils; increases activityof the renin-angiotensin-aldosterone system; decreasesserum potassium concentrations; increases the metabolicrate; and produces psychological effects suchas increased alertness, decreased fatigue, and intensification of emotions. Theseeffectswouldbeexpectedusuallytoenhancesurvival in emergencies such as traumatic hemorrhage or antagonistic encounters where the individual senses an overall threat to well-being or survival.

Phenylethanolamine-N-Methyltransferase and Epinephrine Synthesis

Phenylethanolamine-N-methyltransferase (PNMT)catalyzesthe conversion of norepinephrine to epinephrine in the cytoplasm of chromaffin cells.S-AdenosylmethioninedonatesthemethylgroupforPNMTasfor COMT (Figure 2-19). Three types of mechanism regulate PNMT activity-hormones such as glucocorticoids, which reach the adrenal medulla at high concentrations because of the cortical-medullary course of local blood flow; sympathetic preganglionic nerves,whichreleaseacetylcholine in theadrenalmedulla,stimulating

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cholinergic receptors and thereby increasing transduction of the PNMT gene; and intrinsic cell-specific mechanisms that depend on the PNMT gene itself (1 36). In 1966, Wurtman and Axelrod (137) showed that hypophysectomized rats had decreased adrenal content of PNMT and that dexamethasone reversed this abnormality, providing the first evidence that glucocorticoids contribute to tonic PNMT activity (137). Almost 25 years later, Ross and co-workers (138) reported that the promoter region of the PNMT gene contains a corticosteroidresponsiveelement (CRE), a basisforadrenocorticalregulationof adrenomedullary PNMT. Since patients with hypocorticotrophic hypopituitarism have low plasma epinephrine levels (1 39), the maintenance of normal levels in humans requires intact pituitary-adrenocortical function. In additiontoCRE,glucocorticoidsregulatePNMTactivityviaeffectson production of S-adenosyl methionine and on expression of the immediate early gene, Egr- 1 (140). Acetylcholine, released in the adrenal medulla by stimulation of the nerve supply from the splanchnic nerve, also increases transcription of the PNMT gene, by occupying muscarinic and nicotinic receptors (140). Separate regionsin the promoter region of the PNMT gene contain elements sensitive to muscarinic and nicotinic stimuli. NON-NEURONAL CATECHOLAMINE SYSTEMS

A paradox of clinical neurochemistry is that plasma levels and urinary excretion rates of dopamine and its metabolites exceed those of norepinephrine anditsmetabolites(141).Ifdopaminewereconvertedefficientlyto norepinephrine in sympatheticnervesandtheadrenalmedulla,andsince dopaminergic centers in the brain contribute to only a minor extent to plasma levels or urinary excretion of these compounds, neither dopamine release from noradrenergicterminalsnordopaminerelease in thebrainwouldaccount satisfactorily for the high rates of dopamine production and metabolism in the body as a whole. The resolution of this paradox is that a substantial amount-in fact, most-of dopaminesynthesisandmetabolism in thebodyoccurs in nonneuronal cells. Non-neuronal cells generally do not store newly-synthesized dopamine, which may exit the cells by reverse transport via the Uptake-2 carrier or undergo intracellular conversion to dihydroxyphenylacetic acid (L-DOPAC), homovanillic acid (HVA), or dopamine sulfate. This explains both the high plasma levels and high rates of urinary excretion of these compoundsin humans (142). Thissectiondevelopsthethemesthatsubstantialproductionof catecholamines occurs in non-neuronal cells and that, in particular, dopamine

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63

outside the brain functions as an autocrine/paracrine effector in a system distinct from both the sympathetic nervous and adrenomedullary hormonal systems. Non-Neuronal Catecholamine Synthesis

Investigators until recently viewed dopamine as only an intermediary in the biosynthesis of norepinephrine in sympathetic nerves and of epinephrine in adrenomedullary cells. Recent evidence has supported a physiological role for dopamine as an autocrine/paracrine hormone that influences Na' disposition in the periphery. Most of this dopamine does not derive from either the adrenal medulla or sympathetic nerves but from biosynthesis in non-neuronal cells. For instance, renal denervation does not affect either dopamine excretion or renal interstitial concentrations of dopamine (143). As discussed elsewhere in more detail, an autocrine/paracrine dopaminergic system appears to exist along with thesympathoneuralnoradrenergicandhormonaladrenomedullarysystems (Figure 2-21). Parenchymalcells in severalorgansexpressPNMT(144,145)and presumably synthesize epinephrine extraneuronally, including in the human heart and lung (146,147). Norepinephrine can undergo methylation also by the action of a less specific methyltransferase, NMT, which N-methylates many amines. PNMT can be distinguished from NMT by the ability of NMT to convert dopamine to epinine andby selective effects of PNMT blockers. Since sympathectomy does not alter PNMT activity in masseter muscle of rats with superior cervical ganglionectomy, and 6-hydroxydopamine treatment increases atrialPNMTactivity,PNMTcanexistasanon-neuronalenzyme. In parenchymal organs, as in the adrenal gland, glucocorticoids induce PNMT activity (148). Extra-adrenal synthesis of epinephrine probably contributes little tocirculatingepinephrineconcentrations,whichareverylow in adrenaldemedullated rats (1 49) and in adrenalectomized patients (1 50,15 1).

Kidneys The renal DOPA-dopamine system constitutes the most well studied non-neuronalcatecholaminesystem(Figure2-22).L-DOPA in thetubular filtrate undergoes Na+-dependent uptake into proximal tubular cells. Dopamine formed intracellularly by decarboxylation of the L-DOPA can exit the cell to occupy basolateral membrane D l and D2 receptors and apical membrane D1 receptors. The former inhibit Na+/K+ ATPase and the latter transmembrane

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e- 1

Autocrine/Paracrine Hormonal Neuronal NE EPI

DA

Figure 2-21 Three peripheral catecholamine systems. In the sympathetic nervous system, norepinephrine (NE) is released from sympathetic nerve terminals and inactivated by neuronal reuptake (Uptake-l). In the adrenomedullary hormonal system, epinephrine (EPI) is released from the adrenal medulla and inactivated mainly by extraneuronal uptake from the circulation (Uptake-2). In the DOPAdopamine (DA) system, DA acts locally as an autocrine/paracrine factor and is inactivated especially by monoamine-preferring phenolsulfotransferae (m-PST).

Na+-H+exchange.Bybothactions,renaldopamineactsasan autocrine/paracrine agent that augments natriuresis. At a relatively low “renal dose” (2-5 pg/kg/min), infused dopamine produces renal vasodilation, diuresis, and natriuresis. At a moderate dose (5-15 13pg/kg/min), tachycardia and increased cardiac contractility occur, from adrenoceptor stimulation. High doses (2 about 10 pg/kg/min) elicit systemic vasoconstriction,froma-adrenoceptoragonism.Theminimumplasma dopamine concentrations required to produce endocrine, renal, and hemodynamic effects during dopamine infusion far exceed those actually attained during exposure to most stressors (1 52). In isolated renal cortical tubules, L-DOPA undergoes uptake by an active transport process inhibited by corticosterone and by organic cation transport inhibitors in a pH-dependent manner, the latter consistent with uptake by an organic cation-H+ exchanger (153-155). Outward transport of the newly-formed DA appears to depend on a Na+-H+ exchanger, since amiloride reduces renal dopamine outflow. ThekidneyexpressesaCAMP-regulatedphosphoprotein,termed DARPP32(156).PKA-inducedphosphorylationofDARPP32inhibitsa

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65

Figure 2-22 The renal DOPA-dopamine (DA)system. In thissystem, renal production of DA, the only natriuretic catecholamine, depends on synthesis of DA in proximal tubular cells after uptake of L-DOPA from the circulation. The natriuretic effect of DA results at least partly from occupation ofDA receptors, leading to inhibition of Na+/K+ ATPase. protein phosphatase, PPI, whichin turn dephosphorylates and activates Na+/K+ ATPase.a-AdrenoceptoragonistscandephosphorylateDARPP32,via calcineurin. Thus, neuronal norepinephrine and autocrine/paracrine dopamine exert opposing effects on intracellular signaling mechanisms regulating Na+/K+ ATPase and sodium excretion. High salt intake increases urinary dopamine excretion and decreases renal interstitial concentrations of dopamine, as indicated by in vivo microdialysis (144). According to the model in Figure 2-22, increased entry of Na+ via the basolateralmembranewouldpromoteuptakeofcirculatingL-DOPAby proximaltubularcells,andincreasedNa+inthetubularfiltratewould simultaneouslypromotedopamineegress,viacouplingtotheNa+/H+ exchanger. In response to gludopa, renal dopamine excretion increases proportionatelymorethandoesinterstitialdopamine,consistentwith preferential release of renal dopamine into the tubular lumen.

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Gastrointestinal tract Both in laboratory animals (1 53) and in humans (1 54), more production and metabolism of dopamine takes place in mesenteric organs than in the brain, sympathetic nervous system, or adrenal medulla. Non-neuronalcellsconstituteamajorsourceofdopamine in the gastrointestinal tract. High concentrations of dopamine are foundin gastric juice of chemically sympathectomized as well as in intact rats (155). Gastric parietal cells (1 56) and pancreatic exocrine cells (1 57) contain tyrosine hydroxylase, as evidenced by immunostaining (much of which persists even after chemical sympathectomy), tyrosine hydroxylase enzyme activity, detectable dopamine, and immunostaining for the plasma membrane dopamine transporter as well as the vesicular monoamine transporters VMAT-l and VMAT-2. Moreover, gastric mucosal cells take up [3H]-dopamine, and GBR 12909, a specific inhibitor of the membrane dopamine transporter, blocks this uptake. Duodenal and gastric secretion of bicarbonate alkalinizes the mucus gel adherenttomucosalcells,protectingthemfromacidicinjury.D1receptor stimulation increases duodenal bicarbonate secretion in rats. In enterocytes these agonistsincreaseproductionofCAMP.PeripheralCOMTinhibitionby nitecapone also increases bicarbonate secretion. Thus, dopamine may play a role in a “brain-gut axis” that modulates bicarbonate secretion (1 58- 160). ExtraneuronaluptakeofL-DOPAandsubsequentintracellular decarboxylationconstitutesanotherpotentialnon-neuronalmechanismfor dopamine production in the gastrointestinal tract. Thus, about 112 of dopamine sulfateproduction in mesentericorgansappearstoderivefromuptake, decarboxylation, and sulfoconjugation of circulating L-DOPA (161). NON-CHOLINERGIC, NON-ADRENERGIC NEUROTRANSMISSION Nitric oxide

Nitric oxide (NO) may play several roles in autonomic neuroeffector function. These include: (1) as an endogenous vasodilator; (2) as the mediator of acetylcholine-inducedvasodilation; (3) as a modulatorofreleaseof norepinephrine from sympathetic terminals; (4) as a modulator of effects of catecholamines at cardiovascular smooth muscle cells; and (5) from effects of NO in the central nervous system on autonomic outflows. Much of the evidence that NO acts in vivo as an endogenous vasodilator derives from effects of N(G)-monomethyl-L-arginine (LMMA), a stereospecific inhibitor of NO synthase. Intravenous infusion of LMMA in humans increases blood pressure and reflexively decreases skeletal muscle sympathetic activity (162,163) and plasma norepinephrine levels (1 64). When infused into the

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brachial artery of healthy subjects during blockade of norepinephrine releaseby bretylium, l3-adrenoceptors by propranolol, and a-adrenoceptors by phentolamine,LMMAmarkedlyincreasesforearmvascularresistance, confirming alocalvasodilatoreffectofendogenousNOindependentof adrenoceptors or exocytotic release of norepinephrine (165). Analogously, brachial intra-arterial infusion of LMMA increases digital vascular resistance and decreases forearm and cutaneous blood flow (166). ConsistentwiththeviewthatNOexertstonicvasodilation,mice overexpressing endothelial NO are hypotensive (167), and mice with knockout of endothelial nitric oxide synthase are hypertensive (168). Several studies have reported findings supporting the concept that NO opposes noradrenergic neurogenic vasoconstriction (6,7,169). After rhythmic handgrip exercise of one arm to fatigue, followed by post-exercise ischemia, both intra-arterial LMMA and intra-arterial atropine infused into the opposite arm abolish the increase in blood flow in the opposite arm (1 70), indicating that release of NO, via occupation of cholinergic muscarinic receptors, mediates active vasodilation that counters the vasoconstriction produced by activation of sympathoneural outflows. Consistent with this view, patients with impaired endothelialfunctionhaveaugmented sympathetically-mediated coronary vasoconstriction (1 7 1). As noted above, occupation of muscarinic cholinergic receptors increases generation of NO, which, via production of cGMP, determinesin large measure the vasodilator effects of acetylcholine. Thus, in humans, brachial intra-arterial administration of LMMA inhibits vasodilation produced by acetylcholine (56). In cardiac myocytes, norepinephrine promotes growth, as indicated by incorporation of [3H]-leucine. Since LMMA augments and the NO donor Snitroso-N-acetyl-d,L-penicillamine(SNAP)inhibitsnorepinephrine-induced incorporation of [3H]-leucine, NO may limit norepinephrine-induced cardiac hypertrophy (1 72). Numerous brain centers that participate in autonomic outflows contain nitric oxide synthase, and many studies have assessed effects of intracerebroventricular, intravenous, or local administration of NO analogs or LMMA on blood pressure and sympathoneural outflows; however, the rapidly burgeoning literature on this topic includes several inconsistencies. In the pig rostral ventrolateral medulla (RVLM), the site of origin of most descending fibers to sympathetic preganglionic neurons, LMMA enhances renalsympathoneuralresponsestohypoxia,consistentwithNO-induced buffering of hypoxia-induced activation of sympathetic outflows (173). In the rat RVLM, microinjection of L-arginine decreases blood pressure and renal nerve activity (174), supporting an inhibitory effect of NO on RVLM function. In anesthetized cats, RVLM microinjection of NG-nitro-L-arginine to inhibit NO synthesis increases thoracic sympathetic nerve traffic, and microinjection of the

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NO donor compounds glyceryltrinitrate, S-nitroso-N-acetylpenicillamine, or sodium nitroprusside decreases sympathetic traffic (175,176). Injection of NO donors into the caudal ventrolateral medulla (CLVM) reverses the effects of injection of the drugs into the RVLM (176). In the rabbit RVLM, however, microinjection of sodium nitroprusside increases renal nerve activity and blood pressure, microinjection of L-arginine produces slight decreases in values for these variables, and microinjection of N(G)-nitro-L-arginine methyl ester (L-NAME) produces substantial decreasesin a pressor and blood pressure and renal nerve activity. These findings suggest sympathoexcitatory action of NO in the RVLM (1 8 1). Microinjection of L-arginine into the rat nucleus of the solitary tract (NTS), the site of the initial synapse for baroreflex buffering of blood pressure and sympathoneural outflows, decreases blood pressure and renal nerve activity (177), suggesting a facilitatory effect of NO on NTS function. In rabbits, NTS microinjection of LMMA increases renal nerve traffic and blood pressure(1 78), supporting this idea; however, microinjection of theNO donor NOC l 8 into the rat NTS increases blood pressure and renal nerve activity, and microinjection of L-NAMEdecreasesvaluesforbothvariables,whichwouldsuggestthe opposite-release by NO of inhibitory modulation by the NTS (1 79). In the hypothalamic paraventricular nucleus (PVN) of rats, microinjection of the NO donor sodium nitroprusside, decreases renal nerve activity and blood pressure,andmicroinjectionofNomega-nitro-L-argininemethylester(LNAME) or of LMMA, both inhibitors of nitric oxide synthase, increases renal nerve activity and blood pressure (180,18 1). At the risk of oversimplification, it appears that NO usually inhibits functionsofbrainstemregionsthatparticipate in regulationofcentral sympathetic outflows (Figure 2-23). Thus, in the PVN and RVLM, NO may elicit sympathoinhibition and decreased blood pressure, and in the NTS and CVLM, NO may elicit sympathoexcitation and increased blood pressure. Given these different effects, which appear to depend on the particular brainstem region under study, one might predict inconsistency in the results of studies using intracerebroventricular (i.c.v.) injection of drugs to assess “overall” function of NO in thecentralnervoussystemonsympatheticoutflows.Theresearch literature to date fits with this prediction. In rats, acute i.c.v. administration of L-NAME increases blood pressure (1 82); however, chronic i.c.v. administration of L-NAME or LMMA produces little or no changes in blood pressure or plasma norepinephrine levels (1 83,184). In cats, acute i.v. administration of NG-nitro-L-arginine does not affect cardiac sympathetic nerve activity (185). In rabbits, neither NG-nitro-L-arginine nor 7-nitroindazole, another N O synthase inhibitor,affectsrenalsympatheticnervetraffic(186). In pigs,i.c.v.7nitroindazole elicits only slight increases in renal sympathetic nerve activity and does not affect blood pressure (187). And in humans, i.v. administration of

69

Overview of the A.N.S.

LNO

PVN

NO-

+

1 NO

-?

4 +

1

+

+

CVLM (A1 )

SNS

Figure 2-23 Possible central neural sites of action of nitric oxide (NO) that would affect sympathetic nervous system outflows. These sites includetheparaventricular nucleus of thehypothalamus (PVN), nucleus of the solitary tract (NTS), rostral ventrolateral medulla (RVLM), and caudal ventrolateral medulla (CVLM).

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LMMA increases blood pressure and decreases skeletal muscle sympathetic nerve traffic (163), as would be expected from blockade NO of production in the periphery. Endothelins

Endothelial cells also release peptides called endothelins, which occur in threeisoforms-ET-l,ET-2,andET-3.Endothelin-l,whichissecreted abluminally, binds to endothelin A and B2 receptors on vascular smooth muscle cells and to B1 receptors on endothelial cells. In a manner somewhat analogous tonorepinephrine,stimulationofendothelinAandB2receptorsinduces vascular smooth muscle contraction and proliferation, whereas stimulation of1B receptors induces relaxation, possibly via increased generation of nitric oxide (188). The possible roles of endothelin in neurocirculatory regulation remain poorly understood. The recent introduction of endothelin receptor antagonists and of knockout mice may help this situation. Surprisingly, despite ET-l acting as a potent pressor, mice with knockout of the ET-l gene have hypertension. Although the mechanism of hypertension is unknown, one possibility is that congenital ET- 1 deficiency increases sympathetic neuronal outflows(1 89). Postganglionic sympathetic nerves express ET-1 (1 90); however, effects of ET- 1 on sympathetic neurotransmission and norepinephrine release appear complex (1 90). ADRENOCEPTORS

Adrenoceptors in the brain and periphery mediate the physiological effects of catecholamines. The myriad different effects exerted by only three endogenous catecholamines-norepinephrine, epinephrine,and dopamine-in different organsdependonthenumeroustypesandsubtypes of adrenoceptorsand intracellular mechanisms (Tables 2-2 and 2-3). Becauseofdifferentinvestigativetraditions,mosttextsconsider adrenoreceptors for norepinephrine and epinephrine separately from receptors for dopamine. This presentation includes receptors for all three catecholamines. Alladrenoceptorsshareseveralstructuralcharacteristics-anaminoterminal, glycosylated polypeptide chain from the cell membrane extending into the extracellular fluid; 7 polypeptide membrane-spanning domains, each domain consistingofabout20-28hydrophobicaminoacids in a na - h e l i c a l arrangement, with highly conserved sequences; and a long carboxy-terminal polypeptide chain extending from the internal surface of the cell membrane into the cytoplasm. The membrane-spanning domains determine the ligand binding characteristics of the receptor. The cytoplasmic domains, comprising three loops and the tail ending in the carboxy terminus, regulate specific coupling with G proteins and phosphorylating enzymes in the cascade of intracellular events

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leading to cellular activation or inhibition. The carboxy terminal tail, which contains a serine- and threonine-rich domain, is a site of phosphorylation by protein kinases such as protein kinase C, R-adrenergic receptor kinase (BARK), and cyclic AMP-dependentprotein kinase. Adrenoceptors also share the same process for transducing signals to alter cellular functions-via G-proteins (guanine-nucleotide regulatory proteins), located near the receptor on the inner portion of the cell membrane. G-protein complexes consist of an a subunit, responsible for the specificity of the Gprotein,and R and y subunits.TheheterotrimericG-proteinsconstitutea “superfamily,” with multiple subunits. Differences in the effects of norepinephrine and epinephrine result from different actions at two types of receptor, a and R. In general, R-adrenoceptors mediate the positive inotropic and chronotropic effects of catecholamines in the heart; stimulation of vascular a-adrenoceptors produces vasoconstriction; and stimulationofvascular R-adrenoceptors-especially in skeletalmuscleproduces vasodilation. Non-specific a-blockers include phenoxybenzamine and phentolamine, non-specific R-blockers include propranolol and timolol, nonspecific a-agonists include norepinephrine, and non-specific R-agonists include isoproterenol.Asnotedabove,epinephrinestimulatesboth a- and Radrenoceptors. Differences in effects of dopamine also result from different actions at two families of receptor, as discussed below. At pharmacological concentrations, dopamine also stimulates a-and R-adrenoceptors.

Adrenoceptor Subtypes

a-Adrenoceptors Stimulation of eitherai- or a2-adrenoceptors on vascular smooth muscle cells elicits vasoconstriction. In humans, ai-adrenoceptors play relatively minor roles in mediating catecholamine effects in the heart and kidneys but play an important role in regulation of vascular tone. There is little convincing evidence for pre-synaptic ai-adrenoceptors. In the periphery, a2-adrenoceptors are located mainly pre- and extrasynaptically and can exert either stimulatory or inhibitory effects, depending on the cell type on which they are located. Thus, occupation of a2-adrenoceptors onvascularsmoothmusclecellselicitsmuscularcontraction,whereas occupationofa2-adrenoceptorsonsympatheticnerveterminalsinhibits exocytotic release of norepinephrine. The three subtypes of a2-adrenoceptor all couple via pertussis toxinsensitive Gi and G, G-proteins to inhibit adenyl cylcase, activate receptoroperated membrane K+ channels, and inhibit voltage-sensitive Ca++ channels. a2~-Adrenoceptorshave lowaffinityforprazosinandhighaffinityfor

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TABLE 2-2 Adrenergic Receptors

2d Msg. Antagonist Agonist PLC-R PLC4 PLC4 PLC4 Inh. AC Inh. AC Inh. AC Inh. AC

Phenylephrine Prazosin Tamsulosin WB4101 (Low affinity) Phentolamine a-MethylNorepinephrine Oxymetazoline BRL 44408 Prazosin* ARC 239 Prazosin*

AC AC AC AC

Isoproterenol Propranolol Dobutamine Metoprolol Terbutaline BRL 37344

AC AC AC Inh. AC Inh. AC Inh. AC Inh. AC

Fenoldopam SCH 33390

Bromocriptine Raclopride Haloperidol AJ 76 Clozapine

(*) Prazosin also blocks ai-adrenoceptors non-selectively.

oxymetazoline and yohimbine, whereas a2~-adrenoceptors have high affinity forprazosin(whichalsoblocks a 1-adrenoceptors)andlowaffinityfor oxymetazolineandyohimbine.a2~-Adrenoceptorsappearresponsiblefor centrally-mediatedhypotensiveresponsestoa2-adrenoceptoragonists(in contrast with suggestions that these agonists work byway of interactions with imidazoline receptors) and for sedative, anesthetic-sparing, and analgesic effects

73

Overview of the A.N.S.

TABLE 2-3 Adrenoceptor Effects in Various Organs

Organ

Inhibitor

Parameter

Rate Heart Contractility Conduction Automaticity Cor. Artery Smooth Muscle NorepinephrineRelease Vascular Resistance Renal Na’ Reabsorption ReninSecretion NorepinephrineRelease SkeletalMuscle Vascular Resistance K+ Uptake NorepinephrineRelease Adipose Tissue Lipolysis Aldosterone Secretion Adrenal Gastrointestinal BicarbonateSecretion Motility Vascular Resistance Glucose Production Liver Tracheobronch. SmoothMuscle Lungs Pancreas SecretionInsulin Secretion Amylase Salivary Viscous Saliva Secretion Eccrine Skin Sweat Muscle Pilomotor Ejaculation Genitourinary GenitourinarySmoothMuscle Platelet BloodElementsAggregation CiliaryMuscle Eye Muscle) (Radial Iris Vigilance Central Nervous Ventilation Vasopressin Secretion Prolactin Secretion Growth Hormone Secretion Secretion CRH

132 a2 D1 D1 D2 a1

D2 132

a2 D2 a1 a 2 13

132 13

132 a2

a1

“I a1 CY-1

a1

132

a2 a1 a1

a2 132 a2

132 a1 131

D2 a2 a1

Chapter 2

74

Melatonin Synthesis Emesis

R D2

of a2-adrenoceptor agonists. Whether the pre-synaptic a2-adrenoceptors on sympathetic nerve terminals are structurally unique is unknown. Mice with knockout of the a2~-adrenoceptor haveincreased systolic pressure, heart rate, and plasma norepinephrine levels (191). Agonistoccupationofa2-adrenoceptorsinhibitsadenylcyclase by interactionwithaninhibitoryG-protein, Gi. Thisdecreasesintracellular formation of cyclic AMP and therefore decreases activity of protein kinase A. Themechanismforvasoconstrictioninducedbystimulation of a2adrenoceptors has not been established. Agonist occupation of ai-adrenoceptors leads to a different cascade of intracellulareventsfromthatconsequenttoagonistoccupation of Radrenoceptors (Figure 2-24). The ai-adrenoceptor is linked to a different Gprotein, G,,. Occupation of the receptorby the agonist leads to activation of the G-protein by GTP hydrolysis. This activates phospholipase C, which catalyzes thehydrolysis of phosphatidylinositol4,5-diphosphatetoformtwoactive subunits,inositoltriphosphateanddiacylglycerol.Diacylglycerolactivates protein kinase C (PKC), leading to cellular activation by unclear mechanisms. Inositol triphosphate binds to another receptor on the endoplasmic reticulum, releasing Ca++ from the stores into the cytoplasm, also activating the cell.

J-Adrenoceptors G, is the G-protein responsible for cellular activationupon occupation of R-adrenoceptors (Figure 2-25). Adjacent to the G-protein complex is adenyl cyclase, which spans the cell membrane. Under resting conditions, guanosine diphosphate (GDP) binds to the G-protein. Binding of the agonist to the receptor results in a receptor-ligand complex. In the presence of guanosine triphosphate (GTP), receptor occupation results in substitution of GTP for GDP at the binding site of the G-protein. This activates the G-protein. The activated as subunit separates from the R and y subunits, stimulating adenyl cyclase, which catalyzes the synthesis of cyclic AMP from ATP. Aslong as GTP isboundtothe a, subunit,cyclicAMPcanbe generated.TheprocessceaseswhentheGTPboundtothe as subunit is converted to GDP, inactivating both the G-protein and the cyclase. Cyclic adenosine monophosphate, or (cyclic AMP, CAMP), an intracellular “second messenger” (the first messenger being the hormone binding to the receptor), stimulates cyclic AMP-dependent protein kinase (protein kinase A, PKA), a

75

Overview of the A.N.S.

pa, -AGONIST

.c

e.g., PH€NYLEPHR/NE PHOSPHOLIPASE C

CONTRA CTION ENDOPLASMlC RETICUL UM

Figure 2-24 Intracellular events after occupation of membrane ai-adrenoceptors on vascular smooth muscle cells. tetramer including two regulatory and two catalytic subunits. Binding of CAMP to the regulatory subunits of PKA releases them, leading to phosphorylation of manyproteins,evokingchanges in cellularactivitysuchascontractionor secretion. PKA also catalyzes phosphorylation of the receptor, desensitizing Radrenoceptor-mediated processes. The phosphorylation appears to change the conformation of the as subunit, interfering with the function of the G-protein. Other mediators of desensitization includeR-adrenergic receptor kinase (BARK) nd the intracellular protein, R-arrestin. Agonist occupation of all R-adrenoceptor subtypes stimulates adenyl cyclase. Whereas activation of l32-adrenoceptors on myocardial smooth muscle cells stimulates cellular contraction, activation of R2-adrenoceptors on vascular smooth muscle cells causes vascular relaxation. Several polymorphisms of the R2-adrenoceptor have been described. These include a Thr-to-Ile switch at position 164 in the fourth transmembrane spanning domain, Arg or Gly at amino acid16 and Gln or Glu at amino acid 27 in the amino terminus of the receptor, and an Arg or Cys at position 19 of a 5’ leading cistron 102 base pairs upstream of the receptor coding region (192). In mice, the Thr-to-lle switch at position 164 is associated with decreased resting heartrate,decreasedvaluesforindicesofcontractility,anddecreased

76

Chapter 2

4” B-AGONIST f

e. g . , ISOPROTERENOL

U

%

GTP

ADENYL CYCLASE

GDPCAMP ATP

l

I+

I

I Ca*

ACTOMYOSIN

Figure 2-25 Intracellular events after occupation of membrane P-adrenoceptors on myocardial cells. isoproterenol-stimulatedadenylcyclaseactivity.Therolesofthese polymorphisms in influencing effects of catecholamines on cardiac functionin humans remains unknown. Fat cells such as in brown adipose tissue possess high concentrations of 03-adrenoceptors. A single residue substitution (Trp to Arg) at position 64 has been associated with a tendency towards obesity in humans; however, whether this substitution actually affects caloric balance and lipolysis remains unknown (193,194). The human heart also contains functional k~-adrenoceptors, which appear to exert negative inotropic effects (195). Genetically obese mice or mice made obese by high-fat feeding have decreased adipocyte expression of all three sub-types of 0-adrenoceptors. Adrenoceptor desensitization, resensitization, and sensitization The terms “up-regulation’’ and “down-regulation” have been used to describechanges in boththenumbers of membrane-boundreceptors,as quantifiedfromligand-bindingstudies,andchanges in totalnumbers of receptors in the cells. Adrenoceptordesensitizationreflectsseveralprocesses,including phosphorylation of the receptor, sequestration (agonist-induced dissociation of the receptor from the cell membrane), inactivation of intracellular messengers, anddecreasedsynthesisofreceptorprotein.Onecanreadilydemonstrate

Overview of the A.N.S.

77

desensitization of B-adrenoceptor-mediated responses (e.g., CAMP generationin response to application of a R-adrenoceptor agonist)in in vitro preparations, and a large body of research has concentrated on mechanisms of this phenomenon. Patientswithheartfailure,aconditionassociatedwithmarkedlyincreased cardiac spillover of norepinephrine, have low numbers of fl-adrenoceptors on (196,197). 81-adrenoceptor lymphocytesand in myocardialbiopsytissue numbers seem decreased selectively in this setting. In contrast, relatively few studies have concentrated on desensitization of responses mediated by a-adrenoceptors, and the available literature about aadrenoceptordesensitizationhasbeeninconsistent.Desensitizationof aladrenoceptor-mediated responses is thought to be analogous to desensitization of R-adrenoceptor-mediated responses, with the receptor uncoupled from the Gprotein due to phosphorylation of the receptor by PKA or PKC. Whether a2adrenoceptor numbers or affinities are subject to up- and down-regulation has been unclear. Homologous desensitization refers to a situation where production of an intracellular second messenger, such as cyclic AMP, decreases in response to stimulation of specific receptors but not in response to stimulation of other receptorsusingthesamesecondmessenger.Homologousdesensitization therefore is agonist-specific. Heterologous desensitization entails attenuated responsestoallagonistsusingthesamesecondmessenger.Heterologous desensitization is therefore agonist-nonspecific. Several mechanisms of homologous desensitization have been proposed, and whereas evidence for eachhas been obtained in in vitro systems, the roles of thesemechanisms in vivoisincompletelyunderstood.Onemechanismis internalization, where the number of receptor binding sitesin the cell membrane decreases and the numberin the cytosol increases. A second form of homologous desensitization is by “uncoupling,” where the receptor dissociates from its G-protein. Uncoupling is an integral part of the normal cascade of events after occupation of receptors that use G-proteins, because after the protein binds GTP, not only is the formation of second messenger enhanced, but also the G-protein-GTP complex decreases the affinity of the receptor for the agonist. Phosphorylation of the receptor can produce this formofdesensitizationbyuncoupling. BARK phosphorylatestheagonistoccupied form of the B-receptor, decreasing the affinity of the receptor for the agonist. Homologous desensitization by DARK is thought to occur only when thereceptorisoccupied,andthephosphorylationmaydependonanother endogenous compound, R-arrestin. Clinically relevant research about sensitization and desensitization has SO far been limited mainly to adaptive responses to exogenously administered pharmacologic agents. Mechanisms of desensitization resulting from chronically repeated episodes of sympathetically-mediated norepinephrine release, and

78

Chapter 2

mechanisms of denervation supersensitivity, originally described by Bernard and Cannon ( 1 9 9 , remain obscure. Resensitizationoccursrapidlyuponremovaloftheagonist,bythe actions of phosphatases that catalyze dephosphorylation of the receptor (198). Thephosphatasesarelatent,membrane-associatedmembersofthePP-2A family. One, designated the G protein-coupled receptor phosphatase (GRP), has theabilitytodephosphorylatenotonlytheBARK-phosphorylated R2adrenoceptorbutalsotheBARK-phosphorylateda2c-adrenoceptor. Resensitization by dephosphorylation appears to require sequestration of the receptor from the membrane, into a cytoplasmic population of vesicles. Blockade of ganglionic neurotransmission augments pressor responses to vasoconstrictorssuchasnorepinephrine(199).Althoughthesefindingsare consistent with al-adrenoceptor up-regulation after blockade of exocytotic norepinephrine release, interference with baroreflex buffering of blood pressure can also explain them. During acute ischemia, the number of myocardial aladrenoceptors, as assessed by 3H-prazosin binding, increases, and increased a ~ adrenoceptor-mediated responsiveness may contribute to the pathophysiologic changes attending ischemia and reperfusion. Dopamine Receptors

Fivestructurallydistinctdopaminereceptorsubtypeshavebeen identified, in twofamilies,called“Dl-like’’and“D2-like”(Table2-2). FenoldapamstimulatesandSCH23390blocksDl-likereceptors,and bromocriptinestimulatesanddomperidoneandracloprideblockD2-like receptors. Renal, mesenteric, coronary, and cerebral arteries possess D 1 -receptors, withreceptorstimulationproducingvasodilationdirectly.D2-receptors in gangliaandonsympatheticnerveendingsexertinhibitorymodulationof norepinephrine release, producing vasodilation indirectly. Whether beneficial cardiovascular effects of dopaminein the treatment of heart failure result directly fromincreasedcontractility,viabindingtomyocardialdopamineor Badrenoceptors, or indirectly, from vasodilation, increased renal blood flow, and natriuresis, remains unclear. AUTONOMIC PHARMACOLOGY Physiological Effects of Catecholamines

Catecholamines affect cardiovascular function by at least three general mechanisms: actions at cardiovascular adrenoceptors, eliciting changesin cardiac andvascularfunctiondirectly;actions in thenervoussystem,influencing

79

Overview of the A.N.S.

TABLE 2 4 Epinephrine Hormonal Effects

Cardiovascular

Increased Heart Rate Increased Myocardial Automaticity Increased Myocardial Contractility Skeletal Vasodilation Cutaneous Vasoconstriction Glucose

Increased Glucose Glycogenolysis Insulin Antagonism Blood Components

Increased Platelet Aggregability Leukocyte “Pavementing” Gastrointestinal

Decreased Gut Motility Pulmonary

Bronchodilation Hyperventilation PsychologicaUBehavioral

Alertness Emotional Intensification Anti-Fatigue Effect Metabolic

Increased Metabolic Rate Increased Lactate Production Hypokalemia

80

Chapter 2

sympathoneural and adrenomedullary outflows and activities of several other stress systems of the body; and actions in the kidney, affecting renal handling of sodium and thereby blood volume and pressure. Epinephrine exerts numerous hormonal effects (Table 2-4). Circulatory effects include increased cardiac output, which enhances delivery of oxygen and glucosethroughoutthebody;redistributionofbloodvolumetothe cardiopulmonary area, which preserves perfusion of the heart and brain; and increased skeletal muscle vasodilation and cutaneous, renal, and splanchnic vasoconstriction, which support increased skeletal metabolism during “fight or flight” behaviors. Epinephrine induces relatively small changes in pulmonary, cerebral, and coronary vascular resistance, due to complex interactions between adrenoceptor-mediatedactionsandeffectsofalterations in myocardial metabolism, as discussed above. Systemicinjectionofnorepinephrineproducesvirtuallyuniversal vasoconstriction.Onemustbear in mind,however,thatnorepinephrine functions in the body mainly as a neurotransmitter, not as a hormone (Table 15). The increased blood pressure stimulates arterial baroreceptors, and heart rate tends to decrease reflexively. Thus, althoughin suitable preparations stimulation of a-adrenoceptors increases cardiac contractility, baroreflexes usually mask the cardiaceffectsofinjecteda-adrenoceptoragonists.Cardiacresponsesto circulatingepinephrineresemblethoseproducedtocardiacsympathetic stimulation:tachycardiarelatedtoincreasedsinoatrialnodeautomaticity, increased cardiac contractility, accelerated atrioventricular conduction, decreased refractory periods, and decreased thresholds for ventricular arrhythmias. The increases in circulating glucose levels that attend emotional distress result importantly from epinephrine-induced glycogenolysis in the liver. Studies about mechanisms of epinephrine-induced glycogenolysis led to key discoveries aboutsecondmessengersandaboutenzymeactivation by phophorylation (Figure 2-26). The glycogenolytic response involves both B-adrenoceptors and ai-adrenoceptors. Sympathoneural stimulation augments renal sodium retention, by several mechanisms.Renalvasoconstrictiondecreaseslocalperfusionandthereby decreasestheglomerularfiltration of sodium.Stimulation of renal B,adrenoceptors increases secretion of renin, increasing production of angiotensin 11, which both acts as a potent vasoconstrictor and also augments adrenocortical secretion of aldosterone, the latter inducing Na+/K+ exchange in the kidneys and causing hrther retention of sodium. Norepinephrine can exert an anti-natriuretic effect by direct actions at renal tubular cells.As noted elsewhere in this chapter, exogenously administered dopamine increases renal blood flow (via occupation of Dl receptors), inhibits norepinephrine release from vascular sympathetic nerve terminals(via D2 receptors),and inhibits Na’K’ATPase in proximal renal

81

Overview of the A.N.S.

* l

E-Receptor Occupat!on

ATP

a,-Receptor Occupatm

1

Phosphdlpase C

n PKA

-A A

Phosphofylase b Klnase

Diacylglycerol

A

n

Phosphorylase b Klnase

(Inactwe) t

(Inhlbltion of Glycogen Synthase)

ATP

Phosphorylase b

Phosphorylase a

Glycogen

Glucose 1 -phosphate

U Glycogen Synthase

-

Glucose 6phosphate

1

Embden-Meynhof pathway

Pyruvate ATP

Figure 2-26 Pathways of epinephrine-induced glycogenolysis. Note the central roles of the second messengers adenyl cyclase and phospholipase C and of activation of enzymes by phosphorylation.

tubular cells (via both receptor types), a combination eliciting natriuresis and diuresis. Catecholaminesgenerallyinhibitgutmotilityandsuspenddigestive processes. The usually concurrent splanchnic vasoconstriction shunts blood to the heart, lungs, brain, and skeletal muscle. Cannon showed that the adrenal effluent and epinephrine itself relax intestinal muscle. Indeed, the prominent relaxation of intestinal muscle by epinephrine in bioassays provided the basis for the first demonstration that emotional stress increases adrenal release of epinephrine.Both a- and8-adrenoceptorsmediatethegastrointestinal inhibition. Pallor,cyanosis,sweating,shivering,andpiloerectioncausedby sympathoneural stimulation constitute major signs of emotional distress and shock,Administrationofeithernorepinephrineorepinephrineproduces cutaneous vasoconstriction, due to stimulation of ai-and 1x2-adrenoceptors on vascularsmoothmusclecells.Sympatheticnoradrenergicstimulation of apocrineglandsinducesaxillaryemotionalsweating,whereassympathetic cholinergic stimulation of eccrine glands induces thermoregulatory sweating. In contrast with skeletal sympathoneural activity, which is especially responsive to alterationsinbaroreflexactivity,cutaneoussympathoneuralactivityis

82

Chapter 2

TABLE 2-5 Neurotransmitter Effects of Norepinephrine Cardiovascular

Variable Heart Rate Effects (D 1- vs. a ) IncreasedMyocardialAutomaticity IncreasedMyocardialContractility Diffuse Vasoconstriction Glucose

Increased Glucose (Hepatic Nerves) Gastrointestinal

Decreased Gut Motility PsychologicallBehavioral Emotional Sweating (?) EmotionalFlushing (?) Other

IncreasedRenin-Angiotensin-AldosteroneSystemActivity (Renal Vasoconstriction) Sodium Retention

responsivetoemotionalstressorsandtoalterations in environmental temperature. Facialsweatingandflushingassociatedwithbodyheatingor embarrassmentdependimportantlyonactive,post-ganglionicsympathetic innervation. Sympathetic vasodilator fibers seem to accompany sudomotor and vasoconstrictor fibers to the face. Catecholamine-induced thermogenesis probably resultsfrom the lipolytic effect of B-adrenoceptor agonism. Since physiological increments in plasma epinephrinelevelsincreasemetabolicrate,endogenousepinephrinemay participate in maintenance of body weight. Epinephrine decreases the serum potassium concentration, by a mechanism dependent on 02-adrenoceptors. The effect occurs independently of insulin, aldosterone, and renal function. Complex interactions among thyroid hormones and the sympathoneural andadrenomedullarysystemsprobablydeterminebasalmetabolicrate. Hyperthyroidismoftenpresentsclinicallywithsignsofcardiovascular

Overview of the A.N.S.

83

sympatheticstimulation,includingtachycardia,systolichypertension,and arrhythmias,perhapsbecausethyroidhormoneincreasesthenumbers of myocardial R-adrenoceptors. Thyroidectomy augments plasma norepinephrine responses to exposure to cold in laboratory animals. Cannon wrote that epinephrine release during stress responses promotes hemostasis, not only by vasoconstriction but also by accelerated blood clotting. These effects would have afforded an adaptive advantage in evolution, by minimizing hemorrhage after trauma. Epinephrine and norepinephrine both cause plateletaggregation(epinephrine is morepotent).Theconcentrationof epinephrine required to produce platelet aggregation directly in vitro is much higher than the endogenous concentration. The combination of epinephrine in vitro withotheragentsthatactivateplatelets(e.g.,thrombin,collagen, adenosine diphosphate, vasopressin), however, markedly decreases epinephrine concentrationsrequiredtoinduceplateletaggregation.Thus,duringstress responses involving activation of several neuroendocrine systems simultaneously,relativelysmallincreases in circulatingepinephrinelevels might enhance platelet aggregability. The mechanism of epinephrine-induced platelet aggregation is thought to be via stimulation of a2-adrenoceptors. Exogenously administered catecholamines induce a lymphocytosis, a phenomenonoppositetothatproducedbyexogenouslyadministered corticosteroids. In laboratoryanimals,sympatheticstimulationcontractsthe spleen. Splenic contraction expands circulating blood volume and therefore aids in counteringeffectsoftraumatichemorrhage.Epinephrine-induced vasoconstriction slows the microcirculation in injured regions. This fosters the adhesion of leukocytes to the vascular endothelium (“pavementing”); leukocytes migrate through small blood vessel walls within a few minutes of injury. Many behavioral effects of epinephrine have been described, including anxiety, increased alertness, trembling, and an energizing effect, with decreased muscular and psychological fatigue. Because of the effective blood-brain barrier for catecholamines, one would expect that circulating catecholamines should not reach most adrenoceptors in the central nervous system. The bases for central neural effects of circulating catecholamines remain poorly understood. Perhaps circulatingcatecholaminesexertcentralneuraleffectsviaactionsatthe circumventricular organs, which lack an effective blood-brain barrier. Epinephrine increases the intensity of mental concentration and enhances performance of perceptual-motor tasks, despite epinephrine-induced tremor. Epinephrine also enhances emotional experiences. Cannon described the antifatigue effect of epinephrinein preparations of skeletal and cardiac muscle. The mechanism of the anti-fatigue effect of epinephrine, and more generally the basis for anti-fatigue effects of emotion, are poorly understood. Learning appetitive or avoidance behaviors requires recollection of pleasurable and painful experiences. Thelong-termpotentiationofexcitatorysynapticinputs in thebrainhas

a4

Chapter 2

provided the basis for a cellular model of learning and memory. Depletion of norepinephrine in the brain blocks this long-term potentiation. Theirispossesseshighconcentrationsofcatecholamine-fluorescent terminals. The radial muscle contains both a-and D-adrenoceptors. O-Adrenergic blockade produces pupillary constriction. Pulmonaryeffectsofepinephrineincludebronchiolardilationand hyperventilation.Cliniciansexploittheformereffectwhentheyinject epinephrine to abort asthma attacks; and sudden awakening by a noise increases the rate of breathing within a few seconds. The mechanism of ventilatory stimulationbyepinephrineisunknown.Thesuggestionthatepinephrine directlystimulatesamedullarycenterregulatingventilationmusttake intoaccounttheblood-brainbarrierforepinephrine.Perhapsblood-borne catecholamines reach medullary sites via the area postrema, a circumventricular organ lacking a blood-brain barrier. Possibly important autocrine/paracrine effects of endogenous dopamine include cardiovascular stimulation, decreased gastric acid secretion, natriuresis, and inhibition of adrenocortical secretion of aldosterone (Table 2-6). Dopamine receptors occur at high concentrations in the kidneys. Renal Dl-receptors are localized to the media of microvessels, the cortical collecting ducts, and, perhaps most importantly, the proximal convoluted tubules; whereas D2-receptors are thought to be localized on sympathetic nerve terminals in the adventitia and media of renal blood vessels andin the glomeruli. Locally produced dopamine acts as an autocrine/paracrine substance, by a mechanismthatincludesoccupationofDl-receptorsonthemembraneof proximaltubularcells.AgonistoccupationofDl-receptorsinhibitsNa/K ATPase activity, by CAMP-dependent phosphorylation of an inhibitory protein, the “DA- and CAMP-regulated phosphoprotein of Mr 32,000,” or DARPP-32 (200). Activated DARPP-32 inhibits protein phosphatase-l, in turn interfering with activation of the Na+/K+ ATPase complex. Inhibition of Na+/K+ ATPase allows Na+ to enter the cell, and the increased cytoplasmic Na’ concentration augments net Na’ release into the tubular lumen. The ATPase inhibition appears to require simultaneous activation ofD l - and D2-receptors (201). This mechanism represents a potentially important new physiological regulatory system, where an autocrine/paracrine substance formed intracellularly from a circulating precursor affects transmembrane movement of an ion. Since the receptors probably cycle between the membrane surface and the cytoplasm, alterations in the synthesis rate of dopamine may also influence the numbers of receptors available in the membrane, but this has not been studied directly.

Overview of the A.N.S.

85

TABLE 2-6 Dopamine Autocrine/paracrine Effects

Cardiovascular

Increased Myocardial Automaticity Increased Myocardial Contractility(R) Diffuse Vasodilation, then Vasoconstriction at High Doses (fl then a) Gastrointestinal

Decreased Acid Secretion Renal

Natriuresis Diuresis Other

Decreased Aldosterone Secretion

Drugs that Act Pre-Synaptically

Severalclassicalneuropharmacologicalagentsmodulatereleaseof norepinephrine from sympathetic terminals, as discussed above in the section aboutnoradrenergicneurotransmission.Briefly,acetylcholine(atnicotinic receptors),epinephrine(atR*-adrenoceptors),angiotensin 11, corticotropin, pituitary adenylate cyclase-activating polypeptide (PACAP), y-aminobutyric acid (at y-aminobutyric aCidA receptors), and vasoactive intestinal peptide all stimulateorfacilitatenorepinephrinerelease.y-Aminobutyricacid(at yaminobutyric acidg receptors), acetylcholine (at muscarinic M 1 receptors), adenosine (at A1 purinoceptors), neuropeptide Y (atY2 receptors), somatostatin (at SRIFl receptors), opioids (at 6 and K receptors), prostaglandins of the E series, nitric oxide, dopamine, bretylium, and norepinephrine itself (at 1x2adrenoceptors) all inhibit norepinephrine release (Figure 2-27). Ganglion blockershtimulants Drugs that block ganglionic neurotransmission, such as trimethaphan, hexamethonium, and pentolinium, decrease the rate of bursts of sympathetic post-ganglionicnervetraffictovirtuallyzero. Loss ofsympathetic vasoconstrictor tone explains decreased total peripheral and forearm vascular

86

Chapter 2

resistance, dilation of conjunctival blood vessels, and nasal congestion during ganglion blockade. Drugs that block ganglionic neurotransmission also produce symptoms and signs of parasympathetic inhibition, including dry mouth and decreasedgastrointestinalandurinarybladdermotility.Conversely, parasympathetic stimulation plays an important role in the “cephalic phase” of digestion,increasingsalivation,secretionofinsulinandgastrin,and gastrointestinal motility. Theeffectsofacuteadministrationofnicotine,whichaugments ganglionic neurotransmission, result mainly from increased adrenomedullary secretion of epinephrine. In adrenomedullary cells, nicotine acts directly to evoke catecholamine release, via increasesin intracellular concentrations of Ca++ (202). a2-Adrenoceptor agonists Asnotedabove in thesectionaboutmodulationofnorepinephrine release, endogenous norepinephrine inhibits its own release, by stimulating inhibitory a2-adrenoceptors on sympathetic nerves. This modulatory action is prominent in skeletal muscle, moderate in the heart, weak in the kidneys, and virtually absent in the adrenals. Conversely, in humans, systemic administration of the a2-adrenoceptor blocker, yohimbine, produces much larger proportionate increases in forearm norepinephrine spillover than in directly recorded skeletal muscle sympathetic activity (203), providing strong evidence that in human limbs,a2-adrenoceptorsonsympatheticnerveendingstonicallyinhibit norepinephrine release. a-MethylDOPA, aneffectivedrug in thetreatmentofhighblood pressure,inhibitsL-aromatic-amino-aciddecarboxylaseandtherefore norepinephrinesynthesis,butthisinhibitiondoesnotexplaintheantihypertensive action of the drug. Instead, a-methylnorepinephrine, formed from a-methylDOPA in cells that contain dopamine-R-hydroxylase, stimulates a2adrenoceptors in the brain that inhibit sympathetic outflows. Bretylium Bretylium, a quaternary ammonium compound, prolongs cardiac action potentials,inhibitsreuptakeofnorepinephrine,and, by poorlyunderstood mechanisms, inhibits exocytotic release of norepinephrine. The inhibitory effect of bretylium on norepinephrine release depends on uptake of the drug by sympathetic nerve terminals. Bretylium is used in the treatment of ventricular fibrillation, according to current advanced cardiac life support protocols. It is a class 111 anti-arrhythmic

87

Overview of the A.N.S.

Trimeihaphan Pentolinium Clonidine Nitroprusside

DOPAC-

' Aldomet Carbidopa

I TYR

.c

$.

jsr, "i*

Demser

DOPAC D PG

C O U TCI O M T I

DOPA

9

NE;

1 NMN

MHPG

HVA

BLOODSTREAM

Figure 2-27 Sites of action of drugs affecting the release, reuptake, or metabolism of norepinephrine released from sympathetic nerve terminals.

(204). Hypotensive effects, probably from the inhibition of norepinephrine release, limit the use of bretylium asan anti-arrhythmic drug (195). Local intravenous administration of bretylium also is used to treat limb pain in patients with reflex sympathetic dystrophy, also called complex regional pain syndrome Type-1, as noted in the chapter about mysterious or controversial entities (205,206). Tetrodotoxin

Tetrodotoxin is a potent poison derived from fish such as the puffer fish, some newts, and a frog native to Costa Rica. The drug blocks Na' channels, preventing generation of action potentials and thereby preventing exocytosis.

Chapter 2

88

Thedecrease in exocytoticreleaseofnorepinephrineprobablyexplains hypotension produced by the drug. Terotodotoxin is used commonly in ex vivo studies of mechanisms of exocytosis. Reserpine Reserpine,analkaloidderivedfromtheIndianclimbingshrub, Rauwolfia serptentina, was the first drug found to interfere with sympathetic neuroeffector hnction in humans. Reserpine effectively, selectively, and probably irreversibly blocks the vesicular transport of amines from the axoplasm into vesicles. This not only shuts down conversion of dopamine to norepinephrine but also prevents the conservative recycling of norepinephrine, serotonin, and dopamine. Reserpine therefore depletes tissue stores of all three monoamines. Reserpine also increases activity of tyrosine hydroxylase and thereby catecholamine synthesis. After reserpine injection, plasma dihydroxyphenylglycol levels increase rapidly, reflecting marked net leakage of norepinephrine from vesicular stores, and then decline to very low levels, reflecting the abolition of vesicular uptake and B-hydroxylation of dopamine (3 1). Uptake-l blockers Many drugs or in vitro conditions inhibit Uptake- 1, including cocaine, tricyclic antidepressants, low extracellularNa' concentrations, Li', ouabain, and nitrogen mustards. In contrast, no endogenous compound has been shown to regulate Uptake-l activity. Tricyclic antidepressants

Thetricyclicantidepressant,desipramine,blocksneuronaluptakeof norepinephrine.Thisaugmentspressorresponsesduringsympathetic stimulation or administration of catecholamines. The fact that desipramine and other tricyclic antidepressants block uptake by noradrenergic neurons more effectively than they block uptake by dopaminergic neurons indicates distinct transporters for norepinephrine and dopamine, and, as noted above, molecular genetic studies have confirmed this distinction. Unlikecocaine,tricyclicantidepressantsdonotnecessarilyincrease norepinephrineconcentrationsinextracellularfluid.Thisisbecause administration of tricyclic antidepressants produces marked concurrent decreases in rates of post-ganglionic sympathetic nerve traffic (1 18-12 1). Desipramine usually increases plasma epinephrine levels (207), possibly reflecting different effects of the drug on sympathoneural and adrenomedullary outflows.

Overview of the A.N.S.

89

MAO-A inhibitors

Drugs that inhibit MAO-A decrease oxidative metabolism of norepinephrineanddopamine in sympatheticterminals.Clorgylineblocks MAO-A,anddeprenylandpargylineblockMAO-B.SinceMAO-A predominates in neural tissue, whereas both subtypes exist in non-neuronal tissue, inhibitors of MAO-A potentiate the pressor effects of tyramine, whereas inhibitors of MAO-B do not. MAO inhibitors are effective antidepressants. As noted above, the “cheese effect”limitstheirclinicaluse. In patientstakingMAOinhibitors, administration of sympathomimetic amines such as in many non-prescription decongestants, or ingestion of foods such as aged cheese, wine, or meat, which contain tyramine, can produce paroxysmal hypertension. When given alone, MAOinhibitorsusuallydecreasebloodpressureandproduceorthostatic hypotension, by unknown mechanisms.

Sympathomimetic amines Theterm,“sympathomimeticamine,”referstodrugswith a Rphenylethylamine structure (Figure 2-28) that exert effects that sympathetic nerve stimulation produces. Catecholamines are sympathomimetic amines with hydroxyl groups at the 3 and 4 positions of the benzene ring-i.e., catecholsand are 3,4-dihydroxyphenylethylamines. Isoproterenol is a catecholamine with an isopropyl group at the terminal amine. Because of alkylation at the N-terminus, sympathomimetic amines such as phenylephrine, isoproterenol, and metaproterenol are taken up poorly by the membrane monoamine transporter. In general, the more extensive the alkylation at the terminal amine, the moreR-adrenoceptoragonistproperties of thedrug.Thisexplainswhy norepinephrine is a poor agonist at R2-adrenoceptors7 whereas epinephrine, which is N-methyl-norepinephrine, is an excellent agonist at R2-adrenoceptors, and isoproterenol and metaproterenol, which both have isopropyl groups at the terminalamine,areR-agonistswithlittleifanya-adrenoceptoragonist properties. Sympathomimeticaminessuchastyramine,amphetamines,and metaraminol, which lack alklylation of the terminal amine, are taken up avidly by sympathetic nerves. These drugs are then translocated into the vesicles via the vesicular monoamine transporter and displace norepinephrine from the vesicular stores. They appear to release norepinephrine non-exocytotically, since tyramine releases norepinephrine independently of calcium and does not release dopamine-R-hydroxylase. Because of the norepinephrine release, tyramine,

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amphetamines, and metaraminol act indirectly as ai-adrenoceptor agonists and increase blood pressure. Hydroxylation of the benzene ring decreases the ability of sympathomimetic amines to penetrate the blood-brain barrier, Catechols such as isoproterenoland4-hydroxylatedphenylethylaminessuchastyramineand phenylephrine do not exert prominent central neural effects. SubstitutionofanhydroxylgroupattheR-carbonalsodecreases penetration of the blood-brain barrier, whereas methylation at the terminal group increases penetration of the blood-brain barrier. Thus, phenylpropanolamine, a widely used nasal decongestant, has a similar peripheral mode of action to that of ephedrine, but with less central stimulation, and methamphetamine, which is structurally identical to ephedrine except for the absence of a hydroxyl group at theR-carbon,hasprominentcentralstimulatoryeffects.Ephedrine, amphetamines, phentermine, and phenylpropanolamine, which lack hydroxylation of the benzene ring, all produce central nervous stimulation. Ephedrine, which acts as an agonist at a- and 8-adrenoceptors and also as a central stimulant, has been used to treat narcolepsy and hypotension. Until relatively recently, several commonly prescribed bronchodilator compounds to treat asthma included ephedrine. Ephedrineis the active ingredient in mu huang, a Chinese herbal remedy derived from the Chinese ephedra plant (208), and also in “herbalecstacy,”analternativedrugofabusethatcanevokesevere hypertension and arrhythmias (209). Substitutionatthea-carbonrenders a sympathomimeticamine insensitivetodegradation by monoamineoxidase.Sincenon-catechol sympathomimetic amines are not substrates for catechol-0-methyltransferase, non-catechol sympathomimetic amines that have a substitution at the a-carbon are not metabolized by two of the main degradative enzymes in the gut wall, and these compounds have much higher bioavailability and longer durations of action than do catecholamines. Phentermine prescribed with fenfluramine (“Fen-Phen”) is an effective anorecticcombination.Becauseofclinicaltoxicity-especiallypulmonary hypertension and cardiac valvular fibrosis-and highly publicized lawsuits, this combination is no longer used for weight loss. a-Methyltyrosine a-Methyltyrosine(DemserTM)competeswithtyrosinefortyrosine hydroxylase. This decreases formation of endogenous L-DOPA and depletes stores of catecholamines. a-Methyltyrosine is effective in the management of patientswithpheochromocytoma,atumorthatsynthesizesandsecretes catecholamines. Clinical manifestations of pheochromocytoma include acute hypertensiveparoxysms,associatedwithheadache,sweating,cardiac

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TYRAMINE

c

m

N

H

PHENYLEPHRINE

2

AMPHETAMINE

METHAMPHETAMINE

EPHEDRINE

PHENTERMINE

PHENYLPROPANOLAMINE

FENFLURAMINE

Figure 2-28 Some sympathomimetic amines. All share a R-phenylethylamine structure.Amphetamine,methamphetamine,phentermine,phenylpropanolamine,and fenfluramine have d- and l-isomers because of the 4 different substituents at the a

arrhythmias, and risk of stroke, due to release of catecholamines by the tumor. Depletion of catecholamine stores in the tumor cells can ameliorate or prevent acute episodes. a-Methyltyrosine also inhibits the synthesis and thereby depletes cellular stores of dopamine in the central nervous system. The depletion can induce parkinsonian signs and symptoms in patients taking the drug. a-MethylDOPAformedfromhydroxylationofa-methyltyrosine, undergoesconversiontoa-methylnorepinephrine,anagonistat a2adrenoceptors.Stimulationofa2-adrenoceptors in thebraindecreases

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sympathetic neuronal outflows. Thus, for a-methyltyrosine to decrease blood pressure in patients with pheochromocytoma does not require depletion of norepinephrine stores, and a-MethylDOPA (AldometTM) is an effective antihypertensive agent. Stimulation of 1x2-adrenoceptors elicits sedation, and the carbon. Alkylation at the a carbon, without hydroxylation at the benzene ring, appears to enable central stimulant and anorectic effects.

sedative effect of a-MethylDOPA and a2-adrenoceptor agonists has limited their clinical use in the treatment of essential hypertension.

Drugs that Act Post-Synaptically Most drugs that act post-synaptically exert effects at receptors for the neuroeffectorcompounds,suchasatadrenoceptors,discussed in detail previously. In addition, however, some drugs act by influencing extraneuronal catecholamine synthesis, uptake (Uptake-2), or intracellular enzymes.

L-DOPA and L-DOPS

L-dihydroxyphenylalanine (L-DOPA) and L-dihydroxyphenylserine (LDOPS) are both catechol amino acids. By the actions of L-aromatic amino acid decarboxylase, L-DOPA undergoes conversion to dopamine and L-DOPS to norepinephrine. These conversions probably take place mainlyin non-neuronal cells in the periphery. L-DOPA, combined with a drug that inhibits L-aromatic amino acid decarboxylase in the periphery but which does not penetrate the blood-brain barrier(carbidopa,benserazide),constitutesamainstay in the treatment of Parkinson’s disease. After crossing the blood-brain barrier, L-DOPA undergoes conversiontodopamine,whichisdeficient in thenigrostriatalsystem in patientswithParkinson’sdisease.Thecellularsiteofthisconversionis incompletelyunderstood. It ispossiblethattheconversiontakesplace in astrocytes, since these non-neuronal cells, which contribute importantly to the blood-brainbarrierforcatecholamines,containL-aromaticaminoacid decarboxylase (1 99). Because of the 8-hydroxyl groupin L-DOPS, there are four stereoisomers of DOPS but two of DOPA. In humans, the L-threo stereoisomer of DOPS undergoes metabolic conversion to norepinephrine and has proven remarkably effective in thetreatmentoforthostatichypotensionfromdopamine-8hydroxylasedeficiency(210).L-DOPSmayalsobeeffective in treating orthostatic hypotension in other chronic primary autonomic failure syndromes (2 1 1).

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COMT inhibitors The COMT inhibitors, tolcapone and entacapone, are nitrocatechols that prolong effects of L-DOPA by attenuating its breakdown via 0-methylation (212). This allows more L-DOPA to cross the blood-brain barrier. COMT inhibitors have been introduced in the treatment of patients with Parkinson’s disease who have fluctuating symptoms (“on-off’ phenomenon). Because of reported cases of fulminant hepatitis with the use of tolcapone, some countries have removed this compound from the market.

MAO-B inhibitors Itis generally accepted that catecholamine-synthesizing cells express MAO-A but not MAO-B. Thus, administrationof an MAO-B inhibitor such as deprenyl does not affect plasma levels of dihydroxyphenylglycol, the neuronal deaminated metabolite of norepinephrine. L-Deprenyl,thefirstclinicallyusedMAO-Binhibitor,isrelated structurally to phenylethylamine butis not a sympathomimetic amine. Deprenyl is an effective adjunct in the treatment of Parkinson’s disease. The basis for the beneficial effects of deprenyl in this condition are unknown. The experimental neurotoxin, 1-methyld-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), destroys dopaminergiccellsafterconversionto l-methyl-4-phenylpyridinium ion (MPP’) by MAO-B in non-neuronal cells in the brain. Blockade of MAO-B prevents MPTP-induced neurotoxicity. This raises the possibility that deprenyl inhibits production ofan analogous neurotoxic substancein Parkinson’s disease, such as isoquinolines (213). Phosphodiesterase inhibitors Phosphodiesterase catalyzes the metabolic breakdownof cyclic GMP and cyclic AMP. Phosphodiesterase inhibitors therefore enhance or prolong effects mediated by these compounds. Caffeine and theophylline are methylxanthines that differ only in that caffeine has a methyl group at the 7 position in the xanthine structure. Caffeine has important effectson autonomic neuroeffector function.First, the drug inhibits phosphodiesterase. This facilitates cardiovascular effects of drugs such as B-adrenoceptors that depend for their action on generation of CAMP. Second, caffeine increases sympathoneural and especially adrenomedullaryoutflows,resulting in increases in plasmalevelsof norepinephrine, epinephrine, and renin activity (214,215). Tolerance develops rapidly to caffeine after repeated administrationin humans. In this setting, acute caffeineadministrationproducesmarkedlysmallereffectsonvaluesfor

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hemodynamic variables and on plasma catecholamine levels than in caffeinena’ive individuals (216). Peoplewith“caffeinesensitivity”reporttachycardia,palpitations, sweatiness, and anxiety or panic after caffeine ingestion. The exact mechanistic basis for this sensitivity remains obscure.

Uptake-2 inhibitors Uptake-2 plays a relatively small role in the inactivation of endogenous norepinephrine. As a result, drugs that block Uptake-2, such as steroids and 0methylatedmetabolitesofcatecholamines,donotimportantlyinfluence sympathetic neuroeffector function. “Long-Distance” Effects of Drugs

Many drugs affect autonomic neurocirculatory function indirectly, via actions in the central nervous system that influence autonomic neural outflows or via hemodynamic alterations that influence circulatory reflexes (Figure 2-29). These “long distance” effects, which constitute important components of several homeostatic reflexes, receive more detailed attentionin the chapters about central neuralregulationofautonomicoutflowsandaboutclinicalevaluationof dysautonomias. For example, clonidine, atenolol, and caffeine exert “local effects” at sympathetic neuroeffector junctions, in that clonidine inhibits norepinephrine release for a given amount of sympathetic nerve traffic, atenolol inhibits effects of norepinephrine mediated by l3l-adrenoceptors, and caffeine increases the amount of intracellular CAMP for a given amount of adenyl cyclase activation, by blocking phosphiesterase. In contrast, sodium nitroprusside produces “long distance” effects, by directlyproducingvasodilation by mechanismslargelyindependentof adrenoceptor-mediated processes in vascular smooth muscle cells, and this alters feedback from arterial baroreceptors that disinhibits sympathoneural outflows. Trimethaphan, by blocking ganglionic neurotransmission, decreases the amount of sympathetic nerve traffic for a given amount of activation of sympathetic preganglionic neurons. Finally, diazepam, by effects at upper brainstem, limbic, and cortical centers, decreases experienced distress and the associated increases in adrenomedullary outflows. Thesedistinctionscommonlyblurbecauseofbothlocalandlong distance effects of the same drugs. Thus, clonidine exerts prominent sedative and sympathoinhibitory effects, in addition to inhibiting norepinephrine release from sympathetic terminals for a given amount of sympathetic nerve traffic; and caffeine augments adrenomedullary secretion and can elicit anxiety or panic, in

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7 Regulator

c

DIAZEPAM

TRIMETHAPHAN

CLONlOlNE

DRUG

1

+ 1

Feedback

Phosphorylation

Cellular

Activity

NITROPRUSSIDE

Figure 2-29 Local and “long-distance” effects of drugs.

addition to augmenting tachycardic effects of B-adrenoceptor agonists. Other examples of this phenomenon include reflexive sympathetic stimulation as a resultofinsulin-inducedvasodilation, in additiontoadrenomedullary stimulationbyinsulin-inducedhypoglycemia;andincreasedsympathetic neuronal outflows as a result of high concentrations of angiotensin I1 at central neural receptors outside the blood-brain barrier,in addition to direct stimulation of adrenomedullary secretion by angiotensinI1 and reflexive sympathoinhibition in response to vasoconstrictor effects exerted by angiotensin11. Reflexive “long-distance” feedback pathways, via high- and low-pressure baroreceptors,elicitreflexivechanges in sympathoneuralimpulseactivity. Pharmacological approaches to assess baroreflex-cardiac gain (usually termed

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baroreflex “sensitivity”) rely on measurements of the extent of change in electrocardiographic R-R interval for the change in systolic blood pressure afterbolus iv. injection of phenylephrine and nitroglycerine (starting doses usually 50 pg). Phenylephrine, by stimulating ai-adrenoceptors, elicits diffuse vasoconstriction, and nitroglycerine dilates veins, decreasing venous return to the heart and thereby decreasing stroke volume and systolic blood pressure (216). Neither drug exerts direct effects on heart rate. Measurements of arterial baroreflex sensitivity by pharmacological means are discussed in detail in the chapter about clinical evaluation of dysautonomias (Chapter 6). EMBRYOLOGY AND DEVELOPMENT Sympathetic Function in the Fetus

During embryogenesis the postsynaptic components of the sympathetic nervoussystemappearbeforethepresynapticcomponents.Activationof adrenoceptorsbycatecholaminesreleasedfromsympathoadrenalsources eventually supplants activation by catecholamines released from non-neuronal and extra-adrenal chromaffin tissue (2 17). Plasma catecholamines increase during the last quarter of gestation (2 1 S), and non-neuronal extra-adrenal sources of catecholamines atrophy in the postnatal period (2 19). Since the fetus exists in a largely protected environment, it is perhaps not surprisingthatthesympatheticnervoussystemdevelopsrelativelylate in gestation (220,221). The appearance of pressor and plasma catecholamine responses to hypoxemia during the last quarter parallels the development of vascular neuroeffector mechanisms, indicating an increasingly important role of the sympathetic nervous system in appropriate circulatory responses to this stressor (222-224). Markedimpairmentofcirculatoryresponsesduring adrenoceptor blockade, and attenuated increases in plasma concentrations of catecholamines after sympathectomy, indicate the importance of adrenergic mechanisms in the circulatory responsesto fetal hypoxemia (225-229). Transition from the Fetal to the Neonatal Environment

Transition from the fetal to the neonatal environment constitutes a drastic environmentalchallenge.Profoundhemodynamicandcardiopulmonary adjustments to the air-breathing environment accompany this transition(230). In the fetus, relatively little blood enters the pulmonary circulation. About 2/3 of blood pumped by the right heart enters the descending aorta directly, via the ductus arteriosus; about 1/3 enters the left ventricle via the foramen ovale in the inter-atrialseptumandisejectedintotheascendingaorta.Ventilation, oxygenation, and umbilical vessel occlusion soon after birth results in the series

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arrangement of pulmonary and sytemic circulations that characterizes normal adult mammals (23 1,232). Sympathoneural and adrenomedullary activation plays an important role in these circulatory changes, by supporting cardiac function and arterial pressure (233) and by promoting readsorption of lung fluid, surfactant release, and nonshivering thermogenesis (233). Thus, circulating levels of norepinephrine and epinephrine increase abruptly and markedly at birth (234-237). Hypoxemia and exposure to relatively cold room temperature probably constitute key stimuli for this activation (238,239). Increases in plasmanorepinephrinelevelsatbirthnotonlyreflect increased spillover of norepinephrine into the circulation but also decreased clearance of catecholamines from the plasma (237). The placenta, a tissue that actively removes catecholamines from the bloodstream (238), accounts fornearly 50% of catecholamine clearance in the term fetus (240). Loss of the placental circulation probably determines the reduced clearance of catecholaminesat birth. At birth the sympathetic nervoussystem is not fully developed or capable of the full range of responses of the adult(241-243). Sympathetic innervation in thenewbornheart is onlypartiallydeveloped,andmyocardialstoresof norepinephrineareonly 1/3 those in theadult (244,245). Adrenoceptor sensitivity to adrenergic stimulation increases with the development of neuronal input (245). Cardiopulmonary baroreflex control of sympathetic activity is also much less sensitive in newborn than in 6- to 8-week old sheep (246,247). Changes in theresponsivenessofthesympatheticnervoussystemto environmental stimuli continue to develop in the postnatal period and also as a function of normal aging. In contrast with the sympathetic innervation of the heart, which matures post-natally, parasympathetic innervation of the heart is well developed by birth (248).

“Fetaldistress”causesdecelerationoftheheartrateduringuterine contractions. The neurocirculatory basis for the phenomenon in humans is unknown.Catecholamineconcentrations in umbilicalarterialplasmaof newborns with fetal distress are higherthan in those without fetal distress (249). Anoxia and acidosis might block cardiac effects of catecholamines in this setting, or increased cardiovagal outflow might occur. Neurotrophic Factors

Thediscoveryofnervegrowthfactor(NGF),thefirstidentified neurotrophic substance, by Rita Levi-Montalcini and Stanley Cohen led to their sharing the Nobel Prize for Physiology or Medicine in 1986. The discovery depended importantly on observations of effects of mouse sarcomas on growth of sympathetic ganglia(250,25 1).

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Not only the development but also the maintenance of adult sympathetic neurons requires target-derived, diffusible neurotrophic factors. Abnormalitiesin the dynamic, trophic, interacting relationships between neurons and their targets therefore can help to explain breakdowns of neuronal homeostasisin response to neurotoxic agents or aging. Thus, many studies have reported that treatment with neutrotrophic factors ameliorates or prevents evidence of neurotoxic injury producedby6-hydroxydopamine,whichdestroysnerveterminalsof catecholamine cells. Most research on this topic has focused on central dopaminergic systems. Whether pre-treatment with neurotrophic factors attenuates 6-hydroxydopaminedestruction of peripheral sympathetic terminals has received much less attention. The availableevidence supports the notion that pre-treatment accelerates recovery from 6-hydroxydopamine neurotoxicity (252); however, no studies about effects of neurotrophic factors on the rate of terminal re-innervation of cardiovascular structures after 6-hydroxydopamine-induced chemical sympathectomy have appeared. Administration antiserum of against NGF produces an “immunosympathectomy,”withdegenerativelossofsympatheticnerve terminals (253). adults, In sympathetic innervation regenerates; immunosympathectomy in neonatalanimals,however,induceslong-term decreases in terminal innervation. Spontaneously hypertensive rats (SHRs) have increased expression of NGF, compared to values in Wistar-Kyoto (WKY) control rats (254-262), consistent with a pathophysiological role of NGF in the sympathetic hyper-innervation in this animal model of hypertension. Thus, treatment of neonatal SHRs with antiserum to NGF, especially in combination with guanethidine, attenuates or prevents the development of hypertension and vascular hypertrophy in this animal model (263-267). By now, a large family of trophic factors, including neurotrophic factors, have been described. Neurotrophic factors include NGF, neurotrophin-4 (NT-4), brain-derived neurotrophic factor (BDNF), NT-3, ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF). NGF binds to tyrosine kinase (Trk) A receptors (Figure 2-30), NT-4 and BDNF to Trk B receptors, NT-3 to Trk A and Trk C receptors, and CNTF to a CNTF receptor complex (268). The most recently described group of neurotrophic factors occur in a family of molecules related to transforming growth factor-beta (TGF-B). These include neurturin, persepherin, and glial cell line-derived neurotrophic factor (GDNF)(269-273).UnlikeNGF,BDNF,andNT-3,GDNFbindstoand signals via a novel receptor system that includes the Ret receptor tyrosine kinase, the ligand (GDNF or neurturin), a glycosyl-phosphatidylinositol (GP1)linked accessory molecule that determines high affinity binding of the ligand, andaccessorymolecules,denotedGFRalpha.Activation of Retmutations

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causes multiple endocrine neoplasia type-2, which features a predisposition to the development of epinephrine-synthesizing pheochromocytomas, as discussed in the chapter about hyper-adrenergicstates. GDNFbindstoGFRalphal,GFRalpha2,andGFRalpha3receptors. Unlike GFRalphal and GFRalpha2 receptors, expressed bothin developing and mature brain, GFRalpha3 receptors are expressed only during development (274). Mature sympathetic neurons expressall three receptor types. Human heart, spleen, dorsal root ganglia, and spinal cord express mRNA for both NGF and BNDF, and human sympathetic ganglia express mRNA for TrkAandthep75lowaffinityNGFreceptor(275).Inchickens,tissues receiving sympathetic innervation express mRNA GDNF, which promotes the survival of the innervating neurons (276); and whereas NGF stimulates both sympathetic and ciliary ganglia, GDNF more selectively stimulates sympathetic ganglia(277).SympatheticneuroblastsexpressbothNT-3andTrk C and require NT3 to proliferate, differentiate, and survive; in adults, NT-3 and NGF promote survival of sympathetic neurons (278). Exactly how neurotrophic factors elicit their effects remains unclear. NGF injected into target tissue undergoes transmembrane uptake into nerve terminals and retrograde transport to the cell bodies (279,280); however, studies using compartmentalized cultures of sympathetic neurons have indicated that neurite outgrowth depends at least partly on local effects of NGF at the level of the neurites themselves (281). Studies to date have not tested concepts about the relative importance of endocytosis of the protein-receptor complex vs. local generation of intracellular messengers consequent to receptor occupation, in explaining the survival-enhancing properties of NGF and other neurotrophic factors. Among the determinants of expression of NGF, catecholamines stimulate NGF production in target cells (282). The consequent sprouting of neurites that release norepinephrine suggest a positive feedback loop for the development of the sympathetic neuroeffector apparatus.

NoradrenergiclCholinergic Phenotype Whereas the main neurotransmitter of sympathetic preganglionic neurons isacetylcholine,themainneurotransmitterofsympatheticpostganglionic neurons in most organs (with the exception of sweat glands) is norepinephrine. Development of the noradrenergic postganglionic phenotype depends on the acetylcholine-induceddepolarization,sincebothganglionblockadeand

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FACTOR

NGF

BDNF T GCFT-NR NF"T'-N 4T-3 FarnilyRelated GDNF"' Persephin Neurturm

RECEPTOR receptor CTNFRet TrkB TrkC Trk TrkB TrkA TrkA TrkB

Receptor GFRalphal Complex GFRalpha2 GFRalpha3 GPI-linked"" Coreceptor MAP kinasesignalling

'CTNF = "TGF-R '"GDNF ""GP1

pathway

Ciliary neurotrophlcfactor = Transforrnmg growthfactor-beta

= Glial-cell-line-derived neutorophic facto] = Glycosylphosphatidylinositol

Figure 2-30 Neurotrophic factors and their receptors.

transection of presynaptic nerves prevent the normal development of tyrosine hydoxylase activity in postsynaptic neurons (283). Sympathetic nerves innervating sweat glands in normal adults release acetylcholineandpeptidesratherthannorepinephrine.Theswitch in neurotransmitter occurs post-natally. Whether development of the cholinergicpeptidergic phenotype depends on elaboration of a regulating factor by the target cells remains unresolved (284-287). The differentiation does appear to require preceding noradrenergic innervation. CIRCADIAN RHYTHMS

Plasma levels of catecholamines tend to increase in the early morning hours. Both awakening and orthostasis probably contribute to the increases. Since the frequency of coronary events also peaks in the morning, investigators have speculated that sympathetic or adrenomedullary activation contributes to the diurnal variation in coronary risk (288,289). In particular, B-adrenoceptor blockademitigatesthemorningincrease in theincidenceofmyocardial infarction (290), as discussed in the section about the sympathetic nervous system in disase states.

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Changes in Parasympathetic Function with Aging

Althoughheartrateunderrestingconditionsdoesnotchangeasa function of aging in humans (291), global indices of heart rate variability decline (292,293), as do heart rate responses to orthostasis (291), tilt, deep breathing, and performance of the Valsalva maneuver (294,295). Administration ofatropineproduceslesstachycardia in elderlythan in youngsubjects, indicating decreased vagal modulation of heart rate (293). Vagally-mediated, reflexive bradycardic responses to acute increasesin blood pressure also decrease (296-298). Tachycardic responses to orthostasis diminish (291). In contrast with evidence for unchanged or decreased vagal influences on heart rate with increased age in humans, serum concentrations of pancreatic polypeptide, used as an index of vagal influences on gastrointestinal function, increase with age and are higher in men than in age-matched women (299). Changes in Sympathetic Function with Aging

Changes inpre-andpost-synapticcomponentsofthesympathetic nervous system with advancing age interact complexly in determining altered reactivity of the cardiovascular system to changes in the internal and external environment.Mostindicesofsympatheticneuronaloutflowsincrease,as discussed below; however, cardiac reactivity to mental challenge, exercise, and orthostasisdiminishes,duemainlytodecreasedR-adrenoceptor-mediated responsiveness (300-303). Pressor responses to mental challenge and exercise increase(302,304),probablyfromaugmentedvasoconstrictorresponses secondary to diminished R-adrenoceptor mediated vasodilation and increased norepinephrine concentrations at vascular neuroeffector junctions (302,304,305). Arterial baroreflex-mediated alterations in sympathetic nerve traffic to skeletal muscle do not change as a function of aging (297,298),in contrast with blunted cardiovagal responses. Although sympathetic outflows generally increase with advancing age, whether this contributes to the development of hypertension or other cardiovascular disorders, as opposed to reflecting adaptive responses to changes in the internal environment (e.g., decreased end organ responsiveness), remains unclear. Increases in plasma norepinephrine concentrations with normal aging result from both reduced clearance and increased spillover of norepinephrine in the body as a whole(306-3 15). An aging-associated decrease in the efficiency of neuronal reuptake has been proposed to explain both these changes. Some studies have suggested decreased Uptake-l efficiency (313,3 16,3 17), but others havenot(312,318,319).Mostevidencesupportstheconclusionsthatthe

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increased total body norepinephrine spillover reflects increases in sympathoneuraloutflows in severalinnervatedorgans,andthedecreased clearance from arterial plasma reflects reduced cardiac output. Waist circumference increases with aging, especially in men, and this variable constitutes a better predictor of norepinephrine spillover than does aging itself (314). Conversely, the higher rate of norepinephrine spillover in elderly menthan in elderlywomendependsatleastpartlyongreaterwaist circumference in elderly men (320). Norepinephrine spillover specifically in the heart increases with age (3 15). This appears to result at least partly from decreases in Uptake-] activity, since elderly humans have a reduced cardiac extraction fraction of 3H-norepinephrine (321). Decreased Uptake-l activity, in turn, may explain larger increments in cardiac norepinephrine spillover during exercise or mental stress in elderly than young adult subjects. Microneurographic recordings of muscle sympathetic nerve traffic indicate greater sympathetic outflow to skeletal muscle in older than in younger individuals (298,322-324). Renal and hepatomesenteric norepinephrine spillovers do not appear to change as a function of normal aging in humans (313,315). Whereas findings based on plasma norepinephrine levels indicate agingassociated increased responsiveness to a variety of stressors (302,305), findings from direct recordings of muscle sympathetic activity indicate no important changes(325,326).Thisdifferencecouldreflectregionalvariations in sympathetic reactivity (32 1) or the influence of hemodynamic responses on the clearance of catecholamines (327). For example, with aging the ability to maintainbloodpressureduringorthostasiswanes,withoutfailureof sympathetic responses (328,329). Decreased cardiac output during orthostatic hypotension would decrease the clearance of norepinephrine from the circulation, increasing plasma concentrations for a given rate of sympathetic traffic (330). In general, the contribution of R-adrenoceptors to heart rate at rest does notchangewithage(293);however,stressresponsesmediatedby Radrenoceptors decline. This includes not only cardiac rate responses but also thermogeneticresponsestoisoproterenol(331).Agedratshavedecreased myocardial contractile responses mediated by both Rl- and R2-adrenoceptor subtypes,associatedwithdecreasedreceptornumbers(332).Since NO contributes to vasodilation elicited by R-adrenoceptor agonists, aging-related decreases in generationofNOmayalsocontributetothedecline in Radrenoceptor-mediated processes (333). Forearmvasoconstriction in responsetointra-arterialinfusionof norepinephrine decreases with aging in humans (334), consistent with decreased a-adrenoceptor-mediated responsiveness of vascular smooth muscle. Sympathetic cholinergic function, assessed from QSART responses, are larger in men than in women (294,295). Whereas QSART responses in the leg

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decline with increasing age, responses in the forearm do not (294). The latency of skin sympathetic responses evoked by a sudden loud noise increases with increasing subject age (335), and sympathetic cholinergic sudomotor function assessed using the impression mold technique decreases (336). Since no currently available test of sympathetic cholinergic function includes a measure of release of acetylcholine from the nerve terminals, one cannot distinguish decreased acetylcholine release from decreased numbers of post-synapticreceptorsorattenuatedmechanismsofintracellularsignal transduction in determining decreased sympathetic cholinergic function with aging in humans.Histochemicalandimmunohistochemicalstudieshave suggested a decreased density of sympathetic innervation of sweat glands in elderly people (337). Changes in Adrenomedullary Function with Aging

Whereas total body spillover of norepinephrine increases with aging, as noted above, spillover of epinephrine decreases (338). Elderly people appear to have about the same neuroendocrine responses to insulin-induced hypoglycemia as do younger adults, although older people have more cognitive impairment and fewer warning symptoms (339). In contrast, elderly people have smaller increments in epinephrine levels in response to mental stress or exercise than do younger people (338). CHOLINERGIC-CATECHOLAMINE INTERACTIONS

Cholinergic and catecholamine systems interact importantly at several levels. In general, cholinergic stimulation inhibits sympathoneural release of norepinephrine and augments adrenomedullary release of epinephrine. At some end-organs,suchaseccrinesweatglands,sympatheticnervesrelease acetylcholine as the effector compound. Cholinergic Inhibition of Sympathetic Function

Changes in sympathetic nervous activity usually occur in the opposite direction of those in parasympathetic nervous activity. For instance, increases in arterial baroreceptor afferent activity reflexively inhibit sympathoneural outflows and stimulate vagal cardiac outflow. Stimulation of the anterior hypothalamus usuallyproducesvagallymediatedbradycardiaandhypotension,whereas stimulation of the posterior hypothalamus produces sympathetically mediated tachycardia and hypertension (340). Vagal stimulation can abolish tachycardic responses to right stellate ganglion stimulation in anesthetized dogs (341). Stimulationofmuscariniccholinergicreceptors in theheartinhibits

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norepinephrine release during sympathetic stimulation (342-347). In neurally mediated depressor reactions, increased vagal outflows generally combine with decreased sympathetic outflows (348). Differenteffectsoncyclicnucleotidesatthecellularlevel,both prejunctionally and postjunctionally, may explain the antagonism between the two divisions of the autonomic nervous system. Prejunctionally, acetylcholine appears to bind to muscarinic receptors to inhibit release of norepinephrine duringsympatheticstimulation.Theintracellularmechanismisunknown. Postjunctionally, vagal stimulation increases intracellular cGMP levels, whereas B-adrenoceptorstimulationincreasesCAMPlevels.Muscarinicstimulation increases activity of an inhibitory G-protein, Gi, which both inhibits adenyl cyclase and catalyzes the hydrolysis of GTP to GDP. The latter may decrease the availability of GTP for activation of the stimulatory G protein for adenylate cyclase, G,. Thus, the net postjunctional effect of muscarinic stimulation is to block B-adrenoceptor-mediated stimulation of adenyl cyclase and therefore to inhibit formation of CAMP. Nevertheless, stimulating selected hypothalamic sites can differentially altercentralneuralprocessesmediatingparasympatheticandsympathetic outflows (349). Atropine, which blocks muscarinic receptors, also tends to inhibit sympathetic neuronal outflows (350). After meal ingestion, sympathetic neuronal outflow to skeletal muscle generally increases, and so does vagal outflow to mesenteric organs, as part of the cephalic phase of digestion. Moreover, some pathophysiological states feature parallel changes in vagal and sympathetic outflows. For instance, increases in vagal outflow to the heart can evoke complete heartblock and secondarily recruit cardiac sympathetic outflows to maintain cardiac performance; and dysautonomias can feature both failure of reflexive sympathetically-mediated vasoconstriction and failure of reflexive parasympathetically-mediated bradycardia. Accentuated antagonism “Accentuated antagonism” (351) refers to the augmented bradycardic effect of cholinergic stimulationin the presence of increased cardiac sympathetic tone. A given amount of vagal stimulation decreases heart rate more in the presence of concurrentsympatheticstimulationthanintheabsenceofsympathetic stimulation.Suchsympathetic-vagalinteractionsappearimportant in influencing both cardiac contractility and automaticity (344,345,352). They may also help to explain increases in pulse rate and blood pressure just prior to vasodepressor reactions insome-but by no means all-patients (353,354). During emotional stress or myocardial infarction, situations associated with increased cardiac sympathetic activity, increased cardiac vagal activity may help to maintain myocardial electrical stability (355-358).

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Central Cholinergic Effects

Stimulation of central cholinergic receptors generally increases efferent sympathetic nerve traffic, adrenomedullary catecholamine release, and blood pressure (359). This system appears to be tonically inactive. In rats, nicotine microinjection into the rostral ventrolateral medulla increases blood pressure, pulserate,andrenalsympatheticnerveactivity(360).Inhumans,central cholinergicstimulationincreasesplasmaepinephrinemorethanplasma norepinephrine levels (361,362). Adrenomedullary Stimulation

Acetylcholinepotentlystimulatesadrenomedullarysecretion,via occupationofnicotinicreceptorsonchromaffincells.Thisexplainswhy cigarette smoking or nicotine administration increases plasma epinephrine levels in humans(363-366).Adrenomedullarystimulationinduced by cigarette smoking occurs even in nicotine-addicted chronic smokers, whereas little if any sympathetic nervous stimulation occurs (367). During vasovagal depressor reactions, adrenomedullary secretion increases markedly, whereas sympathetic nervous activity decreases (368-370). The usual antagonism between the parasympathetic and sympathetic nervous systems thereforedoesnotapplytotheadrenomedullaryhormonalsystem in this setting. SUMMARY AND CONCLUSIONS

According to Langley’s conceptualization, the autonomic nervous system consistsofparasympatheticandsympatheticcomponents.Cannondefined sympathetic and adrenomedullary catecholamine systems in a “sympathicoadrenal” system. The parasympathetic system subserves mainly vegetative, conservative processes. In general, when sympathoneural activity increases, parasympathetic activity decreases, but exceptions to this generalization occur. Cell bodies of the parasympathetic preganglionic neurons are located in brainstem nuclei for the third, seventh, ninth, and tenth (vagal) cranial nerves and in the intermediolateral columns of the sacral spinal cord. Vagal ganglia generally lie near or within the innervated organs, andso the vagus consists of pre-ganglionic fibers. Vagal stimulation contracts bronchial smooth muscle cells, increases bronchial secretion of mucus, augments gastrointestinal peristalsis, evokes gastric and pancretic secretion, and relaxes the pyloric and ileocolic sphincters..

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Parasympathetic fibers originating in the intermediolateral columns of the sacral spinal cord participate importantly in penile erection and micturition. All parasympathetic nerves release acetylcholine as the neurotransmitter. Acetylcholine acts as a vasodilator, probably at least partly via occupation of M3 receptors and local generation of nitric oxide. Specific receptors mediate the effects of acetylcholine. Classically they have been divided into nicotinic and muscarinic. Agonist occupation of nicotinic receptors increases entry of Ca++, andagonistoccupationofmuscarinicreceptorsleadstocomplexeffects mediatedbyG-proteins.Muscarinicagonistsstimulategutsmoothmuscle contraction and glandular secretion and inhibit norepinephrine release from sympathetic nerve terminals. Atropine blocks muscarinic receptors selectively. Nicotinic receptors mediate cholinergic transmission in parasympathetic ganglia and cholinergic stimulation of adrenomedullary secretion. The sympathetic nervous system consists of nerve networks. Diffuse sympathetic stimulation increases total arteriolar resistance to blood flow, and since sympathetic activation in the heart increases the force and rate of cardiac contraction, blood pressure increases from both increased peripheral resistance and increased cardiac output. The sympathetic preganglionic neurons discharge spontaneously at a slow rate. Their tonic activity depends mainly on input from chemoreceptor, somatic, and visceral afferent nerve trafficto the spinal cord and importantly on descending input from supraspinal structures. The most well known chemical transmitter at sympathetic nerve endings is norepinephrine. Norepinephrine biosynthesis begins with uptake of the neutral L-aminoacid,tyrosine,intothecytoplasm.Tyrosinehydroxylaseisthe enzymatic rate-limiting step in norepinephrine synthesis. The L-DOPA formed undergoes conversion to dopamine by L-aromatic-amino-acid decarbxoylase in the cytoplasm and the dopamine conversion to norepinephrine by dopamine8hydroxylase in the vesicles. Other putative sympathetic co-transmitters are ATP, neuropeptide Y, and chromogranin A. Accordingtotheexocytotictheoryofnorepinephrinerelease, acetylcholine depolarizes the terminal membranes by increasing membrane permeability to Na+. The increase in intracellular Na+ directly or indirectly enhances transmembrane influx of Ca", via voltage-gated Ca++ channels. The increasedcytoplasmicCa++concentrationevokes acascadeofasyet incompletely defined biomechanical events resulting in fusion of the vesicular and axoplasmic membranes. The interior of the vesicle exchanges briefly with the extracellular compartment, and the soluble contents of the vesicles diffuse into the extracellular space. Endogenous norepinephrine can regulate its own release, by stimulatinginhibitory 1x2-adrenoceptors on sympathetic nerves. Sympatheticnerveendingscanalsoreleasenorepinephrinebycalciumindependent, non-exocytotic mechanisms.

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Unlikeacetylcholine,which is inactivatedmainlybyextracellular enzymes,norepinephrineisinactivatedmainlybyuptakeintocellsand subsequent intracellular metabolism or vesicular sequestration. Reuptake into nerveterminals-Uptake-l-isthepredominantmeansofterminatingthe actions of released norepinephrine. Many drugs or in vitro conditions inhibit Uptake-l, including cocaine and tricyclic antidepressants. Non-neuronal cells remove norepinephrine actively by a process called Uptake-2, characterized by theabilitytotransportisoproterenolandsusceptibilitytoblockadeby 0methylated catecholamines and steroids. In cardiac sympathetic nerves, over 90% of norepinephrine removedby neuronal uptake returns to storage vesicles. The adrenomedullary system is hormonal. Epinephrine rapidly increases the rate and force of cardiac contraction; increases myocardial cell automaticity; dilates bronchioles and increases the rate of breathing; redistributes blood volume toward the heart, brain, and skeletal muscle and away from the skin, kidneys, and gut; enhances the aggregability of platelets; relaxes smooth muscle of the uterus and gut; increases blood glucose by a variety of means including glycogenolysis and antagonizing insulin; dilates pupils; increases activity of the renin-angiotensin-aldosterone system; decreases serum potassium concentrations; increases the metabolic rate; and produces psychological effects such as increased alertness, decreased fatigue, and intensification of emotions. Most of dopamine synthesis and metabolism in the body as a whole occurs in non-neuronal cells. The renal DOPA-dopamine system constitutes the most well-studied non-neuronal catecholamine system. L-DOPA in the tubular filtrate undergoes Na+-dependent uptake into proximal tubular cells. Dopamine formed intracellularly by decarboxylation of the L-DOPA can exit the cellto act as an autocrine/paracrine agent that augments natriuresis. More production and metabolism of dopamine takes place in mesenteric organs than in the brain, sympatheticnervoussystem,oradrenalmedulla.Non-neuronalcellsalso constitute a major source of dopaminein the gastrointestinal tract. Nitric oxide (NO) opposes noradrenergic neurogenic vasoconstriction.NO also usually inhibits functions of brainstem regions that participate in regulation of central sympathetic outflows. Adrenoceptors in the brain and periphery mediate the physiological effects of catecholamines. The myriad different effects exerted by only three endogenous catecholamines in different organs depend on the numerous types and subtypes of adrenoceptors and intracellular mechanisms. Adrenoceptors share the same process for transducing signals to alter cellular functions-via G-proteins. Differences in the effects of norepinephrine and epinephrine result from different actions at two types of receptor, a and R. In general, R-adrenoceptors mediate the positive inotropic and chronotropic effects of catecholamines in the heart; stimulationofvasculara-adrenoceptorsproducesvasoconstriction;and stimulationofvascular R-adrenoceptors-especially in skeletalmuscle-

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produces vasodilation. Adrenoceptor desensitization reflects several processes, includingphosphorylationofthereceptor,sequestration(agonist-induced dissociation of the receptor from the cell membrane), inactivation of intracellular messengers,anddecreasedsynthesisofreceptorprotein.Fivestructurally distinct dopamine receptor subtypes have been identified, in two familes, called “Dl-like’’ and “D2-like.” Many drugs affect autonomic neurocirculatory function indirectly, via actions in the central nervous system that influence autonomic neural outflows or via hemodynamic alterations that influence circulatory reflexes. The sympathetic nervous system develops relatively late in gestation. Profound hemodynamic and cardiopulmonary adjustments to the air-breathing environment occur soon after birth.In contrast with the sympathetic innervation of the heart, which matures post-natally, parasympathetic innervation of the heart iswelldevelopedbybirth.Developmentofthenoradrenergic postganglionic phenotype depends on the acetylcholine-induced depolarization. The development and maintenance of adult sympathetic neurons requires target-derived, diffusible neurotrophic factors, the first identified being nerve growth factor (NGF). Administration of antiserum against NGF produces an “immunosympathectomy,”withdegenerativelossofsympatheticnerve terminals. Spontaneously hypertensive rats have increased expression of NGF, comparedtovalues in Wistar-Kyotocontrolrats,consistentwith a pathophysiological role of NGF in the sympathetic hyper-innervation in this animal model of hypertension. Plasma levels of catecholamines tend to increase in the early morning hours. With aging, most indices of sympathetic neuronal outflows increase. Cholinergic and catecholamine systems interact importantly at several levels. Changes in sympathetic nervous activity usually occur in the opposite directionofthoseinparasympatheticnervousactivity.“Accentuated antagonism’’referstotheaugmentedbradycardiceffectofcholinergic stimulation in the presence of increased cardiac sympathetic tone. Stimulation of central cholinergic receptors generally increases efferent sympathetic nerve traffic, adrenomedullarycatecholaminerelease,andbloodpressure.Acetylcholine potentlystimulatesadrenomedullarysecretion,viaoccupation of nicotinic receptors on chromaffin cells. This explains why cigarette smoking or nicotine administration increases plasma epinephrine levelsin humans. During vasovagal depressor reactions, adrenomedullary secretion increases markedly,whereassympatheticnervousactivitydecreases.Theusual antagonism between the parasympathetic and sympathetic nervous systems thereforedoesnotapplytotheadrenomedullaryhormonalsystem in this setting. Regulationoftheviscerathereforedependsoncholinergicand catecholamine systems. Acetylcholine is released by parasympathetic nerves and

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some sympathetic nerves. Norepinephrine, epinephrine, and dopamine function as effector compounds for three related but independently regulated systemsthe sympathetic nervous system, the adrenomedullary hormonal system, and the DOPA-dopamine autocrine/paracrine system.

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358.DasPK.Interaction of sympatheticandparasympathetic systems under stress. In: Beamish RE, Panagia V, Dhalla NS., eds. Pathogenesis of Stress-Induced Heart Disease. Boston: Martinus Nijhoff Publishing, 1984:20-33. 359. Brezcnoff HE, Giuliano R. Cardiovascular control by cholinergic mechanisms in the central nervous system. Ann Rev Pharmacol Toxicol 1982; 22:341-381. 360. Tseng CJ, Appalsamy M, Robertson D, Mosqueda-Garcia R. Effects of nicotine onbrainstem mechanisms ofcardiovascularcontrol. J PharmacolExp Ther 1993; 265:1511-1518. 361. Janowsky DS, Risch SC, HueyLY,KennedyB, ZieglerM.Effects of physostigmine on pulse,bloodpressure,andserumepinephrinelevels.Am J Psychiatry 1985; 142:738-740. 362. Kennedy B, JanowskyDS, Risch SC,Ziegler MG. Centralcholinergic stimulation causes adrenalepinephrinerelease. J Clin Invest 1984; 74:972975. 363. Cryer PE, Haymone MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamicand metabolic events. NEngl J Med 1976; 295573-577. 364. Gourlay SG, Benowitz NL. Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotinenasal spray, and intravenous nicotine. Clin Pharmacol Ther 1997; 621453-463. 365. Haass M, Kubler W. Nicotine and sympathetic neurotransmission. Cardiovasc Drugs Ther 1997;10:657-665. 366. Grassi G, Seravalle G, Calhoun DA, Bolla GB, Giannattasio C, Marabini M, Del Bo A, Mancia G. Mechanisms responsible for sympathetic activation by cigarette smoking inhumans.Circulation1994;90:248-253. 367.NiedermaierON,SmithML,BeightolLA,Zukowska-Grojec Z, GoldsteinDS, Eckberg DL.Influence of cigarette smoking on human autonomic function. Circulation 1993; 88:562-571. 368. Wallin BG, Sundlof G. Sympathetic outflow to muscles during vasovagal syncope. J Autonom Nerv Sys 1982; 6:287-291. 369. Ziegler MG,EchonC, Wilner KD, Specho P, LakeCR, McCutchen JA. Sympatheticnervouswithdrawalinthevasodepressor (vasovagal) reaction. J AutonNerv Sys 1986;17:273-278. 370. Goldstein DS, Spanarkel M, Pitterman A, Toltzis R, Gratz E, Epstein S, Keiser HR.Circulatorycontrol mechanisms in vasodepressor syncope. Am Heart J 1982; 104:1071-1075.

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HISTORICAL AND CONCEPTUAL INTRODUCTION

Research about central neural regulation of autonomic outflows to the cardiovascular system developed along two lines: efferent and afferent. The former centered on local and systemic effects of stimulation of parasympathetic or sympathetic nerves and the latter on input from internal receptors to the brain. Efforts to identify the central neural sites where afferent reflexive pathways terminate and efferent sympathetic pathways originate continue to this day. Only withinthepastthreedecadeshasneurophysiologicalresearchtracedthe neuroanatomic basis for even the simplest neurocirculatory reflex arc. In 1863, Bernard reported that transection of the cervical spinal cord produced immediate, marked hypotension-probably the first evidence that the brainregulatesoverallcardiovascular“tone.” In 1883,Pavlovreportedhis studies about “centrifugal nerves of the heart” that accelerated and augmented cardiaccontraction(l),andGaskell (2) tracedthesourceofefferent vasoconstrictor fibers to the lateral horns of the spinal cord.By the beginning of the 20th century, the anatomy and physiology of the sympathetic innervation of the heart had been describedin detail (3,4). At about the same time, investigators first demonstrated clearly that stimulating afferent neural pathways to the brain evoked indirect, reflexive cardiovascular effects. In 1836, Sir Astley Cooper showed that occlusion of the common carotid arteries increased blood pressure and heart rate (5). He attributed these effects to cerebral ischemia. Experiments reported by Siciliano in 1900 (6), however, refuted Cooper’s explanation and indicated instead that a signal to the brain emanated from the region of the bifurcation of the carotid artery. In 1923, Hering found that mechanical stimulation of the wall of the carotid sinus, a small area of dilatationin the region of the carotid bifurcation, produced marked bradycardia and hypotension. Cutting a branch of the glossopharyngeal nerve, the carotid sinus nerve (also known as Hering’s nerve), prevented these effects, and stimulation of the nerve reproduced the bradycardia and hypotension (7). This proved the reflexive basis for the effects of carotid occlusion on blood pressure noted by Cooper about a century previously. 137

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Ideas about the organization of brain mechanisms of neurocirculatory regulation also evolved in stages. In 1870, Dittmar (8) reported that destruction ofthemedullaoblongataabolishedpressorresponsestosciaticnerve stimulation, but pontine transection did not, demonstrating probably for the firsttimethatmedullaryvasomotorcentersregulateacutebloodpressure responses.Thenextyear,Owsjannikovnotedthatarterialpressurefell successively after cutting the brainstem between the level of the inferior colliculi andtheobex.Thesefindingsestablishedtheimportanceofthemedulla in circulatory regulation. Numerousattemptsduringthesubsequentcenturyfailedtoidentify specific “centers” in the medulla where lesions could reproduce the hypotension caused by spinal cord section. In 1916, Ranson and Billingsley reported that electrical stimulation of a discrete areas on the dorsal surface of the medulla of the brainstem decreased blood pressure, and stimulation rostral and lateral to this site increased pressure, suggesting the existence of specific cardiovascular centers in the brainstem (9). Wang and Ranson (10) however, found that the dorsal surface areas described by Ranson and Billingsley actually constituted apices of large pressor and depressor triangles, extending dorsoventrally through virtually the entire brainstem. From the 1950s until the 1970s, the view held sway that projections to sympathetic preganglionic neurons derived from diffusely distributed neurons in thereticularformation,andthesummedactivityofthediffusely interconnectedfibers of the“reticularactivatingsystem”generated sympathoneural outflow randomly (1 1,12), as if an impenetrable neuronal thicket intervened between interoceptive input and neurocirculatory output from the brain. Several developments forced reconsideration of this position and led to current concepts. First, most baroreceptor afferents to the brain were found to terminate in a specific cluster of cellsin the dorsomedial medulla, the nucleus of the solitary tract (13,14), a region now known to serve as both a relay and integration center for the baroreflex. The nucleus of the solitary tract constitutes thelikelylocationofthearterial“barostat,”oneofseveral“homeostats” determining internal apparent steady-states, as discussed in the chapter about stress as a medical scientific idea. Second, evidence accumulated that a small collection of neurons in the rostral ventrolateral medulla, corresponding in location to neurons containingphenylethanolamine-N-methyltransferase, provide a major source of projections to the sympathetic preganglionic neurons in the spinal cord (15,16). Third, studies using novel immunohistochemical tools (1 719) showed that ascending and descending information between lower brainstem andhighercenterstravels in tractsofextensivelyarborizedfibersamong relatively few clusters of neural cells, rather than in a diffuse reticular system. Andfourth,neurophysiologicalstudiesdemonstratedthatpreganglionic

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Figure 3-1 Hierarchy of central neural sites regulating autonomic outflows. Main inputs to this system are from cardiovascular and other interoceptors, sense organs relaying to higher centers, and hormones that traverse the imperfect blood-brain barrier of the circumventricular organs. The main source of sympathetic neuronal outflows is the rostral ventrolateral medulla. The vagal parasympathetic outflows derive from the medulla, with other parasympathetic outflows from the midbrain and pons.

sympathetic neurons discharge rhythmically, the rhythmic discharges depending importantly on lower brainstem networks of coupled oscillators generating the rhythm spontaneously-”pacemakers” for sympathoneural outflows(20,2 1). Thus, according to current concepts, organized, periodic discharges of relativelyfewbrainstemneurons,particularlyintherostralventrolateral medulla, drive activity of the spinal preganglionic neurons in a complexly but not randomly determined manner, with influences by other clusters of cells at several sites in the neuraxis. Many studies have elucidated the neuronal circuitry

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connecting these clusters, and a substantial portion of this chapter summarizes those connections. A web of brain centers therefore seems to determine autonomic outflows. Thepathwaysdepicted in thischapterappearcomplex,buttheyactually oversimplifythesituation.Morethanoneneurotransmittercanactonor emanate from the same neurons and can act on more than one type of receptor on the effector cells. Modulatory interneurons within and between areas probably coordinate the functions of the cell clusters. Pathways relaying information in thebrainprobablyusenotonlyneurotransmittersbutalsohormonesand autocrinelparacrine substances. Moreover, static anatomic depictions cannot convey dynamic neurophysiological processes, such as conditioning and arousal, development, and neurodegeneration. Resetting of “homeostats” during stress probably alters the prominence of some centers with respect to others, and the neuroanatomicrepresentationdoesnotportraythislikelyvariability.Most importantly,autonomicoutflowsdonotoccur in isolationbut in dynamic coordinationwiththeorganism’ssensationsandcognitionsandwith locomotionmediated by skeletalmuscle.Earlierconceptsseparatedthe autonomic and somatic nervous systems. The former was thought to concern internal homeostasis and was thought to be regulated by the limbic system, via a diffuse, non-specific reticular activating system; the latter was thought to concern interactions with the external environment. According to more modem concepts,exemplifiedbythatproposed by Blessing(22,23),organismic survival depends on integrated control of behavior and internal physiology, mediated by the brain and occurring via coordinated patterns: In mammals only the brain has the inbuilt programming for patterned coordination of these activities. The terms autonomic nervous system, limbic system and reticular formation are at odds with this patternedcoordination.Theyshouldbe abandonedandreplacedwiththeterm visceral neurons (afferent and efferent) and with reference to relevant specific neural circuitry in the brain ((22), p. 235). The finding of Dahlstrom and Fuxe (24,25) that brainstem catecholaminergic pathways directly innervate large areas of the telencephalon contrastedwiththethenprevalentview,basedonGolgiimpregnationand antegrade degeneration techniques, that ascending pathways from the lower brainstem terminate in the hypothalamus, with only indirect connections from the lower brainstem to the cerebral cortex (26). Numerous subsequent studies

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confirmed and extended the findings of Dahlstrom and Fuxe and usheredin the era of “chemical neuroanatomy.” It is by now clear that, while few in number, central monoaminergic neurons project widelyin the central nervous system and that catecholamines are present in almost all brain areas. Exactly how central catecholaminergic neurochemical pathways jibe with the neuroanatomic web remains incompletely understood, and this chapter includes several examples whereclustersofcatecholamine-containingcellsdonotseemconfinedto neuroanatomically distinct regions. Based on the presence of brain catecholamine pathways and on the sometimes marked behavioral effects of drugs affecting catecholaminergic function, many theories have proposed how central catecholaminergic pathways may participate in a variety of psychological phenomena, such as the state of wakefulness, arousal, emotion, and memory; specific behaviors, such as eating, drinking,thermoregulation,andsexualactivity;anddisorders in psychiatry (schizophrenia, depression, panic-anxiety, anorexia-bulimia, attention deficit disorder) neurology (Parkinsonism, the Shy-Drager syndrome, disorders of memoryandalertness),andcardiology(cardiomyopathy,arrhythmias, neurocirculatory asthenia, hypertension). Sections later in this chapter analyze someofthesetheories.Nevertheless,nostudyhasproventhatany catecholamine in the central nervous system “mediates” any behavior, and no theory has explained how alterations of catecholaminergic function in the brain can account for so many different phenomena. Most remarkably, despite the likely involvement of both the mesotelencephalic dopamine system and the locus ceruleus norepinephrine system in “enabling” the organism’s responses to environmental input, no concepts have integrated the functions of these two catecholaminergic systems. Central neural catecholamines may instead participate only indirectly in regulatingautonomicoutflows,suchas by modulatingtheelaborationof neuroendocrine response patterns during stress and distress. The bases for these relationships may come to light when researchers consider more seriously the integrated patterns of behavioral, neuroendocrine, and physiological changes that occur in response to stressors, and less the roles of specific “regulatory centers” in the brain. At least three types of information lead to the autonomic outflowsafferentnervesfrominteroceptorsandexteroceptors,hormonesthatreach circumventricularorgans,whichlackanefficientblood-brainbarrier,and cognitive simulations presumably arising in the cerebral cortex (Figure 3-1). Of these, the former have received the most intense study. The efferent pathways emerge from the central nervous system at the level of the parasympathetic preganglionic neurons in the brainstem and sacral spinal cord, the sympathetic preganglionic neurons in the thoracolumbar spinal cord, and the chromaffin cells in the adrenal medulla.

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Pathways participating in parasympathetic and adrenomedullary outflows havereceivedlessattentionthanhavecentralpathwaysparticipating in sympathoneural outflows. As discussed below, several central neuroanatomic pathways terminate in the dorsal motor nucleus of the vagus or the nucleus ambiguus, the main sites of origin of vagal preganglionic outflows. Studies about these connections have not included assessments of the functional effects on acetylcholine release in the innervated organs, because of rapid breakdown of theparasympatheticneurotransmitter in theextracellularfluid,technical difficulty in quantifying acetylcholine concentrations, and relative simplicity of neuropharmacologicalmanipulationsandofindirectphysiologicaland neuroendocrine dependent measures. Because of the traditional concept, dating from the writings of Cannon in the early 20th Century, of the sympathetic nervous and adrenomedullary hormonal systems in the “sympathico-adrenal” system, researchers have so far paid relatively little attention to possible separate centralneuralpathwaysmediatingsympathoneuralvs.adrenomedullary outflows. At each ascending neural level beginning with what is probably a single medullary site of initial termination of input from cardiovascular receptors, the complexityofinteractionsincreases,withthelowercenterssubjectto modulation by higher centers. At the lowest level, cardiovascular structures possessintrinsic“tone,”modulated by locallygeneratedfactorssuchas endothelin and nitric oxide. Outflows from spinal preganglionic neurons depend on descending input from higher centers. At the level of the medulla, simple homeostaticreflexesmaintainapparent“steady-states’’ofcardiovascular performance. Operating characteristics of the medullary homeostats reset as part of hypothalamically-elaborated patterns generated at the next higher level. Finally,atthehighestlevels,limbiccentersmodifythehypothalamicallyevoked patterns, based on emotional memory, conditioning; and higher cortical centers mediate simulations and conscious cognitions.

SPINAL CORD The spinal cord is the most distal site of the central nervous system that generates patterns of autonomic activities. The final common pathway for parasympathetic and sympathetic outflows is the preganglionic neuron. As discussed in more detail in the chapter overviewing the autonomic nervous system, cell bodies of the sympathetic preganglionic neurons (SPNs) are located mainly in the intermediolateral columns of the thoracolumbar spinal cord, and cellbodiesoftheparasympatheticpreganglionicneuronsarelocated in brainstem nuclei for the third, seventh, ninth, and tenth cranial nerves and in the intermediolateral columns of the sacral spinal cord.

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Figure 3-2 Descendingpathwaystothesympatheticpreganglionicneurons in the intermediolateral columns of the thoracolumbar spinal cord. A5 = AS region ; RVLM = rostral ventrolateral medulla. The sympathetic preganglionic neurons discharge spontaneously at a slow rate.Theirtonicactivitynormallydepends on inputfromchemoreceptor, somatic, and visceralafferentnervetraffic to thespinalcord andmore

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importantly on descending input from supraspinal structures, as demonstrated by the marked reduction of activity after spinal cord transection. Cell groups in the rostral ventrolateral medulla, the “defense” area of the lateral hypothalamus, and the paraventricular nucleus of the hypothalamus send direct projections to the intermediolateral columns of the thoracolumbar spinal cord, where the sympathetic preganglionic neurons are situated (Figure 3-2). Other supraspinal structures projecting directly to this region include medullary and pontine raphe nuclei and the Kolliker-Fuse nucleus in the parabrachial nucleus complex of the pons(27).

MEDULLA Whereas feedback from the periphery contributes relatively little to direct regulation of sympathetic preganglionic neuron activity, feedback becomes a prominent feature at the level of the medulla, where visceral afferent fibers synapse. Medullary cardiovascular centers therefore subserve simple homeostatic reflexes. Rostral Ventrolateral Medulla A cluster of epinephrine-synthesizing neurons (i.e., neurons containing immunoreactive phenylethanolamine-N-methyltransferase), the C 1 neurons of therostralventrolateralmedulla(RVLM),constituteamajorsourceof projections determining tonic discharge of sympathetic preganglionic neurons to the heart, vasculature, and adrenal gland (28). RVLM cells are not thought to mediate sweating, pupillary dilation, or piloerection(29). Therostralventrolateralmedullaregioncontainingthe C l cellsisa subdivisionofthenucleusparagigantocellularislateralis(PGi).The nomenclature is confusing, because the neuroanatomic localization does not coincide exactly with the regional neurochemistry: the epinephrine-containing cells of the rostral ventrolateral medulla are not confined specifically in this nucleus (30). Moreover, rostral ventrolateral medulla cells contain many other potential neurotransmitters besides epinephrine, including neuropeptide Y, yaminobutyricacid,glutamate,substance P, acetylcholine,enkephalin, somatostatin,glucagon,andnorepinephrine.Inhumans,becauseofthe relatively large size of the olivary nuclei, the C l cells lie more in the middle of the dorso-ventral plane than in rats. The rostral ventrolateral medulla participates not only in tonic but also in reflexive regulation of sympathetic vasomotor tone. Neurons in the nucleus of the solitary tract project to rostral ventrolateral medulla neurons, either directly or via cells in the caudal ventrolateral medulla;bilateral destruction of the rostral ventrolateral medulla abolishes arterial baroreflexes.

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Figure 3-3 Pathways projecting to the rostral ventrolateral medulla

(RVLM). PVN paraventricular nucleus; LAT = lateral hypothalamic area; LC = locus ceruleus; A5 = A5 noradrenergic cells; PBK-F = parabrachial area, Kolliker-Fuse nucleus; NTS = nucleus of the solitary tract; CVLM = caudal ventrolateral medulla.

=

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Figure 3-4 Pathwaysemanating from therostralventrolateral medulla (RVLM) .PVN = paraventricular nucleus; MP0 = median preoptic area; LC = locus ceruleus; A5 = A5 noradrenergic cells; PB = parabrachial nucleus; NTS = nucleus of the solitary tract.

Numerous centers in the brain project to the Cl cells (Figure 3-3). These include, in the medulla, the nucleus of the solitary tract, A1 neurons of the caudalventrolateralmedulla,raphenuclei,vestibularnuclei,andthe circumventricular area postrema (3 1); in the pons, A5 and locus ceruleus cells, the parabrachial nucleus, and the Kolliker-Fuse nucleus; in the midbrain, the

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periaqueductal gray region; in the hypothalamus, the paraventricular nucleusand lateral hypothalamic area; and, in the limbic system, the amygdala. Efferentsfrom C l cells project widely in the central nervous system (Figure 3-4). In additiontodescendingtotheregionofthesympathetic preganglionicneurons,the C l cellsprojecttothelocusceruleus,the parabrachial nucleus, the paraventricular and median preoptic nuclei of the hypothalamus,theamygdala,raphenuclei,spinaltrigeminalnuclei,the cerebellum, and the nucleus of the solitary tract. The C l neurons that project rostrally to the hypothalamus probably differ from those that project caudally to the intermediolateral columns of the spinal cord (32). About 113 of the C1 cells projecttotheintermediolateralcolumns,about 1/2 ofrostralventrolateral medulla projections the to intermediolateral columns contain phenylethanolamine N-methyltransferase, and about2/3 of the projections from phenylethanolamine N-methyltransferase-containing cells to the intermediolateral columns derive from C l cells (33). Rostral ventrolateral medulla cells mediating sympathetic innervation of theheart,vasculature,andadrenalglandshaveadegreeoftopographic organization (34). Cells regulating cardiac sympathetics overlapbut are centered somewhat rostromedially tocells regulating sympathetic vasoconstrictor outflow to skeletal muscle (35). Thecarotidsinusnervecarriesnotonlybaroreceptorbutalso chemoreceptor information to the brainstem, producing reflexive changes in sympatheticnervoussystemoutflow;andtherostralventrolateralmedulla contains not only neurons that participate importantly in baroreflex circulatory regulation but also non-catecholaminergic neurons that discharge during the inspiratory or expiratory phases of respiration. Cellular activation, as indicated by immunoreactivity forfos, the protein product of the immediate early gene,cfos, occurs in the rostral ventrolateral medulla in response to hypoxia, associated with increased fos immunoreactivity also in the nucleus of the solitary tract, intermediate and caudal parts of the ventrolateral medulla; the Kolliker-Fuse nucleus, locus ceruleus, subceruleus andA5 area in the pons; the periaqueductal gray in the midbrain; and the paraventricular, supraoptic, and arcuate nuclei in the hypothalamus (36). The increased activity of rostral ventrolateral medulla cells in thissettingcouldunderlieorcouldresultfromhypoxia-induced increases in blood pressure. The projections from the Kolliker-Fuse nucleus and nucleus of thesolitary tract to therostral ventrolateral medulla probably actually convey the excitatory chemoreceptor signals(36,37). Caudal Ventrolateral Medulla

Belowtheleveloftheobex,caudaltotheregionof ventrolateral medulla contains A1 noradrenergic cells. Just as

C l cells,the in the rostral

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Figure 3-5 Pathwaysemanatingfromthecaudalventrolateral medulla (CVLM). PVN = paraventricular nucleus; LAT = lateral hypothalamic area; SON = supraoptic nucleus; PAG = periaqueductalgrayregion; PBK-F = parabrachialarea, KollikerFuse nucleus; RVLM = rostral ventrolateral medulla; NTS = nucleus of the solitary tract; NA = nucleus ambiguus.

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ventrolateral medulla no localized neuroanatomical entity corresponds exactly with the location of the C l cells, in the caudal ventrolateral medulla (CVLM) none corresponds exactly with the location of A1 cells(38). Electrical or chemical stimulation of caudal ventrolateral medulla neurons produces opposite effectson sympathetic outflow and blood pressure from those produced by stimulation of rostral ventrolateral medulla neurons (38,39). Blood pressure and pulse rate fall, and caudal ventrolateral medulla stimuation blunts pressor and renal neural responses to hypothalamic stimulation. Conversely, electrolytic lesions of the caudal ventrolateral medulla increase pressure by augmentingsympatheticnervoussystemoutflowsandvasopressinrelease (38,40-43).

Few if any noradrenergic neurons in the caudal ventrolateral medulla project directly to the sympathetic preganglionic neurons, and those that do probably are not catecholaminergic. Instead, axons from neurons of the caudal ventrolateral medulla project to the rostral ventrolateral medulla, the nucleus of the solitary tract, and the nucleus ambiguus and ascend to the Kolliker-Fuse nuclei, the parabrachial nuclei, the periaqueductal gray regions, the intralaminar nuclei of the thalamus, the facial nucleus, the paraventricular and supraoptic nuclei of the hypothalamus, the median eminence, the medial preoptic area, and through the lateral hypothalamus to the bed nucleus of the stria terminalis and organum vasculosum of the lamina terminalis (Figure3-5 depicts some of these projections). The projections to the paraventricular nucleus, basal nucleus of the stria terminalis, supraopticnucleus, median eminence, dorsal hypothalamus, and dorsomedial hypothalamic nucleus appear to be noradrenergic, since they are sensitive to 6-hydroxydopamine,which destroys catecholaminergic terminals. Caudalventrolateralmedullaneuronsinhibitsympatheticactivity primarily by acting on neurons of the rostral ventrolateral medulla region, both directlyandalsoindirectlyviaactions in thehypothalamus.Becauseof extensiveprojections-manyofthemnoradrenergic-fromthecaudal ventrolateral medulla cells to the magnocellular cells of the paraventricular nucleus, many studies have considered the relationship between this medullary region and hypothalamic release of vasopressin. Electrical stimulation of the caudal ventrolateral medulla increases firing rates of vasopressin-containing neurons in the paraventricular nucleus and supraoptic nucleus and evokes release ofvasopressin.Conversely,inhibitionofneuronalactivityinthecaudal ventrolateral medulla abolishes thevasopressin response to hypotension (44). Nucleus of the Solitary Tract

After Hering’s discovery of the reflexive role of the carotid sinus nervein blood pressure regulation, the discovery of where in the brain this nerve leads took about another half century. It is by now known that afferent fibers in the

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Figure 3-6.Pathways Emanating from the nucleus of the solitary tract (NTS) PVN LC = locus ceruleus; PB = parabrachialarea; RVLM =

= paraventricular nucleus;

rostralventrolateralmedulla; DMN-X = dorsalmotor nucleus of the vagus nerve; = nucleus of the solitary tract; CVLM = caudalventrolateralmedulla; NA = nucleus ambiguus.

NTS

glossopharyngeal nerve from carotid sinus mechanoreceptors and in the vagus nerve from cardiopulmonary mechanoreceptors synapse in the nucleus of the solitary tract(NTS, Figure 3-6 (13,14)). The nucleus of the solitary tract relays baroreceptor and chemoreceptor information to other brainstem regions involved in relatively simple, “local”

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reflexive responses of autonomic outflow and also to several rostral structures, includingthehypothalamus,responsibleforeliciting“longdistance” neuroendocrine and behavioral patterns. The efferent projections from the nucleus of the solitary tract probably define the central neural circuitry of the baroreflexes (Figure 3-7), and the afferents to the nucleus of the solitary tract from other central neural sites probably indicate the circuitry for modulation of those reflexes. Many central neural sites interconnect with the nucleus of the solitary tract, including the hypothalamic paraventricular nucleus, the central nucleus of the amygdala, the parabrachial nucleus, and other catecholaminecontaining cell groups in the brainstem. Neurons of the nucleus of the solitary tract do not appear to project directly to sympathetic preganglionic neurons. Baroreceptor stimulation increases metabolic activity, as measured using the 3H-2-deoxyglucose autoradiographic technique, in the nucleus of the solitary tract,thedorsalmotornucleusofthevagus,thenucleusambiguus,the parabrachial nucleus, the inferior olivary nucleus, the ventrolateral medulla, and the hypothalamic paraventricular and supraoptic nuclei (19). Studies based on immunoreactivefis to indicate cellular activation have shown that baroreceptor stimulation increases activity of cells in the nucleus of the solitary tract, area postrema,caudalandintermediateventrolateralmedulla,theparabrachial complex, and the central nucleusof the amygdala (37,45). Most of the activated cellsarenotcatecholaminergic-i.e.,theydonotco-expresstyrosine hydroxylase. Hypotension also increasesfis immunoreactivity in these regions, as well as in the rostral ventrolateral medulla, the AS region, the locus ceruleus and subceruleus, the paraventricular nucleus, the supraoptic nucleus, the arcuate nucleusandthemedialpreopticarea (45). Unlikehypertension,however, hypotension increasesfis expression in catecholaminergic cells in these regions, consistent with the view that increased synthesis of catecholamines in the brain playsarole in reflexiveincreases in sympathetically-mediatedreleaseof catecholamines in the periphery. Sincethenucleusofthesolitarytractdoesnotcontainvagal preganglionic neurons, the baroreceptor-cardiac reflex is not monosynaptic. Baroreceptor-sympathetic reflex arcs may include some direct projections from the nucleus of the solitary tract to C l neurons (46); however, evidence has supportedmainlyindirectprojections,viaA1interneurons in thecaudal ventrolateralmedulla (47). Thus,arterialbaroreceptor-sympatheticand baroreceptor-vagal reflexes consist of polysynaptic arcs that often include caudal ventrolateral medulla interneurons (Figure3-6). Anterogradely labelled terminals from the nucleusof the solitary tract can surround retrogradely labelled neurons in the dorsal motor nucleus of the vagus (46), so that a disynaptic baroreceptor-vagal reflex can occur. Neurons have been identified electrophysiologically in the caudal ventrolateral medulla in a region

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close to the nucleus ambiguus that are activated orthodromically by stimulation of the aortic nerve and antidromically by stimulation of the rostral ventrolateral medulla (48). Thus, it appears that arterial baroreceptor-caridovagal reflexes also canconsistofpolysynapticarcsthatincludecaudalventrolateralmedulla interneurons. The nucleus of the solitary tract receivesnot only cardiovascular but also other interoceptive afferent information, and termination sites of the efferent projections, such as to the nucleus ambiguus, relate not only to cardiovascular reflexregulationbutalsotorespiratoryandgastrointestinalfunction.The anterior portion of the nucleus of the solitary tract appears to receive gustatory and the posterior portion visceral sensory input. Consistent with the central role of the nucleus of the solitary tract in reflexive regulation of the circulation, bilateral ablation of the nucleus produces hypertension in rats (49-51) and rabbits (40) and labile hypertensionin cats (52). As indicated above, baroreflex pathways after the initial synapse in the nucleus of the solitary tract include the rostral ventrolateral medulla (46), caudal ventrolateralmedulla(47,48),andthenucleusambiguusofthemedulla. Although the nucleus of the solitary tract probably does not project directly to the locus ceruleus, the source of most of the norepinephrine in the central nervous system, the nucleus of the solitary tract and locus ceruleus probably interact functionally, since alterations of cardiovascular interoceptive input affect locusceruleusneuronalfiring (53) andreleaseofnorepinephrine in the hippocampus(54), aregionwithnoradrenergicinputderivedvirtually exclusively from the locus ceruleus. The parabrachial nucleus appears to serve as the main relay station for ascending interoceptive information from the nucleus of the solitary tract to the forebrain. Sensory input to the central nervous system from the baroreceptors tends to inhibit cortical activity. In the 1960s, several investigators proposed that baroreceptor afferent activity influences the state of wakefulness or emotional behavior. According to a concept suggested by Lacey ( 5 5 ) , the hypertension accompanying acute emotional behaviors might not indicate “arousal” SO much as the organism’s attempt to restrain further activation by external excitatory processes-i.e., that baroreceptor activation evokes a “stimulus barrier” for gating environmental input. In 1979, Dworkin et al. (56) took this view to an extreme,suggestingthatclinicalhypertensionreflectsanattempttouse increased baroreceptor afferent activity to counter effects of noxious stimulation. These hypotheses did not consider the consequences of acute and chronic baroreflex resetting in acute distress and in chronic hypertension. Since then, researchers seem to have paid little attention to the role of the nucleus of the solitary tract in behaviors mediated by higher cortical structures.

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The midline raphe nuclei of the medulla correspond in general to the medullary “depressor area” (10,57). Stimulation of the medial medulla typically decreases blood pressure and sympathoneural activity(58). Some neurons in the medial medulla project directly to sympathetic preganglionic neurons. Since electrical stimulation of the paramedian reticular nucleus attenuates or abolishes pressor and plasma catecholamine responses to stimulation of the dorsal or ventrolateral medulla (59), the midline nuclei may exert inhibitory modulation of excitatory pathways. y-aminobutyric acid (GABA) and serotonin (5-HT) appear to interact as neurotransmitters responsible for inhibition of sympathoneural outflows during activation of this midline area, with the 5-HT neurons exerting a tonic excitatory influence at the level of the sympathetic preganglionic neurons in the spinal cord and the GABA-ergic neurons exerting a modulatory, inhibitory interneuronal action at the level of the rostral ventrolateral medulla (27,60,61). The dorsal raphe does not project directly to the locus ceruleus; however, caudal raphe nucleiprojecttothePGiarea,which in turnprovidesamajorsourceof innervation of the locus ceruleus (62). Other Medullary Sites

Electricalstimulationofthedorsomedialmedullaelicitslarge, sympathetically-mediated increases in bloodpressure.Sincedescending pathways from the rostral ventrolateral medulla to the spinal cord traverse the dorsal medulla, activation of the fibersin passage could explain the responses to electrical stimulation of the dorsal medulla; however, microinjection of the neuronal excitant, sodium glutamate, in the dorsal medulla also produces large pressor responses and increases in plasma catecholamine levels (59), suggesting that dorsal medullary cell bodies provide another source of excitatory neuronal outflow from the medulla to the sympathetic preganglionic neurons in the intermediolateral columns. Near the ventricular surface of the rostral dorsomedial medulla, cells of the nucleus prepositus hypoglossi (PrH) send inhibitory efferents to the locus ceruleus (63,64). Reciprocal interconnections of the PrH area with vestibular nuclei, cerebellum, cerebral cortex, and projections to the inferior olive, the superior colliculus and pretectum, and extraocular motor nuclei suggest that the PrH participates in the sense of spatial orientation of the organism and ocular gaze. The input from the PrH to the locus ceruleus seems mainly inhibitory; if so, then the activation of locus ceruleus cells during vigilance or orienting behaviors would appear to depend on phasic disinhibition of input from the PrH.

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Medullary sources of parasympathetic cardiac outflows are discussed later in this chapter.

PONS Locus Ceruleus

The locus ceruleus(LC), a small cluster of several thousand cell bodiesin the dorsal pons, including the A6 noradrenergic cells, gives rise to most of the norepinephrine in the brain. Extensive arborization of locus ceruleus neurons explains how so few cells can project so widely in the central nervous system. Noradrenergic neurons of the locus ceruleus project to the thalamus (especially the anteroventral nucleus), the hypothalamus (including the paraventricular, periventricular, supraoptic, and dorsomedial nuclei), the hippocampus, the septal area(includingthebasalnucleusofthestriaterminalis,thecentraland basolateral nuclei of the amygdala, and the olfactory bulb), the cerebellum, and the neocortex, as well as to several brainstem nuclei thought to function as primary sensory or association centers. Locus ceruleus neurons do not project heavily to norepinephrine-containing terminals in the nucleus of the solitary tract (65); andalthoughthelocusceruleusprojectstothehypothalamus, norepinephrine-containing cells in the medulla (A1 and A2 cells) constitute the mainsourceofnoradrenergicprojectionstothisregion.Destructionof catecholaminergiccells in thelocusceruleus, by localinjectionof 6hydroxydopamine, decreases norepinephrine concentrations in the A1 and A2 regions (66), suggesting an indirect route by which the locus ceruleus can influence hypothalamic function. Thelocusceruleusalsodoesnotprojectextensivelydirectlyto sympathetic preganglionic neurons and therefore probably participates only indirectly in regulation of sympathoneural outflows. Locus ceruleus fibers are thoughttoinnervatesacralintermediolateralcellcolumnsmediating parasympathetic outflow (67). Fibers from the locusceruleushbceruleus area or medullary clusters may innervate dorsal horn cells mediating nociception (6871), but few if any project to the intermediolateral columns of the thoracic 1/3 of the norepinephrine spinal cord. The locus ceruleus accounts for about content of the rat spinal cord, the remainder apparently derived mainly from other pontine cell groups. Electrical stimulation of the locus ceruleus increases blood pressure (72), and since ipsilateral ablation of the rostral ventrolateral medulla abolishes the pressor response, the pathway mediating the response traverses the rostral ventrolateral medulla. Thediffuseprojectionsfromthelocusceruleuscontrastwiththe relativelyfewsourcesofafferentsto it-the PGiregionoftherostral

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ventrolateral medulla, corresponding neuroanatomically to the neurochemical localization of C 1 epinephrine- and A 1 norepinephrine-containing cell bodies near the ventral surfaceof the brainstem; and the PrH of the rostral dorsomedial medulla, corresponding to the localization of C3 adrenergic neurones near the dorsal surface of the medulla bordering the fourth ventricle (63,73). Whereas the central nucleus of the amygdala and the nucleus of the solitary tract project heavily to nearby parabrachial area neurons, they do not appear to innervate the locus ceruleus directly. Locus ceruleus cell bodies also receive noradrenergic innervation via collateral axons from other locus ceruleus cells, helping to explain concerted discharges of locus ceruleus cells during sensory responses and concerted inhibition of firing during paradoxical sleep. These two main sources of afferents to the locus ceruleus seem to exert different functions, mediated by different transmitters. Stimulation of the PGi area predominantly excites locus ceruleus neurons, possibly via an excitatory amino acid acting at kainate receptors. Considering the presence of C l cells in thePGiregion,PGiactivationmightalsoreleaseanagonistoccupying inhibitory a2-adrenoceptors in the locus ceruleus. Stimulation of the PrH area generally inhibits locus ceruleus firing, possibly by release of an inhibitory amino acid. The neuroanatomic and neurophysiologic findings have led to the suggestion that locus ceruleus neurons receive phasic, excitatory inputs in response to sensory stimulation and tonic, inhibitory input that modulates locus ceruleus excitability in different behavioral states. The restricted afferent control of the locus ceruleus from the lower brainstem indicates no direct forebrain regulation of locus ceruleus firing, whereas the difhse forebrain projections from thelocusceruleussuggestapossibleroleofthelocusceruleus in global functions such as “gating,” “enabling,” or “vigilance.” Directionally similar changes in locus ceruleus activity and in values for indices of sympathoneural activity occur during a variety of experimental manipulations.Changes in bloodpressureproduced by administrationof vasoactive drugs exemplify internal, non-noxious stimuli. Acute increases in blood pressure decrease locus ceruleus cell firing and norepinephrine release and decrease peripheral (splanchnic or renal) sympathoneural activity; conversely, acute decreases in blood pressure, such as induced by sodium nitroprusside administration, increase both locus ceruleus and peripheral sympathoneural activity (53,66,74-76). Bilateral cervical vagotomy abolishes both the central locus ceruleus and peripheral sympathoneural responses to hemorrhage and abolishes the locus ceruleus responses but leaves intact the peripheral responses to manipulations of blood pressure, suggesting that the locus ceruleus responds especially sensitively to changes in input from the low-pressure cardiopulmonary baroreceptors. Thelocusceruleusalsorespondstochanges in inputfromother interoceptors, including stretch receptors in the walls of the urinary bladder,

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distal colon, or stomach. One may speculate that intense interoceptive input evokescorticalactivationviapathwaysthroughthelocusceruleus.Since stimulationofcutaneousnociceptorsactivateslocusceruleusneurons in anesthetizedrats (75), locusceruleusresponsestoexteroceptivenoxious stimulation do not require consciousness. Whether locus ceruleus neurons respond to non-distressing exteroceptive input remains unclear (77). In cats, locus ceruleus single-unit activity increases in animals exhibiting defense reactions during exposure to an aggressive cat or to a dog but not during exposure to a non-aggressive cat(78). In rats, however, locus ceruleus cells respond robustly to non-distressing exteroceptive input(79). Inconsistencies among studies on this topic may to some extent have resulted from inadequate attention to defining characteristics of distress and to the validity of indices of distressin animals. During rapid eye movement (REM) sleep, locus ceruleus firing decreases markedly or disappears (80); however, skeletal muscle sympathoneural activity increases (81), indicating that locus ceruleus neuronal activity and peripheral sympathoneural activity can change differentially at least in some settings.

A5 Region In contrast with the mainly ascending noradrenergic projections from the locusceruleusofthepons,morethan 90% oftheneurons in theA5 noradrenergic region of the ventrolateral pons project caudally to preganglionic neurons in the spinal intermediolateral cell columns (82) or neurons in lamina I of the dorsal horn(83,84). A5 neurons also project to the perifomical area of the hypothalamus(the“HACER”region,discussedbelow),themidbrain periaqueductal gray region, the parabrachial area, the nucleusof the solitary tract, and the central nucleusof the amygdala and connect reciprocally with the caudal ventrolateral medulla (85). The physiological roles of A5 neurons remain unclear. A5 cells may facilitate chemoreflex-induced stimulation of sympathetic outflows (86), but if so this occurs by mechanisms independent of norepinephrine (87). They may participate in thermoregulation (88), lipolysis (89), responses to hypotensive hemorrhage (go), or, via a descending pathway to the dorsal horn, nociception (83,84).

Activation of A5 cells appears to elicit complex regional sympathetic and hemodynamic changes. For instance, in conscious rabbits, glutamate-induced cellular activation in the A5 elicits small increases in renal sympathetic nerve traffic and no change in arterial pressure (91).

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MIDBRAIN Periaqueductal Gray

The periaqueductal gray (PAG) regionof the midbrain acts as a relay and integrationstationbetweenupperandlowerbrainstemstructures in the expression of emotion-related behavioral responses. Periaqueductal gray cells havebeen organized in overlapping longitudinal columns, including the ventrolateral (vlPAG) and lateral (IPAG) columns (9294). The vlPAG seems associated with passive, immobile, quiescent coping behaviors and the lPAG with active, defensive behaviors, including running and vocalization. The rostral portion of the lPAG is a “fight” region, stimulation of which increases skeletal muscle, renal, and mesenteric vascular resistance and threat behavior; in contrast, stimulation of the caudal “flight” region elicits skeletal muscle vasodilation and avoidance behavior. Consistent with these different behaviors, stimulation of the vlPAG decreases blood pressure and heart rate and induces a state of quiescence and hyporeactivity, whereas stimulationof the lPAG increases blood pressure and heart rate. The periaqueductal gray projects not only to vagal preganglionic neurons but also to sympathetic preganglionic neurons, mainly indirectly via the rostral ventrolateral medulla (95,96). The vlPAG also projects, however, to the caudal medial medulla and to the caudal ventrolateral medulla, stimulation of which evokes vasodepression (97). The periaqueductal gray figures prominently in nociception (98). In the gray matter of the spinal cord, the most dorsally situated cells, in lamina I, respond specifically to noxious and thermal stimuli, contributing fibers to the contralateral spinothalamic tract (99). In cats, three times as many lamina I neurons project to the periaqueductal gray as to the thalamus (100). IPAG stimulationrapidlyelicitsopiate-independentanalgesia,asaresult of interference with transmission of primary nociceptor information in the dorsal horn, whereas vlPAG stimulation gradually elicits opiate-dependent analgesia. a2-Adrenoceptors in the dorsal horn appear to mediate the anti-nociceptive action of the vlPAG (101). Consistent with the view that visceral nociceptor stimulation elicits passive coping, whereas cutaneous nociceptor stimulation is more likely to elicit active coping, deep somatic or visceral pain selectively activates the vlPAG(93) The periaqueductal gray also participates importantly in central nervous system regulation of micturition(1 02). In the cat, four brainstem regions appear to regulate micturition-Barrington’s nucleus (or the pontine micturition center) in the dorsomedial pons, the periaqueductal gray, the preoptic area of the hypothalamus, and an area in the ventrolateral pons called the L-region. It has beensuggestedthatcells in Barrington’snucleusdirectlyexcitebladder

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motoneurons and indirectly inhibit internal urethral sphincter motoneurons, preoptic hypothalamic cells regulate initiation of micturition, L-region cells control motoneuronsinnervatingthepelvicfloor(includingtheexternalurethral sphincter), and periaqueductal gray cells receive afferent input about bladder filling.Positronemissiontomographicscanningstudiesofhumanshave indicated activation of the same regions associated with urination or the attempt to urinate (102). Finally, the periaqueductal gray participates in vocalization-particularly non-verbal, emotional-related behaviors such as laughing, crying, and moaning (103). Thus, the periaqueductal gray receives input from sense organs, limbic structures probably related to motivation, the anterior cingulate cortex, and of the proprioceptors in the larynx and lungs, the latter routed via the nucleus solitary tract.

HYPOTHALAMUS The hypothalamus regulates functions of internal organs indirectly, via expressionofcoordinated,patternedresponsesofseveralneuroendocrine systems,includingthesympatheticnervoussystemandadrenomedullary hormonalsystem.Learning,memory,attention,andmotivation,involving limbic and higher cortical centers, modify elicitationof these patterns. Whereasmedullarymechanismsdeterminingsympatheticoutflow subserve relatively simple homeostatic reflexes, higher centers modify activity of themedullarycentersbyresettingthereflexes,inessencere-defining homeostasis (104). Clusters of hypothalamic cells determine the expression of patterned neuroendocrine responses during stress; however, littleis known about interactions among these clusters during different stress responses. Instead, investigatorshaveusuallyattemptedtoidentify“regulatory”centersor neurochemical pathways for particular systems or for hemodynamic parameters in anesthetizedanimals,independentofthebehaviorssubservedunder naturalistic conditions. One can view the hypothalamus as consisting of several groups of cells thattransduceenvironmentalperceptionsandemotionalexperiencesinto autonomic responses. The paraventricular nucleus and lateral hypothalamic area have attracted particular attention as sites of origin for both direct and indirect projectionstothesympatheticpreganglionicneurons.Thesehypothalamic regionsreceiveinputfromseverallowerbrainstemnucleiresponsiblefor homeostatic circulatory regulation, as well as from the limbic cortex. Stimulation or destruction of hypothalamic nuclei produces disturbances of blood pressure, body temperature, drinking, eating, sexual activity, emotional behavior, and sleep, all accompanied by changes in sympathoneural activity. Electrical stimulation of different hypothalamic regions can elicit markedly

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different patterns of responses of plasma norepinephrine and epinephrine levels and associated cardiovascular responses. When hypothalamic stimulation elicits “fight or flight” behavior, however, plasma levels of both catecholamines virtually always increase. Traditionally, the hypothalamus has been divided neuroanatomically into 3 longitudinal zones (periventricular, medial, and lateral) and 4 rostro-caudal levels (preoptic, supraoptic, tuberal, and mammillary)-i.e., into 12 compartments. The periventricular zone contains magnocellular neurosecretory cells that regulate posterior pituitary function and parvocellular cells that project to autonomic centers in the brainstem and spinal cord. This zone also contains the suprachiasmatic nucleus, which receives input from the retina and appears to generateneuroendocrineandbehavioralcircadianrhythms.Inputstothe periventricular zone derive from the lateral and medial zones; the bed nucleus of thestriaterminalis,amajorway-stationforfibersfromtheamygdalaand hippocampus; some brainstem cell groups; and the circumventricular subfornical organ. The medial zone appears to receive cognitive inputs from the limbic systemand,toalesserextent,visceralinputsfromlowerbrainstemsites, relaying ascending or descending information via the medial forebrain bundle especially to the lateral hypothalamic zone, the amygdala and septum, midbrain central gray region, and portions of the periventricular zone. The mammillary body in the medial zone may participate in learning and memory processes, the ventromedialnucleus in lordosisreflexes,andthemedialpreopticarea in parentalandthermoregulatorybehaviors.Thelateralzoneisthoughtto participate in cortical arousal and autonomic and cardiovascular accompaniments of emotional behaviors, as discussed below. Cells in this zone often project to theperiventricularzone,thelimbicsystem,thetelencephalon,andcellsof origin of effector somatomotor and autonomic systems. Hessdistinguishedananterior“trophotropic”zone,involvedwith vegetative, inwardly-directed responses, and an “ergotrophic” posterior zone, stimulation of which elicits defensive or attack behavior (Hess, 1949). Hess’s work indicated an important role of the posterolateral hypothalamus in the interpretation of sensory information and expression of emotional behaviors such as eating and drinking, aggression, and reproduction. He characterized the feline“defenseresponse” in terms of aconstellationofbehavioralsigns: alerting,turningthehead,archingtheback,mydriasis,earflattening, piloerection,hissing,growling,andclaw-baring,culminating in sudden, directed attack accompanied by marked cardiovascular changes. Electrical or chemical stimulation of the hypothalamic “defense area” increases heart rate and blood pressure by increasing sympathetic outflow to most vascular beds and increasing nerve traffic to the adrenal gland, with preserved skeletal muscle bloodflow.Lateralhypothalamicneuronsappeartomediateconditioned, sympathetically-mediated cardiovascular responses, and the neurocirculatory

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accompaniments of emotional behaviors depend on this integrative function. Thus, lesions of the lateral hypothalamus attenuate classically conditionedblood pressure responses, whereas unconditioned pressor responses to electric shock and conditioned behavioral responses are preserved 05). (1 Paraventricular Nucleus

Theparaventricularnucleus(PVN)containsnon-catecholaminergic, vasopressin-synthesizing magnocellular neurons that project to the median eminence (a relay center for anterior pituitary release of corticotropin), to the posterior pituitary (the site of oxytocin and vasopressin secretion), and to the lower brainstem and spinal cord. Cells in three locations provide the main innervation of the magnocellular neurons-A1 cells of the caudal ventrolateral medulla, the subfornical organ, and the median preoptic nucleus. A 1 cells provide the main source of ascending baroreceptor information to the magnocellular neurons (Figure 3-7). Conversely, paraventricular nucleus stimulation can activate the same cell bodies of the nucleusofthesolitarytractthatantidromicvagalstimulationactivates, indicatingthattheparaventricularnucleusplaysaroleinmodulationof medullary baroreflex mechanisms by higher centers. In general, paraventricular nucleus stimulation and arterial baroreflex stimulation produce opposite effects oncellularsingleunitactivity in thenucleusofthesolitarytract(106). Although the paraventricular nucleus cells synthesize vasopressin, and although exogenously administered vasopressin increases blood pressure, the hypertension produced by paraventricular nucleus stimulation in rats does not depend on vasopressin release (107). The paraventricular nucleus also contains parvocellular neurons that synthesize any of several peptides, including corticotropin-releasing hormone, enkephalins, cholecystokinin, and (in adrenalectomized animals) vasopressin and angiotensin 11. Vasopressin, corticotropin-releasing hormone, and angiotensin I1 all increase pituitary release of corticotropin, and circulating glucocorticoids feedback-inhibit synthesis of all three peptides. The dorso-medial parvocellular portion of the paraventricular nucleus contains densely concentrated corticotropin-releasing hormone neurons that project heavily to the median eminence, where the hormone is released into the portal circulation to the anterior pituitary. The cerebral cortex provides indirect inputtothecorticotropin-releasinghormone-synthesizingcellsinthe paraventricular nucleus, via the hippocampus and amygdala through the basal nucleus of the stria terminalis. Neurons in this same dorsomedial parvocellular region of the paraventricular nucleus receive noradrenergic input fromA2 cells in the nucleus of the solitary tract, adrenergic innervation from the C1-C3 cells, and serotonergic innervation from midbrain raphe nuclei. Afferents from the

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PVN

'Also Cl, C2, C3

Figure 3-7 Pathways to the paraventricular nucleus of the hypothalamus (PVN). SS somatostatin; TRH = thyrotropin-releasing hormone; CRH = corticotropinreleasing hormone; AVP = arginine vasopressin; OXY = oxytocin; SON = supraoptic nucleus; A6 = locus cemleus noradrenergic cells; PB = parabrachial area; A2 = nucleus of the solitary tract noradrenergic cells; A1 = caudal ventrolateral medulla noradrenergic cells. =

nucleus of the solitary tract to the parvocellular region also ascend indirectly via the parabrachial nucleus andA1 and C1 cells. Parvocellular neuronsof the paraventricular nucleus send long descending mons to the nucleusof the solitary tract, the dorsal motor nucleusof the vagus inthemedulla,anddirectlytosympatheticpreganglionicneurons.The neurotransmitter or transmitters used by the parvocellular paraventricular nucleus cells in producing sympathoexcitation remain unidentified.

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Electrical stimulation of the paraventricular nucleus in rats evokes a circulatory pattern reminiscent of that accompanying the defense reaction in cats, with increased sympathoneural outflow, tachycardia, hypertension, renal and splanchnic vasoconstriction, inhibition of baroreflex-mediated bradycardia, and skeletalmusclevasodilation.Thehindlimbvasodilatorresponseseemsto (108) depend on adrenomedullary release of epinephrine. Porter and Brody suggested that the pathway from the paraventricular nucleus to the nucleus of the solitary tract specifically mediates adrenomedullary catecholamine secretion and that the pathway from the paraventricular nucleus to the rostral ventrolateral medulla specifically mediates sympathoneural vasoconstriction. Leptin, secreted by adipose tissue, decreases food intake. When given i.v., leptin increases activity of parvocellular neurons in the paraventricular nucleus that project to sympathetic preganglionic neurons (109). The increased paraventricular nucleus cellular activity appears to involve a pathway from the ventromedialhypothalamicnucleus(110).Thispathwaymayprovidea neuroanatomic basis for effects of leptin on thermogenesis mediated by the autonomic nervous system.

HACER In non-human primates, cells determining cardiovascular responses during the defense reaction reside in the lateral hypothalamus-perifomical area, called the“HACER,”for“hypothalamicareacontrollingemotionalresponses.” Withoutformingadiscretenucleus,HACERcellsprojectbothtothe sympathetic preganglionic neurons and to the rostral ventrolateral medulla. Stimulation of HACER cells produces rapid renal vasoconstriction, tachycardia, hypertension,anddelayedincreases in skeletal muscle blood flow. Innonhuman primates, destruction of the HACER region eliminates autonomicallymediated cardiovascular responses but does not alter behavioral manifestations of conditioned emotional responses (1 1 l), analogous to the above findings in rats. HACER cells, therefore, may link behavioral with autonomic concomitants of emotion in primates. Densedescendinginputstothelateralhypothalamusarisefromthe amygdala, septum, and hippocampus, and pontine A6 andA I and medullary A1 andA2cellsprovideascendingnoradrenergicinputtotheposterolateral hypothalamus. Projections from the lateral hypothalamus reach virtually the entire central nervous system, including the cortical mantle, amygdala and septum, parts of the thalamus, most of the rest of the hypothalamus, and numerous lower brainstem sites (often with reciprocal innervation of the lateral hypothalamus), and the spinal cord. Posterior hypothalamic stimulation interferes with arterial baroreflexcardiacresponses (1 12).Conversely,sinoaorticbaroreceptordenervation

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augments pressor, vasoconstrictor, and sympathoneural responses to posterior hypothalamic stimulation (1 13).

AV3V The anteroventral third ventricle region of the hypothalamus (AV3V) participates in neurocirculatory adjustments to regulate body fluids. This rather largeareaincludestheorganumvasculosumofthelaminaterminalis,the median preoptic nucleus, and the periventricular preoptic nucleus. Stimulation of the AV3V region asa whole produces a pattern of modestly decreased blood pressure,splanchnicandrenalvasoconstriction,skeletalvasodilation,and bradycardia--reminiscent of vasovagal reactions. Stimulation of discrete areas within the AV3V region, however, can elicit selective vascular responses. Acute AV3Vlesionscauseadipsia,hypernatremia,anddehydration.Uponfull recovery, fluid balance, blood pressure, and behavior appear normal. AV3V lesions abolish dipsogenic and pressor responses to centrally administered angiotensin I1 and protect rats from developing one-kidney, low-renin renal hypertension and two-kidney, one-clip, high-renin renovascular hypertension. The median preoptic nucleus in the AV3V appears to be required for the acute pressor and dipsogenic actions of centrally administered angiotensin I1 and for hypertension resulting from sino-aortic deafferentiation, destruction of the deoxycorticosterone/salt administration. nucleus of the solitary tract, or

LIMBIC SYSTEM The“limbicsystem”encirclingthebrainstemprovidesthemain functional connection between the cerebral cortex and hypothalamus. The system includesstructuresofthelimbiclobe(thesubcallosal,cingulate,and parahippocampalgyri)andassociatedsubcorticalnuclei(includingthe amygdaloidcomplex,septalnuclei,hypothalamus,epithalamus,anterior thalamic nuclei, and portions of the basal ganglia). Investigators have differedin their definitions of the exact components.

Amygdala Researchaboutthelimbicsystemandautonomicfunctionhas concentrated on the amygdala, which is unique in that it has direct anatomic connectionsbothtoneocortexandtobrainstemregionsinvolvedwith sympatheticoutflows.Efferentsfromthecentralnucleusoftheamygdala descend via the perifornical region of the hypothalamus, suggesting a role in conditioned fear responses and defense reactions (1 14). Direct descending projections from the amygdala to the nucleus of the solitary tract, the dorsal

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motor nucleus of the vagus, and the C l neurons of the rostral ventrolateral medulla provide a potential neuroanatomic substrate for modulatory influences of the amygdala on baroreflex regulation of parasympathetic and sympathetic outflows. The central nucleus of the amygdala has numerous interconnections with brainstem catecholaminergic centers, the physiological meanings of which to a large extent remain obscure. According to a model proposed by Gray (1 15,116), pathways from the amygdala to dopaminergic cells in the A8 and A9 areas participate in startle, locomotor, and thermoregulatory responses; pathways to locus ceruleus cells in the A6 area participate in arousal and facilitation; and pathways to the A2 cells in the nucleus of the solitary tract and C l cells in the rostral ventrolateral medulla participatein autonomic outflows, both directly and also indirectly via altered baroreflex function. Tract-tracing studies have failed to confirm direct input to the locus ceruleus from the amygdala (62,63); the amygdala does project to the parabrachial area adjacent to the locus ceruleus. In humans, amygdaloid stimulation produces hypertension and pupillary dilation, with or without evoking anxiety or fear (1 17). In animals, amygdaloid stimulation elicits neuroendocrine and circulatory responses reminiscent of the “defense reaction”(1 18, l 19). One may hypothesize that the amygdala provides a medium for relaying to the brainstem input based on conscious evaluation and interpretationofstressors(115,116).Thus,amygdaloiddestructionblunts measures of fear and anxiety and learned visceral responses to fear-evoking stimuli.Duringaversiveemotionalconditioninginrats,bloodpressure responses to acoustic stimuli involve transmissionof the sensory signal through theamygdala (1 14,120).Lesionsorcryogenicinactivationofthecentral amygdala blunt pressor and heart rate responses to classically conditioned aversive cues. Catecholaminereleasemayimprovememoryconsolidationduring distress by activation of the amygdala (121). According to one conceptualization, the amygdala functions not as a site of memory storage but as a modulator of storage at other sites, such as in the neocortex, striatum, or hippocampus (1 22).

Hippocampus The hippocampus has been thought to participate in consolidation of long-term memory. Metabolic activity in the hippocampus in humans correlates positivelywithlong-termwordrecall,consistentwiththeroleofthe hippocampus in non-emotional, declarative memory (123). Thehippocampusreceivesnoradrenergicprojectionsfromthelocus ceruleus. Considering the role of the hippocampus in memory, noradrenergic activation of the hippocampus might facilitate long-term memory of distressing

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events.Thus,whenchronicallystressedratsundergoexposuretoanovel stressor, hippocampal norepinephrine release and tyrosine hydroxylation increase markedly (124), providing a possible central neurochemical substrate for the phenomenon of “dishabituation.” CIRCUMVENTRICULAR ORGANS

Humoral input such as by angiotensin I1 in cerebral regions lacking a blood-brain barrier may underlie some central-autonomic neural interactions. The circumventricularsitesincludethesubfornicalorgan,medianeminence, organum vasculosum of the lamina terminalis, and area postrema (Figure 3-8) Angiotensin I1 receptors seem particularly concentrated in circumventricular organs. Area postrema ablation blunts the pressor effect of intravascular angiotensin I1 and blocks the chronic hypertension produced by long-termsystemicadministrationofangiotensin I1 (125).Angiotensin I1 administered into the subfornical organ or organum vasculosum of the lamina terminalisofratsevokesthirst,vasopressinrelease,diffuseincreases in sympathoneural traffic, and increased blood pressure, suggesting a role for circulating angiotensin I1 acting at these organs in countering hypotension or depletion of blood volume(126). Increases in endogenous vasopressin levels during osmotic stimulation appear to augment baroreflex sensitivity by an action in the area postrema (127). The subfornical organ interconnects extensively with other brainstem sites involved in autonomic oiutflows, including the nucleus of the solitary tract and dorsal motor nucleus of the vagus. Subfornical organ stimulation produces diffuse,sympathetically-mediatedvasoconstrictionandincreases in blood pressure, mediated at least partly by the paraventricular nucleus (128). The organum vasculosum of the lamina terminalis, in the circumventricular portion of the AV3V region, probably contains osmoreceptors that relay through the AV3V region to effect vasopressinrelease. CEREBRAL CORTEX

The neocortex has relatively few direct anatomic connections with the hypothalamus or with other centers involved with autonomic outflows. Cannon hypothesized that the most “encephalized” parts of the brain regulate the experience and physiological manifestations of emotion (129), determining the character and intensity of autonomic output. Current concepts about long-term memory of distressing events suggest that the prefrontal cortex inhibits inappropriate responses and distractions and permits working memory to guide behavior (130). In contrast, by inhibiting these prefrontal mechanisms, activation of the amygdala may allow subcortical

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POSTERIOR

PITUITARY

Figure 3-8 Circumventricularorgans.Theseincludethearea postrema (AP), median eminence (ME), subfornical organ (SFO), and organum vasculosum of the lamina terminalis (OVLT). structures to express conditioned emotional responses, and catecholaminergic stimulationintheamygdaladuringdistressmightimprovememory consolidation (1 22). In contrast with the notion of cortical restraint, however, stimulationof the prefrontal cortex increases activity of locus ceruleus cells (13 1). Skinner (132) suggested stress to be a cerebral reaction to a stimulus-event, rather than an inherent feature of the stressor itself. Thus, patients with damaged frontal lobes have blunted conditioned visceral responses; and in patients with frontal lobotomies,verbalreportsandobservedbehaviorsindicateattenuationor absence of the experience of distress, with a corresponding lack of autonomic responses to stimuli expected to be emotionally arousing. CENTRAL CATECHOLAMINE NEUROANATOMY

Central catecholaminergic neurons have several unusual characteristics. They possess numerous collaterals; they exhibit hnctional plasticity; they have non-junctional as well as junctional terminal connections; and they degenerate very slowly. From about lo4 cells, about lo9 varicosities bud from the axonal twigs (17,133), providing a morphologic basis for the hypothesized global functions of central noradrenergic neurons. Unlike neurotransmitters that directly alter ion channels to effect rapid, transient discharges of discrete neurons, catecholamines appear to exert mainly neuromodulatory actions by altering intracellular concentrations of second messengers, resulting in slower but amplified and prolonged.responses. Catecholaminergic cells in rat brain have been grouped into 5 main systems: a pontine system, with noradrenergic locus ceruleus cells projecting

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rostrally to the hypothalamus, limbic system, cerebellum, and telencephalon; a lateral medullary noradrenergic and adrenergic system, with noradrenergic cells projecting mainly rostrally to the hypothalamus and adrenergic cells projecting bothrostrallyanddistally to thesympatheticpreganglionicneurons;a mesencephalic dopaminergic system innervating the corpus striatum, limbic system,andcortex;aperiventriculardopaminergicsysteminnervatingthe hypothalamus by short projections and also projecting caudally in long tracts; and a short system of dopaminergic pathways within the hypothalamus and from the hypothalamus to the pituitary gland. Norepinephrine-containing cell bodies occur only in the pons and medulla, whereas dopaminergic perikarya occur more rostrally. Dahlstrom and Fuxe (24) identified 12 groups of catecholaminergic cells, designated A1 to A12 in ascending anatomic order from the medulla to the hypothalamus, olfactory bulb, and retina of rats. An A13 group was identified later in the rostral zona incerta, an A14 group in the anterior periventricular nucleus of the hypothalamus and preoptic region, and an A15 group in the periglomerular portion of the olfactory bulb. Three main dopaminergic systems in the brain have been described: nigrostriatal,mesocortical,andtuberohypophysial(Figure 3-9). Themost prominentdopaminergicpathway,thenigrostriatal,coursesfromthezona compacta of the substantia nigra of the midbrain (A9 cells) to the corpus striatum (the caudate and putamen). The terminal fields of the nigrostriatal projections contain almost 80% of all the dopamine in the brain. Depletion of striatal dopamine characterizes Parkinson’s disease, associated with and thought to be due toloss of cells in the substantia nigra. The mesocortical dopaminergic pathway extends from cell bodies of the substantia nigra and ventral tegmentum to terminal areas in the amygdala, ventral entorhinal area, and perirhinal and piriform cortex; the septal nuclei, nucleus accumbens, and interstitial nucleus of the stria terminalis; the medial frontal and anterior cingulate cortex; and the olfactory tubercle, anterior olfactory nucleus,andolfactorybulb.Thispathwaymaybedysfunctional in schizophrenia, since many effective neuroleptics appear to work by blocking effects of dopamine releasedin the mesocortical system. The tuberohypophysial dopaminergic pathway originates from A 12 cells in the arcuate and periventricular nuclei of the hypothalamus and projects to the median eminence and to the intermediate lobe of the pituitary. This pathway plays a neuroendocrine role in modulating release of prolactin. Noradrenergic cell bodies in the brain are localized to the medulla and pons. The caudal ventrolateral medulla, extending from the level of the area postrema to the caudal portion of the facial nucleus, contains A1 cells; A2 cells occur in the region of the medial subnucleus of the nucleus of the solitary tract, along the dorsal borders of the dorsal motor nucleus of the vagus nerve, with

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Figure 3-9 Dopamine pathways in the rat brain. Note that all are located in the upper brainstem.

dopaminergic nuclei

about the same rostro-caudal extent as A1 cells; A6 cells occur in the locus ceruleus of the pons; and A5 cells of the pons lie ventral to the locus ceruleus. Cells of the rostral ventrolateral medulla that contain phenylethanolamine N-methyltransferase have been presumed to be adrenergic and designated C l cells. In the rostral portion of theA2 cell group in the regionof the nucleus of the solitary tract, phenylethanolamine N-methyltransferase-positivecells have been designated C2. Three main noradrenergic systems have been describedin the brain-the locus ceruleus-subceruleus system, the dorsal medullary system, and the lateral tegmental system. About 45-50% of the noradrenergic cell bodies are in the locus ceruleus. The subceruleus contains 10-15%, the lateral tegmental system (includingthe A l , A3, A5, and A7 regions)about30%;andthedorsal medullary group ( M )about 10% (133). Noradrenergic cells in these regions project differentially. The locus ceruleusinnervatestheforebrain,cerebellum,andbrainstem;thelateral tegmental system innervating the hypothalamus, limbic system, brainstem, and (in the case of the A5 and A7 neurons) spinal cord; and the dorsal medullary groupinnervatesthehypothalamusandlimbicsystem.Thus,most noradrenergic pathways ascend in the neuraxis rather than descend to the spinal cord (Figure 3-10). The pathways of the dorsal medullary and lateral tegmental noradrenergic systems have not been completely differentiated, and they often are considered together. Neuroanatomically, the most distinctive feature of central noradrenergic neurons is their tremendous arborization throughout the forebrain from relatively few perikarya. It has been estimated that each noradrenergic neuron can give ris to 100,000 varicosities and30 cm of axonal branches(17).

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Figure 3-10 Norepinephrine pathways in the rat brain. All noradrenergic nuclei are located in the lower brainstem. The main source of ascending noradrenergic fibers in the brain is the locus ceruleus, containing the A6 noradrenergic cell bodies. Noradrenergic pathways ascendin four axon bundles: the dorsal tegmental bundle (dorsal noradrenergic bundle, also called dorsal bundle), the medial forebrainbundle,thecentraltegmentaltract,andtheventralmedullary catecholamine bundle. The most prominent pathway from the locus ceruleus is

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via the dorsal noradrenergic bundle, through the central gray and via the dorsal longitudinal fasciculus and central tegmental tract, thereafter spreading diffusely throughout the telencephalon. The median forebrain bundle carries most of the ascending dopaminergic and noradrenergic fibers from the pons and midbrain to the hypothalamus and telencephalon, including the hippocampus. At the border of the midbrain and diencephalon, the dorsal bundle joins the median forebrain bundle. The central tegmental tract carries most of the noradrenergic and adrenergic fibers from the medulla and pons outside the locus ceruleus. After fanning out complexly in the tegmentum, the central tegmental tract joins the median forebrain bundle in the midbrain. The ventral noradrenergic bundle constitutes a caudal extension of the central tegmental tract. Another pathway descends to the ventral portion of the intermediolateral column of the spinal cord. Ingeneral,noradrenergicinnervation of thecerebralcortex,basal forebrain, thalamus, cerebellum, and hippocampus (especially the pyramidal and molecular cell layers) derives from the locus ceruleus, whereas noradrenergic innervation of thehypothalamusandbrainstemderivesfromthelateral tegmental cell groups. Noradrenergic innervation of the hypothalamus and medial preoptic area emanates especially from ventrolateral A1 and dorsal A2 neurons. As noted above, most of the adrenergic innervation of the sympathetic preganglionic neurons derives from the lateral tegmental groups, not the locus ceruleus. The dense noradrenergic innervationof the paraventricular nucleus derives from A1 and A2 cellsof the medulla and to only a minor extent from the locus ceruleus (134-136). A1 and A2 projections innervate the parvocellular division of the paraventricular nucleus, with A2 projections to corticotropin-releasing hormone-containing neurons particularly prominent, whereas A1 projections predominate in the innervation of the magnocellular division of vasopressinsynthesizing cells. The supraoptic nucleus receives innervation from A1 cells, with massive noradrenergic projections to portions of the nucleus populated by vasopressinergic cells. In the lower brainstem, noradrenergic projections of non-locus ceruleus origin innervate primary motor and visceral nuclei such as the motor trigeminal, hypoglossal, and ambiguus nuclei, the dorsal motor nucleus of the vagus, the nucleus of the solitary tract, and the nucleus commissuralis. FUNCTIONS OF CATECHOLAMINES IN THE BRAIN

Dopamine Complete, bilateral lesioning of brain dopamine systems in rats produces a behavioral syndrome including akinesia, sensory inattention, aphagia, and

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adipsia, giving the appearance of generalized behavioral unresponsiveness. This “dopaminedeficiencysyndrome”appliestoallvoluntaryactsrequiring motivation, sustained alertness, and receptiveness to sensory input. Dopaminedeficient animals fail to initiate coordinated motor responses andfail to orient to sensory stimuli. Whereas nigrostriatal dopamine depletion elicits the dopamine deficiency syndrome, mesolimbic dopamine depletion does not. Stricker and Zigmond (1 37) proposed that the dopamine system regulates behavioral responsiveness indirectly, by inhibitory modulation of an inhibitory striatalcontrolmechanism.PatientswithParkinson’sdiseasetherefore experience particular difficulty in initiating and terminating motor activity. Conversely, increased dopaminergic activity, such as produced by L-DOPA, amphetamines,ordopaminereceptoragonists,produceshyperactivityand stereotypy in rats and choreiform movements, dystonia, agitation, or psychosis in humans. AccordingtoBloometal.(138),activation of thecentralneural dopamine system as a whole increases spontaneous locomotor activity and induces species-specific, stereotypic motor behaviors, and inactivation of the systemproducesgeneralbehavioralinactivation,decreasedspontaneous locomotion,reducedresponsivenesstosensoryinput,and, in severecases, aphagiaandadipsia.Thenigrostriatalcomponentappearstomediatethe stereotypy, whereas the mesolimbic component appears to mediate the increased locomotion and reinforcement produced by psychomotor stimulants--not so much due to pleasurable “reward” sensations as due to an “enabling action” that decreases the threshold forinitiating responses. Factors that regulate homeostasis of central monoaminergic systems resemble those regulating homeostasis of norepinephrine concentrations at noradrenergic receptors in the periphery: presynaptic modulation by short- and long-distance feedback and autoreceptors; conservation of releasable stores by neuronal reuptake; coupling of transmitter release with catecholamine synthesis, both by rapid alterations in tyrosine hydroxylase activity and slower increases in the amount of tyrosine hydroxylase enzyme; and adaptive changes in postsynaptic adrenoceptors.

Norepinephrine Research in psychoneuroendocrinology has so far failed to delineate the exact roles of brain norepinephrine in the elaboration of stress responses and in particular of sympathetic and adrenomedullary outflows. When Vogt described the presence of catecholaminergic neurons in the brain (139), she suggested a general relationship between central release of norepinephrine and peripheral catecholaminergicactivation,sincepharmacologicalmanipulationsevoking adrenomedullary secretion depleted norepinephrinein the brain.

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Central neural norepinephrine probably plays several indirect roles in modulating outflows in peripheral catecholaminergic systems. First, ascending pathwaysfromtheA6noradrenergicneuronsparticipatecomplexlyin psychologicalprocessessuchasvigilancebehavior,memory,extinctionof conditioned responses, anxiety, and distress. Alterations in sympathoneural or adrenomedullaryoutflowsvirtuallyalwaysaccompanythesephenomena. Second, in thehypothalamus,norepinephrinederivedmainlyfromlower brainstem cell bodies participates in secretion of releasing hormones, such as thyrotropin-releasing hormone and corticotropin-releasing hormone, which in turnsecondarilyaffectsympatheticandadrenomedullaryoutflows.Indeed, norepinephrinehasbeenconsideredasanintermediary in virtuallyevery neuroendocrine system (140). Third, noradrenergic (or adrenergic) pathways emanating from medullary cell groups appear to modulate transmission of interoceptive information, such as from baroreceptors, to higher centers. Fourth, noradrenergic terminals in the dorsal horn of the spinal cord and on sensory afferents may gate ascending nociceptor information to the brain, influencing distress-induced recruitment of sympathoneural and adrenomedullary responses during exposure to painful stimuli. Local application of norepinephrine in regions innervated by the locus ceruleus produces a slowly progressive behavioral inhibition. Activation of the locus ceruleus during stress might therefore attenuate the organism’s responses, such as in seizures; however, since locally applied norepinephrine stimulates inhibitory a2-adrenoceptors, both pre- and extra-synaptically, the inhibition may not indicate the physiological roleof endogenously released norepinephrine at post-synaptic receptors. More frequently it has been suggested that locus ceruleus activation duringstressisstimulatory,evokingvigilancebehaviorandpossiblythe accompanying increases in autonomic outflows. Exposure to any of a large varietyofstressors(e.g.,cold,footshock,aggregation,hypoxia,exercise) depletes brain norepinephrine, increases norepinephrine turnover, and increases tissue concentrations of norepinephrine metabolites, indicating activation of central noradrenergic neurons. Microdialysis studies have confirmed rather diffuse activation of noradrenergic centers in the brain during distress (54,141144). The hnction of norepinephrine may vary with the level of the neuraxis at which the neurotransmitter is released. According to this view, in the brainstem below the locus ceruleus, endogenous norepinephrine plays a mainly inhibitory role in theregulationofbloodpressureandsympatheticoutflow(145). Norepinephrinereleasedfromtheposteriorhypothalamus,spinalcord,or peripheralsympatheticnerveendingsincreasesbloodpressure,whereas norepinephrine released near the nucleus of the solitary tract or in the anterior hypothalamus has the opposite effect (146). Local injection of tyramine in the

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A2 area decreases blood pressure (147), and injection of tyramine into the C l area decreases blood pressure, pulse rate, and renal sympathetic nerve activity (148), consistent with an inhibitory neurotransmitter role of norepinephrine in these medullary regions. In contrast, Sun and Guyenet (149) reported that tyramine increased the firing rate of rostral ventrolateral medulla pacemaker neurons in tissue slices. Most current concepts about functions of central neural norepinephrine emphasize a neuromodulatory role, where norepinephrine does not directly inhibit or stimulate so much as alter responsiveness to other synaptic inputs. By decreasing“background”dischargesandenhancingphasicexcitatoryor inhibitory inputs, norepinephrine might increase “signal-to-noise’’ ratios, via effects on responsiveness of target neurons or effects on interneurons. The enhancement of signal-to-noise ratios would participate in processes such as attention, memory, and learning. Consistent with the noradrenergic modulation hypothesis, presentation of a neutral cue tends to decrease evoked hippocampal firing during locus ceruleus stimulation, with norepinephrine enhancing the inhibition,whereaswhenhippocampalneuronalactivityincreasesasa classically conditioned response to an appetitive unconditioned stimulus (food reward), norepinephrine enhances the excitation(1 50). Norepinephrine probably functions differently also depending on the types and localization of the adrenoceptors. A substantial proportion of the noradrenergic varicosities in the hypothalamus, limbic system, and cerebellum are axo-dendritic. Administration of norepinephrine exogenously, such as into a cerebral ventricle, could mainly stimulate receptors that inhibit endogenous norepinephrinerelease,andtherelativebalanceofpre-andpost-synaptic adrenoceptorswoulddeterminetheresponsestoendogenouslyreleased norepinephrine. The noradrenergic A6 cells in the locus ceruleus appear to play a role in behavioral extinction. Lesions of the dorsal noradrenergic bundle generally interfere with the acquisition of new, motivation-related behaviors and with the extinction of learned behaviors after removal of reinforcement contingencies, rather than with the retention of previously learned behaviors or the acquisition of simple discrimination tasks. This phenomenon, called the “dorsal bundle extinction effect { 1035)” or the “dorsal bundle effect,” has in turn suggested involvement of the locus ceruleus systemin filtering out irrelevant stimuli orin inhibiting learned behaviors no longer rewarded or else punished. The dorsal bundleeffectmayonlyoccur in learningparadigmsinvolvingdistressor aversive reinforcement contingencies, rather than paradigms involving both appetitive and aversive behaviors. Since destruction of the hippocampus impairs extinction of conditioned behaviors, and since the hippocampus receives dense noradrenergicinnervationfromthelocusceruleus,onemayspeculatethat interference with hippocampal mechanisms subserving extinction mediates the

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dorsal bundle effect. Consistent with involvement of noradrenergic pathways from the locus ceruleus in memory processing, patients with senile dementia of the Alzheimer’s type have aloss of pigmented norepinephrine-synthesizing cells in the locus ceruleus and of noradrenergic terminals in the hippocampus (152154). Habituation of locus ceruleus neurons after repeated exposure to the same sensory cue may reflect not simple adaptation but a more complex process, where the organism continually assesses the motivational significance of cues and adjusts the responsiveness of attention, memory, vigilance, and emotional processes. Locus ceruleus firing does not habituate with repeated exposure to stimuli persistently evoking distress. Natural selection would have favored the evolution of mechanisms fostering memory consolidation during distressing situations, so as to avoid similar situations in the future, and selective attention to cues from the internal or external environment,so as to recognize and respond rapidly to those situations. Perhaps the locus ceruleus noradrenergic system subserves these mechanisms. Alterations in locus ceruleus discharge accompany awakening, orienting, and electroencephalographic spindling. Arousing stimuli that interrupt behaviors such as sleep, grooming, and eating, indicating increased attentiveness to the external environment, produce bursts of activity of locus ceruleus neurons. Bloom et al. (138) suggested that the locus ceruleus system may bias attention towards novel, rapidly changing external signals and away from tonic internal signals.Analogously,Aston-Jones(155)proposedthatthelocusceruleus functions as a gate for the overall orientation of the organism towards attention to novel features of the environment and away from elicitation of vegetative behavior patterns. Jacobs (77) hypothesized that just as the sympathetic nervous system regulates the functioning of numerous body systems during stress, the locus ceruleus functions globally in the brain as an emergency or alarm system. Thus, locus ceruleus firing tends to decrease during “vegetative” behaviors such as grooming, eating, and sleep (especially rapid eye movement sleep). Jacobs thereforehassupportedaroleofthelocusceruleus in vigilance,i.e.,the transition in behavioral state to an increased level of activation, especially in an aversive situation, rather than in determining the level of activation itself. Both external and internal perturbations can activate the locus ceruleus, the latter after sensory processing in medullary nuclei. Thus, if a stimulus were perceived as novel, severe, or threatening, locus ceruleus activation may foster transmission of the signal to higher brain centers, facilitating active attention and memory consolidation and further orienting the organism to the stimulus. The locus ceruleus possesses a high concentration of a2-adrenoceptors, and in individualspredisposedtoanxiety,panic,orpost-traumaticstress disorder, interference with the function of inhibitory a2-adrenoceptors can evoke emotional experiences and accompanying neuroendocrine patterns (1 56-1 59).

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Theroleofendogenousnorepinephrine in depressionhasaroused persistent controversy. Gold et al. (160) have proposed that systems involving corticotropin-releasing hormone and norepinephrine in the brain reinforce each other’sactivitiesandthatdepressionincludesinadequaterestraintofboth systems. This theory, by assuming direct functional connections between the paraventricularnucleusandthelocusceruleus,seemsoverlyrestrictive neuroanatomically,butthenotionofanabnormalityofco-regulationof norepinephrineandcorticotropin-releasinghormone in thecentralnervous system of depressed patientsmay have merit.

Epinephrine Epinephrine is present only at low concentrations in the central nervous system. Since phenylethanolamine N-methyltransferase (PNMT) is cytoplasmic, whereas the epinephrine precursor, norepinephrine, is synthesizedby dopamineR-hydroxylase in the vesicles, for epinephrine to act as a neurotransmitter, norepinephrine must escape the vesicles and undergo N-methylation in the cytoplasm,withthevesiclesthentakingupandstoringtheresulting epinephrine. Whether release of epinephrine and norepinephrine is subject to differential regulation in PNMT-containing cells in the brain is unknown. Epinephrinergic (adrenergic) systems have been divided into two or three cell groups: a ventral C l group, a dorsal C2 group, and a dorsal midline C3 group underlying fourth ventricular ependymal cells. The C l and C2 neurons intermingle with the A1 and A2 noradrenergic neurons in theventrolateral medulla and the nucleus of the solitary tract. Most adrenergic pathways in the brain probably emanate from the C l cells in the rostral ventrolateral medulla. As discussed previously in the section about this brainstem region, C l cells project rostrally to the locus ceruleus, hypothalamus, and periaqueductal gray and distally to the intermediolateral columnsof the spinal cord. Although the majority of the rostral ventrolateral medullary cells that project to the intermediolateral column cells express PNMT (28), this does not imply that epinephrine acts as a neurotransmitter at the synaptic connections with the sympathetic preganglionic neurons. “Pacemaker” cells of the rostral ventrolateral medulla are not necessarily catecholaminergic, and cells containing catecholamine-synthesizing enzymes do not necessarily have pacemaker activity. Thus, despite establishment of a neuroanatomic link between C l cells of the rostral ventrolateral medulla and the intermediolateral columns, the excitatory neurotransmitter producing activation of sympathetic preganglionic neurons during rostral ventrolateral medulla stimulation remains unidentified. Other candidateneurotransmittersfortheexcitatoryprojectionsfromtherostral ventrolateral medulla neurons include substance P, 5-HT, acetylcholine, metand leu-enkephalin, and glutamate.

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CENTRALLY ACTING DRUGS AFFECTING SYMPATHONEURAL OR ADRENOMEDULLARY OUTFLOWS

There is no convincing evidence for a direct role of central neural norepinephrine in the regulation of sympathetic outflow and therefore in the release of catecholamines from sympathetic nerve terminals or the adrenal glands. Instead, although the evidence is incomplete, norepinephrine in the central nervous system seemsto play several indirect roles, as noted above. Directionally similar changes in locus ceruleus activity and sympathoneural activity (or plasma norepinephrine levels) occur during variety a of perturbations of the internal or external environment, often categorized in termsofnoxiousness.Manipulationsofbloodpressureorcardiacfilling exemplify internal, non-noxious stimuli. The locus ceruleus appears to respond especiallysensitivelytoinputfromthelow-pressurecardiopulmonary baroreceptors. A role for the locus ceruleusin arousal or vigilance could provide a teleological explanation for this sensitivity. In humans, orthostasis constitutes the most common cause of acute decreasesin cardiac filling. When vigilant, we stand erect-we “stand guard.” When failing to concentrate on our work, we “lay down on the job.” When we awaken, we wake up. Administration of a wide variety of pharmacological agents affects the firing rate of locus ceruleus neurons. Tricyclic antidepressants, y-aminobutyric acid, clonidine, p-opiate agonists, and cocaine decrease locus ceruleus firing. The 1x2-adrenoceptor antagonist, yohimbine, acetylcholine (via stimulation of local muscarinic receptors), and corticotropin-releasing hormone increase locus ceruleus firing. A model of a central noradrenergic neuron (Figure 3-11) can explainmanydrugeffectsonlocusceruleusfiringandonrelease of norepinephrine from terminals of locus ceruleus neurons. This model includes release of norepinephrinenotonlyfromsynapticbutalsofromaxonal varicosities, so that noradrenergic occupation of a2-adrenoceptors on the cell bodies inhibits cellular firing, and noradrenergic occupation of a2-adrenoceptors on the terminals inhibits norepinephrine release for a given amount of terminal depolarization.DrugsthatblockUptake-lwouldincreasenorepinephrine concentrations at the inhibitory a2-adrenoceptors on the cell body, decreasing locusceruleusfiringyetaugmentingextracellularfluidnorepinephrine concentrations in the terminal region. a2-Adrenoceptor blockade would increase extracellular fluid norepinephrine levels in regions innervated by noradrenergic centers such as the locus ceruleus, due to combination of increased cell firing and augmented norepinephrine release from the terminals for a given amount Of cell firing. Most ideas about adrenoceptor localization, agonism and antagonism, and intracellular mechanisms of action in the brain have been generated based on

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Clonldtne.

Clonldlne

J

Figure 3-11 Model of a central noradrenergic neuron. DM1 = desipramine

studies of these receptors in the periphery. Receptors for each of the three endogenous catecholamines, norepinephrine, epinephrine, and dopamine, have been described in the brain. Norepinephrine and epinephrine exert actions at adrenoceptors of both the a- and R-types. Epinephrine concentrations in most brain areas are so low, it is likely that norepinephrine is the main agonist at aand R-adrenoceptors in the brain. The following discussion concentrates on the a-receptors. Researchaboutadrenoceptorsinthebrainhashadseveralmajor limitations. One has been the limited pharmacological specificity of receptor ligands. Brain tissue often substantially binds ligands non-specifically. Poor penetration of the blood-brain barrier by several adrenoceptor ligands has resulted in insufficient in vivo information. Molecular genetic techniques have identified receptor subtypes for which ligands have not yet been developed. Localization of some adrenoceptor subtypes varies markedly across species. Finally, for some types of adrenoceptors, such as ai-adrenoceptors, a glaring and inadequately explained discrepancy has been noted between the intensity of catecholaminergic innervation and the regional distribution of the receptors. As in the periphery, responses to an adrenoceptor agonist may depend importantly on the type, location, and functions of the receptors. Thus, the actions of norepinephrine in the brain may reflect the localization and functions of its receptors on effector cells. In rat brain, al-adrenoceptor concentrations bear little relationship to the intensity of noradrenergic innervation as indicated by 3H-desipramine binding to label norepinephrine uptake sites. The relatively high concentrations of aladrenoceptors in the thalamus and lamina of the cortex and low concentrations in the hypothalamus suggest a role of al-adrenoceptors in transmission of sensoryinformation,suchas by nociceptors.Humanbrainpossesseshigh

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concentrations of 3H-prazosin binding in the hippocampus, especially in the dentate gyrus. Relatively high concentrations of a]-adrenoceptors are found also in the human supraoptic nucleus and paraventricular nucleus, compared to corresponding regions in other species, suggesting a role of a]-adrenoceptorsin regulation of vasopressin release and water homeostasis in humans (161). As in the periphery, increased IP3 formation is thought to be a major meansby which a 1 -adrenoceptor agonists increase cytoplasmic concentrations of Ca++ and activate cells. Whereas the association between noradrenergic pathways and a]adrenoceptor densities is weak, there is a strong relationship between a drug's ability to bind to a]-adrenoceptors and its ability to increase the formation of IP3. In the brain, unlike in the periphery, stimulation of a]-adrenoceptors also can increase generation of cyclic AMP. A I , A2, A5, and A6 neurons of the lower brainstem possess inhibitory a2-adrenoceptors, whereas areas of the forebrain receiving noradrenergic innervationcanpossessavarietyofadrenergicreceptors.Excitatory a]adrenoceptors predominate in the lateral geniculate and dorsal raphe nuclei and inhibitory 8-adrenoceptors on astrocytes and cerebellar Purkinje cells. Centraladministrationof a 1 -adrenoceptoragonistsstimulates corticotropin release, by a mechanism that appears to depend on vasopressin. In humans, peripheral administration of a 1 -adrenoceptor agonists increases corticotropin secretion (1 62). Thehypothesisthat a 1-adrenoceptorsarestimulatoryand a2adrenoceptorsinhibitory in manybrainregionsresemblesthataboutthe functions of a-adrenoceptor subtypesin the periphery. Since in the periphery the spatial localization of a-adrenoceptors at sympathetic neuroeffector junctions importantly determines the physiological rolesof the receptors, the same may be the case in the central nervous system. As in the periphery, in the brain no convincing evidence has accrued for the existence of functional presynaptic a]adrenoceptors. a2-Adrenoceptorsareconcentrated in severalregionsinvolvedwith sympathoneural outflows. The distribution of a2-adrenoceptors in the brain corresponds roughly to the distribution of noradrenergic terminals. In human post-mortemmaterial,forebraina2-adrenoceptorsareconcentratedinthe neocortex,ventralhypothalamus,hippocampus,andsomethalamicnuclei. Using 3H-p-aminoclonidine or 3H-bromoxidine, high concentrations of a2adrenoceptors have been reported in the visual cortex, the dorsal motor nucleus of the vagus, the locus ceruleus, the nucleus of the solitary tract, the midbrain periaqueductal gray region, and the substantia gelatinosa of the spinal cord. Human brain appears to have higher concentrations of 3H-p-aminoclonidine binding sites in the nucleus of the solitary tract and fewer sites in the raphe nuclei than in the corresponding regions in rats. The basal ganglia, substantia nigra, and raphe nuclei contain only sparse a2-adrenoceptors, suggesting an

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associationbetweena2-adrenoceptorsandnoradrenergic,asopposedto dopaminergic or serotonergic, centers. In the study of Pascual et al. (163), several hypothalamic nuclei, the superior colliculus, the lateral periaqueductal area of the midbrain, the locus ceruleus, the dorsal motor nucleusof the vagus, the stratum granularis and Purkinje molecular layer of the cerebellum, and the substantia gelatinosa of the spinal cord had particularly high concentrations of a2-adrenoceptors. Thebraincontainsthe a 2 ~ - , a 2 ~and - , a2c- subtypesof a2adrenoceptors. The a 2 ~ a n d a 2subtypes B are expressed widely in the forebrain and brainstem, especially in supragranular cerebral cortex, hypothalamus, cranial nervenuclei,andbrainstemnucleithatparticipate in baroreflexesor in regulation of sympathoneural outflows (1 64). In the brain, a2~-adrenOCeptOrS appear to mediate pre-synaptic inhibition of norepinephrine release (165) and they also occur as heteroreceptors on non-noradrenergic cells, including in the rostral ventrolateral medulla (1 66). In contrastwiththeoftenexcitatoryactionsof a]-adrenoceptor stimulation in brainregions,a2-adrenoceptorstimulationvirtuallyalways results in neuronal depression. Systemic administration of a2-adrenoceptor agonists produces sedation, dry mouth, decreases in blood pressure and heart rate, decreased gastrointestinal secretion and motility, hyperphagia, and increases in pituitaryreleaseofgrowthhormoneandthyroid-stimulatinghormone. Systemicadministration of clonidineprolongsbarbiturateanesthesia,and yohimbine shortens anesthesia duration. Prior depletionof brain norepinephrine by 6-hydroxydopamine prevents these effects, indicating that a2-adrenoceptors modulating release of norepinephrine in the brain participate in the state of wakefulness. Intracellular mechanisms of action of a2-adrenoceptors in the nervous system have not been well characterized. Data have been inconsistent about whether a2-adrenoceptor agonists or antagonists affect plasma levels of corticotropin or B-endorphin. AI-Damluji, Boulouxetal.(167)presentedamodelforaninteractionofcentral a2adrenoceptorsandopioidreceptorsonnoradrenergicneuronsthatcould contribute to regulation of corticotropin release. According to this model, inhibitoryopioidreceptorsdecreasenoradrenergiccellularactivity,and inhibitory a2-adrenoceptors on the terminals inhibit norepinephrine release and occupation of post-synaptic stimulatory al-adrenoceptors. Consistent with this model,a2-adrenoceptorblockade by idazoxanenhancescorticotropinand cortisolresponsestonaloxonewithoutaffectingbasallevelsofthese compounds. As in the periphery, in the brain a2-adrenoceptors occur both pre- and post- or extra-synaptically. Lesions of the dorsal noradrenergic bundle fail to decrease a2-adrenoceptor numbers in most brain areas, indicating mainly post-

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synaptic localization. This does not imply that behavioral and neuroendocrine effects of a2-adrenoceptor stimulation result only from actions at post-synaptic receptors, despite the abundance of those receptors. Heal (1 68) concluded that the mydriasis produced by a2-adrenoceptor stimulation depends on actions at post-synapticreceptors,whereasthehypoactivitydependsonpre-synaptic receptors. Also as in the periphery, a2-adrenoceptors in the hypothalamus and a2cerebralcortexinhibittyrosinehydroxylase.Themechanismslinking adrenoceptor-induced inhibition of norepinephrine release with a2-adrenoceptorinduced inhibition of catecholamine biosynthesis in the brain remain obscure. Blockade of central neural a2-adrenoceptors increases sympathoneural outflowstothecardiovascularsystem.Confirmingarelationshipbetween norepinephrine release in the brain and periphery would require assessing effects ofdepletionofcentralneuralnorepinephrineontheseincrements in sympathoneural outflows. Alpha-methylDOPA and clonidine act in the brain to decrease rates of sympathetic nerve traffic. Both are effective anti-hypertensive agents. AlphamethylDOPA is converted to a-methylnorepinephrine, a false neurotransmitter that stimulates a2-adrenoceptors. The depressor effect of clonidine depends on actions in the central nervous system; however, whether clonidine decreases sympathoneural outflows by stimulating a2-adrenoceptors specifically has been controversial. Studies combining lesions and microinjection of clonidine in anesthetized animals have led to the conclusion that thedrug’s main site of antihypertensive action in the brain is in the rostral ventrolateral medulla, where the depressor effect of clonidine may not depend on occupation of local a2adrenoceptors (169). Clonidine structurally is an imidazoline, as well as an a2-adrenoceptor agonist.Ithasbeensuggestedthatclonidinemayelicithypotensionby stimulating imidazoline receptors in the rostral ventrolateral medulla. The use of anesthetized animals in studies of central mechanisms of vasodepression by clonidine could mask effects of clonidineby other mechanisms at higher levels oftheneuraxis.Thus,microinjectionofclonidineintothelocusceruleus produces behavioral sleep and electroencephalographic synchronization, and injection of yohimbine or phentolamine, which also block a2-adrenoceptors, produces behavioral arousal. Since a2-adrenoceptor blockers that donot bind to imidazoline receptors attenuate the hypotensive effect of clonidine, and since clonidinedoesnotexertahypotensiveeffect in micewithdefective a2adrenoceptors, the hypotension does seem to depend on stimulation of a2adrenoceptors (1 70). Pharmacological distinctions have led to subclassification of imidazoline receptors into two groups-an 11-subtype, sensitive to clonidine and idazoxan, andanI2-subtype,sensitivetoidazoxanbutinsensitivetoclonidine.

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Moxonidine is an agonist at 11-receptors. In both laboratory animals and in humans, administration of moxonidine decreases indices of sympathetic nervous (but not adrenomedullary outflows) and decreases blood pressure (171). Stimulation of imidazoline receptors in the rostral ventrolateral medulla leads to sympathoinhibition, similarly to stimulation of a2-adrenoceptors. Although many studies have suggested that agonists at 11-imidazoline receptors decrease blood pressure, sympathetic nerve activity, and plasma norepinephrine levels in hypertensive humans or hypertensive animals, the relative roles of 11imidazoline receptors and a2-adrenoceptors in mediating these effects remain unclear, Experiments involving microinjection of specific antagonists into the rostral ventrolateral medulla, where both moxonidine and clonidine appear to work(atleast in anesthetizedanimals),haveindicatedthat11-receptor occupation activates a2-adrenoceptors (1 72,173). Since neurotoxin-induced destructionofnoradrenergicterminals in therostralventrolateralmedulla selectively blocks the actions of moxonidine but not clonidine,11-receptors may exist on adrenergic terminals and a2-adrenoceptors on cell bodies ofC l cells. Clonidine is alsoaneffectiveadjunctiveanalgesic,possiblybecause agonist binding to a2-adrenoceptors on sensory terminals or in the dorsal gray matterofthespinalcordinhibitsascendingtransmissionofnociceptor information (69). In some brain areas, such as the locus ceruleus and midbrain periaqueductalgrayregion,a2-adrenoceptorsareco-localizedwithopiate receptors; in other areas, a2-adrenoceptors are present on cells containing serotonin, corticotropin-releasing hormone, vasopressin, growth hormone, or thyrotropin-releasing hormone. This co-localization may affect the responses to drugsactingata2-adrenoceptors.Whetherendogenousnorepinephrine stimulatesa2-heteroreceptorsonserotonergiccells is unknown.Putative interactions between agonists at a2-adrenoceptor and at opiate receptors have led to several current clinical trials of opiates with a2-adrenoceptor agonists in the treatment of patients with intractable pain. As with al-adrenoceptors, the distribution ofR-adrenoceptors in the brain appears to correlate only weakly with the distribution of norepinephrine. For instance,thecaudatenucleushas a relativelylowconcentrationof norepinephrine but a high concentration of B-adrenoceptors. Both B l - and B2subtypes ofB-adrenoceptors have been described in the brain. In contrast with rat brain, human brain contains high concentrations of B-adrenoceptors not only in the caudate but also in the nucleus accumbens and putamen (161). High levels are also detected in the hippocampus, globus pallidus, and neocortex. Ocular Badrenoceptors seem remarkably conserved across species, whereas in the pituitary there is substantial inter-specific variation in the density and localization of the receptors. The functional significance of the spatial localization of B]- and B2adrenoceptors in the brain is unknown. Since 82-adrenoceptors appear to be

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dispersedratherhomogeneously in thebrain,whereas81-adrenocepior concentrations can vary by 20-foldin different brain areas, 82-adrenoceptors may be associated with diffusely distributed glial cells or blood vessels and may not be located on neural cells; however, even for 81-adrenoceptors there is no close correlation between the regional concentration of the receptors and the density of noradrenergic innervation. There are at least6 distinct types of dopamine receptors in the brain. The receptors have been separated intotwo general classes, Dl-like and D2-like, with two Dl-like subtypes and four D2-like subtypes. In general, the latter receptors exert inhibitory actions in a wide variety of cell types and regions. For instance, administrationoftheD2receptoragonistbromocriptinedecreasesplasma norepinephrine levels in humans (174); however, in marked contrast with the intensively researched effects of dopamine receptor agonists in Parkinson’s disease and of dopamine receptor antagonistsin schizophrenia, the possible roles and sites of action of dopamine and its receptors in centralregulationof autonomic outflows and neurocirculatory regulation remain poorly understood. The atypical, highly effective neuroleptic drug, clozapine, blocks D4 receptors in the brain. This does not imply that the anti-psychotic effects of the drug result from D4 receptor blockade. Clozapine administration in humans produces remarkably large, sustained increases in plasma norepinephrine levels (175). In rats, clozapine increases microdialysate concentrations of norepinephrine in the frontal cortex, nucleus accumbens, and striatum(1 76,177). CARDIAC PARASYMPATHETICOUTFLOWS

The nucleus ambiguus in the medulla is the main site of origin of vagal efferentsmediatingreflexivebradycardia.Stimulationofthedorsalmotor nucleus of the vagus does not evoke bradycardia, whereas stimulation of the nucleus ambiguus does (13), and most parasympathetic neurons innervating the myocardium derive not from the dorsal motor nucleus of the vagus but from the nucleus ambiguus or neurons close toit (178). As noted above, anterogradely labelled terminals from the nucleus of the solitary tract can surround retrogradely labelled neurons in the dorsal motor nucleus of the vagus (46), providing a neuroanatomic substrate for a disynaptic baroreceptor-vagal reflex. Axons from neurons of the caudal ventrolateral medulla project to the rostral ventrolateral medulla, the nucleus of the solitary tract, and the nucleus ambiguus,andneuronsidentifiedelectrophysiologicallyinthecaudal ventrolateral medulla in a region close to the nucleus ambiguus are activated orthodromicallybystimulationoftheaorticnerveandantidromically by stimulationoftherostralventrolateralmedulla(48).Thus,itappearsthat neurons in thecaudalventrolateralmedullaparticipateimportantly in

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coordinationofbaroreflex-mediatedalterations in vagalandsympathetic outflows to the heart. Clonidine not only causes sympathoinhibition but also evokes vagallymediated bradycardia. Both the dorsal motor nucleus of the vagus and the nucleus ambiguus contain abundant a2-adrenoceptors, and intra-vertrebral arterial injections of a2-adrenoceptor agonists potentiate whereas a]-antagonists inhibit baroreflex-induced vagal bradycardia (1 79). Parvocellular neurons of the paraventricular nucleus send long descending axons to the the dorsal motor nucleus of the vagus. Hypothalamic stimulation can elicit hypotension and bradycardia (1 SO), and direct descending projections fromtheamygdalatothedorsalmotornucleusofthevagusalsoexist. Influences by these centers might provide a neuroanatomic basis for distressrelated syncope or presyncope. The subfornical organ, a circumventricular structure lacking an efficient blood-brain barrier, projects to the dorsal motor nucleus, suggesting a means for indirect influences of circulating factors on cardiac parasympathetic outflows. SUMMARY AND CONCLUSIONS

Activity of sympathetic preganglionic neurons depends importantly on excitatory input from lower brainstem centers that mediate simple homeostatic reflexes, maintaining appropriate "steady-state" cardiovascular performance. At the next higher level, hypothalamically-elaborated patterns reset homeostats. At thehighestlevel,limbicandfrontalstructuresusememory,learning, simulations, and consciousness to interpret afferent signals about the internal and external environments and to determine the occurrence and intensity of the hypothalamically-evoked patterns. Organized, periodic discharges of neurons in the rostral ventrolateral medullageneratesympatheticoutflow in acomplexlybutnotrandomly determined manner, with important influences by clusters of cells at several more rostral sites in the neuraxis, especially during stress, and influences by more caudal medullary sites that receive interoceptiveinput. A network of brain centers therefore determines sympathetic neurocirculatory regulation. Prominent in this network are noradrenergicA2 cells in the nucleus of the solitary tract, the main site of termination of baroreceptor input to the brain; epinephrine-synthesizing C 1 cells of the rostral ventrolateral medulla, which projects caudally to the sympathetic preganglionic neurons and rostrally to severalbrainstemareas;noradrenergic A1 cells of the caudal ventrolateral medulla, which projectsto vasopressin cells of the paraventricular nucleus of the hypothalamus and to the rostral ventrolateral medulla; noradrenergic A6 cells in thelocusceruleus,themainsourceofnorepinephirne in thebrain;the periaqueductal gray region of the midbrain; the paraventricular nucleus and

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HACER area in the hypothalamus, the latter the apparent main subcortical center responsible for the generation of instinctive emotional behaviors in primates; and the central nucleus of the amygdala in the limbic system, a waystation between cortical centers and the brainstem. Catecholaminergic cells in the brain occur in 2 noradrenergic and 3 dopaminergic pathways. Almost 80% of brain dopamine is in the terminal field of the nigrostriatal projection. Central neural dopamine seems to enable action, decreasing the threshold for initiating responses. Parkinson’s disease, associated with degeneration of the substantia nigra, results from depletion of striatal dopamine;andschizophreniaprobablyresultsfromdysfunctionofthe mesocortical dopaminergic system. By decreasing background discharges and enhancing phasic excitatory or inhibitory inputs, norepinephrine increases the signal-to-noise ratio of neuronal responsivity. Locus ceruleus discharge biases attention towards novel, rapidly changing external and interoceptive signals. Receptors for all three endogenous catecholamines have been described in thebrain.al-Adrenoceptors in thebrainaremainlystimulatoryand a2adrenoceptors inhibitory; however, the functions of adrenoceptor subtypes may depend on their cellular localization. Blockade of presynaptic a2-adrenoceptors in the brain increases sympathetic outflows. The depressor effect of clonidine, an a2-adrenoceptor agonist, in the rostral ventrolateral may result partly from stimulating a type of imidazoline receptor. Neurons in the caudal ventrolateral medulla participate importantly in coordination of baroreflex-mediated alterations in parasympathetic outflows to the heart from the nucleus ambiguus and dorsal motor nucleus of the vagus. Little is known about central neural regulation of “sympathico-vagal balance.” Therolesofcentralcatecholaminesspecifically in regulationof sympathetic nervous and adrenomedullary hormonal system outflows probably are indirect and complex. Catecholamines in the central nervous system may help to gate afferent information from exteroceptors and interoceptors, modulate hypothalamic secretion of releasing hormones and elaboration of neuroendocrine responsepatterns,andfacilitatelong-termmemoryofdistressingevents, vigilance, and initiation of motor behavior. Despite the apparent involvement of boththemesotelencephalicdopaminesystemandthelocusceruleus noradrenergicsystem in determiningresponsestoenvironmentaland interoceptor input, no concepts have explained whether and how these two catecholamine systems work together. By participating in arousal, memory, and vigilance behavior, catecholamine pathways in the brain could play a role in hnctional neurocardiologic disorders.

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Stress and Distress THEORIES OF STRESS

Cannon and Homeostasis Walter B. Cannon, extending Claude Bernard’s concept of the internal environment, introduced the tern, “homeostasis,” to describe the product of the “coordinated physiological processes which maintain most of the steady states in the organism” (1 -3). According to Cannon, the same process underlying the phylogenetic development of anatomic patterns-naturalselection-also resulted in the phylogenetic development of physiological and even psychological patterns of response: The perfection of the process of holding a stable state in spite of extensive shifts of outercircumstanceisnotaspecialgift bestowed upon the highest organisms but is the consequence of a gradual evolution. ((3), P. 23) Cannonsuggestedthatrapidactivationofhomeostaticsystemsespecially of what he called the “sympathico-adrenal system”-preserves the internal environment by producing compensatory and anticipatory adjustments that enhance the likelihood of survival (Figure 4-1). These compensatory and anticipatory adjustments would include the emotional responsesof rage and fear, for which he coined the term, “fight or flight”(3). The present homeostatic theory of stress and distress derives importantly from two concepts that Cannon introduced: homeostatic systems maintain the apparentsteadystates in theorganism;andthesympatheticnervousand adrenomedullary hormonal systems contribute importantly to the maintenance of homeostasis during emergency reactions. Neither Bernard’s theory of the internal environment nor Cannon’s of homeostasis incorporated stress per se as a scientific construct, and neither 199

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Inc. Heart Rate Inc. Blood Pressure Inc. Ventilation Inc. Glucose Stress

Actlvation

Dec. Skin 6 Gut Blood Flow Splenic Contraction Hemostasis Sweating Piloerection Dec. Fatigue Dec. Gut Motility

Figure 4-1 Cannon’s conception of stress and the sympathico-adrenal

system.

considered in detail the relationship between stress and disease. Hans Selye concentrated on these issues. Selye and the General Adaptation Syndrome

Selye popularized stress as a scientific and medical idea. Having observed as a medical student that all sick patients seemed to share a “syndrome of just beingsick,”heelaboratedatheoryofstressasaconditionshared by all organisms in their interaction with the environment: “Stress is the nonspecific response of the body to any demand upon it” ((4), p. 14, Figure 4-2). According to Selye’s theory, after removal of specific responses from consideration, a nonspecific syndrome would remain. Although nonspecific with respect to the inciting agents, the stress response itself was viewed to consist of a stereotyped pathological pattern, with three components: enlargement of the adrenal glands, involution of the thymus gland (associated with atrophy of lymph nodes and inhibition of inflammatory responses), and peptic ulceration of the stomach. A decrease in the circulating number of eosinophils was added later to this triad. Exogenous administration of glucocorticoids induces all these changes, but Selye never realized this. The stress response was also thought to have three characteristic stagesthe“GeneralAdaptationSyndrome”(Figure 4-3). The first phase, a rapid “alarm” reaction, included two periods, “shock” and “countershock.” The latter period would result from responses of the adrenal cortex, releasing “corticoids,” and of the adrenal medulla, releasing ‘‘adrenalines.” The countershock responses were thought to reverse the above abnormalities and to induce hypertension, hyperglycemia,increasedbloodvolume,alkalosis,diuresis,andoften

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Stressor Stressor Stressor

General Adaptation Syndrome Adrenalenlargement 0 Gastromtestimalbleeding/ulceratlon 0 Thymtcolymphatic Involution

Figure 4-2 Selye’s conception of stress. Any stressor elicits the same stress response.

hyperthermia (5). Morphologically, there would be enlargement of the adrenal cortex and acute “involution of the thymicolympathic apparatus,” due to the release of anti-inflammatory corticoids(5). After an undefined length of time, a longer-lasting stage of “resistance” would ensue, characterized by increased resistance to the particular stressor but decreased resistance to others (5). During this stage, most of the morphological andbiochemicalchangesofthealarmstagewouldregress.Abalanceof “syntoxic” and “catatoxic” hormones of the adrenal cortex would dominate the stageofresistance.Theadrenalcorticosteroids(cortisol in humans, corticosterone in rats) were thought to be syntoxic, in that they would help the body to put up with aggressors by acting as “tissue tranquilizers,” inhibiting defensive reactions such as immune and inflammatory responses. Catatoxic agents were thought tobe proinflammatory, destroying aggressors by destructive enzymatic attack. The catatoxic hormones were never identified. The stage of resistance would end with depletion of “adaptation energy.” This would usher in the third stage, “exhaustion,” characterized by a resurgence of adrenocortical hyperactivity, gastrointestinal ulcers, immunologic failure, and eventual death of the organism. According to Selye’s theory, stress is not necessarily deleterious. Late in his career, he introduced the term “eustress,” to refer to stress that is not harmful andpossiblyishelpfultothebody.“Distress”referredtodamagingor unpleasant stress (4). Excessive, repeated, or inappropriate stress responses were viewed as maladaptive, and Selye coined the phrase “diseases of adaptation” to refer to situations where the General Adaptation Syndrome is “derailed” (6). Effects of large doses of glucocorticoids or mineralocorticoids suggested the contributions of stress to the diseases of adaptation.If abnormal (hyper-, hypo-, or dys-adaptive) responses did not cause these diseases directly, then they would predispose the individual to develop those diseases, based on tendencies called “conditioning factors.” Selye proposed an immense list of diseases of adaptation. HyperfunctionalanddysfunctionalconditionsincludedCushing’sdisease,

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adrenal tumors, chromaffinomas, renal artery stenosis, hypertension, periarteritis nodosa, nephrosclerosis, nephritis, rheumatic and inflammatory diseases, gouty arthritis, peptic ulceration, eclampsia, diabetes, allergic and hypersensitivity disorders, and psychosomatic disorders. Hypofunctional conditions included Addison’s disease, Waterhouse-Fredrichsen syndrome, cancer, and diseases of resistance in general ( 5 ) . The most severely affected targets were thought to be the cardiovascular system, the joints, and metabolism. Selye’s stress theory became and remains popular. Among other things, the theory provides a ready explanation for how any distressing experience can lead to or worsen virtually any disease state. The theory also aroused intense controversy.AlthoughSelye’sstresstheoryhascertainlyprovokedmuch thought and research, it has proven deficientin several crucial respects. FourcircularitiesvitiateSelye’stheory.Thefirstisbasedonthe assumption that stress is a nonobservable condition that leads invariably to the General Adaptation Syndrome. Stress is the condition producing the syndrome; however, the occurrence of the syndrome is the only means by whichthe existence of the condition can be inferred. In order to explain how different patients could evince different diseases of adaptation, Selye hypothesized that “conditioning factors” would selectively enhance or inhibit particular stress effects. The conditioning factors could be internal (e.g., hereditary predispositions, aging, and sex) or external (e.g., drugs and nutritional factors). Conditioning could explain any deviation from the predictedpatternofstress-inducedlesions;however,thepresenceof conditioning could be detected onlyby this deviation. “Distress” was defined as stress that was unpleasant or harmful to the body. The only means to determine whether a particular stress was a distress or “eustress” was the occurrenceof observable tissue damage or shortened survival. “Adaptation energy” was defined as that which was consumed during adaptive work. Depletion of this energy would usher in the state of exhaustion leading to death. The measure of the success of the adaptive response to a particular stressor was not the ability to mitigate the intensity or noxiousness of the stressor butits effects on pathology and survival.If there were no pathologic consequences to a stress response, then the active and passive defenses were viewed as beingin balance, but if there were pathologic consequences, then they were attributed to an imbalance and maladaptation. The only way to determine whether such an imbalance had occurred was by noting the pathologic effects. Selye claimed that all he knew about adaptation energy was that constant exposure to any stressor would exhaust the adaptation energy (6). The amount of available adaptation energy would, in large measure, determine the duration of the life. Indeed, Selye suggested that there was a findamental, specific element of life, a unit of reactivity to biologic stimuli, that could be used to define life.

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Alarm

I

‘Conlcolds‘ ‘Adrenaltnes’

Re S i st a n c e

l Exhaust ion

Adrenocortical enlargement ‘Thymlco-lympnatlc‘ lnvolutton Gast rolnlesclnalulcers/bleeamg Hyperlenslon Hyperglycemta Hypervolemla Alkalosis Dluresls Hyper! hermla

M3rphoIogcal 8 btocnemlcal alterations dlsappear Balance 01 ‘syntoxlc‘ 8 ‘catatoxlc‘ hormones Syntoxlc ‘tissue tranqutllzers’ Cataloxlc pro-lnllammatory

Spent ‘adaptallonenergyRsurgent pltultary-adrenocorllcal Ulcers lmmunologlc Deal h

actwallon

failure

Figure 4-3 Selye’s General Adaptation Syndrome.

He called this functional unit of life a “reacton.” The idea of adaptation energy not only constitutes a circularity in Selye’s theory, it also smacks of vitalism. Selye defined stress as the nonspecific response of the body to any demand. Elsewhere, he claimed that this was an operationaldefinition and that stress was the “sum of all the wear and tear in the body caused by life at any one time,” or that stress was a nonobservable condition leading invariably to and therefore detectable and measurableby the General Adaptation Syndrome(6). The stage of resistance was thought to be characterized by decreased responsivenesstothestressortowhichtheorganismhadbeenexposed repeatedly, but also increased responsiveness to other stressors. Although several studieshaveconfirmedthisobservation (7,8), termeddishabituation,the existence of this phenomenon argues against the doctrine of nonspecificity. Selye overemphasized analogies to inflammation and the role of the pituitary-adrenocortical system in the stress response. By dwelling on only one effector system, Selye virtually defined the presence or absence of stressby the presence or absence of pituitary-adrenocortical activation; however, many other neuroendocrine systems participate in different stress responses, as discussed in Chapter 5. Because Selye never incorporated these other systems adequately into his theory, he did not consider possible adaptive patterning of responses of these systems. Selye overgeneralized from the effects of pharmacologic doses of adrenocortical steroids to the occurrence of “diseases of adaptation,” thought to

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result from maladaptive stimulation of endogenous release of those steroids. For instance, although Selye was correct that deoxycorticosterone combined with high salt intake produces hypertension in uninephrectomizedrats,andthat clinical diseases such as hyperaldosteronism produce salt-sensitive hypertension, he erred in suggesting that excessive release of mineralocorticoids into the bloodstream characterizes, causes, or contributes to more common forms of hypertension. His suggestion that adrenalectomy or hypophysectomy could be beneficial in hypertensive patients in general (6) has been discarded. Had Selye obtaineddataaboutactivitiesofotherstresseffectorsystemsbesidesthe pituitary-adrenocortical system, he probably would not have proposed the stages of the General Adaptation Syndrome. For instance, repetition of immobilization stress does not result in habituation of plasma catecholamine responses, and no stage of exhaustion occurs(9). Neuroendocrine evidence has suggested that stimuli perceived as novel activate the pituitary-adrenocortical system selectively (1 0,ll). This leads to the hypothesis that the stage of resistance in Selye’s General Adaptation Syndrome may actually reflect habituation of central neural processes regulating pituitaryadrenocortical outflow during repetitive exposureto noxious but no longer novel stimuli. Since hypercortisolemia characterizes a proportion of patients with depression (1 2), the occurrence of pituitary-adrenocortical activation during clinical “giving up” (13,14) may indicate a phenomenon corresponding roughly to the stage of exhaustion. Cannon, to whom Selye referred as the “Great Old Man” (6), was one of the first critics of Selye’s stress theory. Cannon’s critique centered on the doctrineofnonspecificityandtheimplicitassumptionthatastereotyped response pattern can be adaptive, regardless of the character of the stressor. The General Adaptation Syndrome could be viewed as adaptive in the sense of preserving the internal environment effectively in the face of widely differing challenges. Since a nonspecific stress response would not have provided an advantage in natural selection, a stereotyped stress response would not have evolved. As research has uncovered more and more systems that participate in stress responses and serve distinct homeostatic needs, it becomes less and less clear whether, after removing these specific reactions from consideration, any truly nonspecific reactions would remain. Mason (15,16) also disputed Selye’s doctrine of nonspecificity, noting that in response to different stressors, activity ofthepituitary-adrenocorticalsystemcanincrease,decrease,orremain unaffected. This means that the triad of the General Adaptation Syndrome could not reliably indicate the occurrence of stress. Mason suggested that the basis for similarities in neuroendocrine responses to different physical stressors was not the nonspecificity of responses of the body to any demand but that all the stressors used in Selye’s research produced the experience of emotional distress,

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resulting in similar neuroendocrine consequences. A central nervous system source of distress responses would also help to explain one of the main admitted failures of stress research testingSelye’s theory: the inability to identify carriers of the “alarm signals” from peripheral sites (17). More than a half century elapsed before Selye’s doctrine of non-specificity finally underwent direct analysis and experimental testing ( 1 8). Pacak et al. showed mathematically that, without simplifying assumptions, the doctrine of nonspecificitycannotbedisproved.Evenwithsimplifyingassumptions, appropriate testing of the doctrine of nonspecificity would require a very complex study, involving multiple stressors at different intensities and multiple simultaneously assessed dependent measures. Although a wealth of literature described effects of graded intensities of stressors on neuroendocrine dependent measures, none of this literature applied to the issue of the validity of the doctrine of nonspecificity, until the study by Pacak et al. (1 8). The doctrine of nonspecificitycouldbetested,givenoneoftwoassumptionsaboutthe existence of a threshold stressor intensity for the nonspecific response or about the magnitude of the specific response above the threshold stressor intensity. Data about ACTH and epinephrine responses to hemorrhage and to formalin subcutaneous injection fit the assumptions required to test the doctrine of nonspecificity. The doctrine of nonspecificity failed to predict the experimental results.Thisstudyledtothefollowingconclusions.Withoutsimplifying assumptions, which may or may not be acceptable for particular stressors, the doctrine of nonspecificity is impossible to disprove and is therefore of little scientific value. Yet with acceptable simplifying assumptions, the doctrine of nonspecificityfailstopredicttheobtainedexperimentalresults.Giventhe simplifying assumptions, then, the data were inconsistent with Selye’s stress theory and refuted the existence of a unitary “stress syndrome.” Two conclusions from Selye’s theory and experiments do seem justified, (1) Stress is an unobservable condition and the present theory incorporates them: that leads to adaptive responses; and (2) Adrenal release of glucocorticoids often accompanies stress responses.

Modern Cannon rarely used the term “stress”and never definedit: Perhaps a comparative study would show that every complex organization must have more or less effective self-right adjustments in order to prevent a check on its functions or a rapid disintegration of its parts when it is subjected to stress....((3), pp. 23-25)

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One may infer that he viewed stress as a stimulus, such as decreased externaltemperatureorhypoglycemia,arousingincreasedactivityofthe sympathico-adrenal system as a compensatory process. Some modem theorists continue to define stress the same way: “In psychological and biological terms, stress may be defined as any stimulus or interference with the organism that results in a change in bodily functions” ((19), p. 232). By considering stress to reflect the imposition ofan external influence on the organism, this approach fails to take into account the contribution to the responses by theorganism’sperceptionandinterpretationofevents in the externalandinternalenvironment.BothCannonandSelyeimposedsuch overwhelming threats, such as asphyxia, hemorrhage, sepsis, and injections of largedosesoftoxicsubstances,thattheirtheoriescouldignorethese perceptions. Current stress theories presume that in the absence of a perception or sensation of a threat to homeostasis, stress responses do not and cannot occur. Conversely, the perceptions of the individual probably constitute the main determinant of the occurrence and character of stress responses, even if those perceptions are erroneous or elicited by conditioned or symbolic stimuli thatactuallyposenochallengetohomeostasis. In modernsociety,direct agonistic confrontation evokes distress relatively rarely, compared with the frequent experience of distress in response to subtle psychosocial cues at home or work. This interpretive process affects not only the occurrence but also the character of cardiovascular and neuroendocrine stress responses. For instance, in response to contrived laboratory psychological stressors in humans, cognitions influence importantly the quality and intensity of emotional experiences (20,21). Field observations of nonhuman primates have supported this view (22,23). The interpretation of environmental and internal stimuli in the elaboration of stress responses is a key element of several stress theories. Skinner (24) has suggested that stress is a cerebral reaction of a particular individual to a stimulus event, rather than being an inherent feature of the stressor itself. Pickering (25) has suggested that three types of factors mediate the relationship between stress andcardiovasculardisorders:thenatureoftheenvironmentalstressor, personalityorindividualfactors,andtheindividual’sphysiological susceptibility (the latter apparently not very different from Selye’s conditioning factors). Krantz and Lazar (26) have proposed that psychological stress should be defined not solely in terms of environmental conditions or response variables but in terms of a “transaction” between the organism and the environment. Weiner (27) has argued that although physiological responses to several stressors are similar, species differ in the interpretation of the stressors. Lazarus (28) has statedthatadefinitionofpsychologicalstressrequiresreferencestothe

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individual’smotivationandhowtheindividualdefinesandevaluates relationships with the environment-a process of appraisal. And Levine and Ursin (29) have viewed stress as part of an adaptive biological system, where a state is created when a central processorregisters an informational discrepancy. Most modem stress theories therefore ignore or discard Selye’s notions about the nonspecificity and stereotyped nature of the stress response, in favor of adaptive, compensatory response patterns elicited by challenges to homeostasis as the organism perceives those challenges. According to Weiner (27,30), stressors are selective pressures from the physical and social environment that threaten or challenge the organism, and they elicit compensatory response patterns. Weiner also asserts that the concept of homeostasis has by now lost its usefulness because there are no truly steady states in living organisms, and that the body’s “fundamental operating modes” are oscillatory. Weiner argues that illness or disease occurs when the stability of a system’s usual operating mode is lost. Thecirculardefinitionproposed by Eliot (31) alsoemphasizesthe importance of perceptionsin the elicitation of stress responses: We now know the consequences of “stress” more precisely than we know the definition of it. Stress may be viewed as the body’s responsetoanyrealorimaginedevents perceivedasrequiringsomeadaptive response and/or producing strain. ((3 l), p. 1) As noted above, a major weakness of the doctrine of nonspecificity in Selye’stheoryisthecharacterizationofstress in terms of a nonspecific, stereotypedresponsepattern,sincethisignorestheoperationofselective pressures favoring the evolution of truly adaptive responses. Weiner (27,30) has applied Darwin’s theory of natural selection to derive a concept about the adaptiveness (and therefore specificity) of responses to stress. The present theory agrees with this; however, Weiner(32) does not carefully distinguish stress as a stimulusexternaltotheorganismfromstressasanexperiencewithinthe organism:“Theterm‘stress’coversawidevarietyofphenomenaand experiences occurring external to the organism”((32), p. 405). Eliot and Buell (33) and Eliot (34) proposed a chronological dimension of stress, analogous to that of Selye, with the hypothesis that sympathetic activation predominates during short-term stress, exemplified by fight-or-flight responses; and that pituitary-adrenocortical activation predominates during longterm stress (“vigilance”), when the individual struggles continually to maintain control and self-esteem. They offer no experimental support for this distinction, norfortheirviewthatbothformsofstresscontributetocardiovascular

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morbidity and mortality. On the contrary, current evidence indicates that chronic emotional distress is associated with long-term activation of catecholaminergic as well as pituitary-adrenocortical systems (Henry, 1992). Chrousos and Gold (35,36) have defined stress as a state of disharmony or of threatened homeostasis, evoking adaptive responses that can be specificto the stressor or generalized and nonspecific and that usually occur stereotypically when the threat to homeostasis exceeds a threshold. The theory dwells on homeostasis as a psychological sense of well-being. The authors have postulated that increased or decreased activity of “the stress system”, consisting mainly of corticotropin-releasing hormone (CRH) and the “locus ceruleusnorepinephrine/sympathetic system,” produces abnormal levels of glucocorticoids,norepinephrine,andepinephrineintheperipheryand contributes to several disorders, ranging from psychiatric (e.g., melancholic depression, anorexia nervosa, and obsessive-compulsive disorder), to medical (e.g., hypothyroidism, Cushing’s syndrome, and inflammatory disease). These views resemble Selye’s doctrine of nonspecificity, his listing of numerous “diseases of adaptation,” and his emphasis on “adrenalines” and especially on the pituitary-adrenocortical system in stress. Both theories do not recognize stressor-specificity of responses of the adrenomedullary, sympathoneural, and other effector systems; neither theory distinguishes clearly stress from distress; and both explain stress-related disorders circularly in terms of maladaptiveness. Chrousos and Gold have deleted several of Selye’s “diseases of adaptation,” most notably peptic ulceration and hypertension, from the list of 21 disorders associated with dysregulation of “the stress system.” A HOMEOSTATIC THEORY OF STRESS AND DISTRESS

Selye appeared to be closer to a valid definition when he conceptualized stress as a “condition” or a “state” rather than as a nonspecific, stereotyped response pattern. In the former sense, stresscan be thought of as a generic form of what in psychology is called an “intervening variable.” This is the starting point for the present definition (Figure 4-4). Motivational states such as hunger are intervening variables. If one were to deprive an individual of food, one would make that individual hungry, but the stimulus, the withdrawal of food, would not itself be the hunger. Observing anindividualgorginghimselfatabuffettable,onemightinferthatthe individual must be hungry, but the behavior, while perhaps indicating the intensity of the hunger, would not be the hunger itself. Hunger is not directly observable. It is experiential. Emotionssuchasangerarealsoareinterveningvariables.Certain stimulus situations are likely to elicit this emotion, and several behaviors or

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measurements of hemodynamic or biochemical parameters may measure its intensity, but the anger itself, although experienced by the individual, cannot be observed directly. The present theory views stress as a type of intervening variable. The stimulus and response may be physiological or psychological. Indeed, in some cases,suchasconditionedavoidanceresponsesattendedbyautonomic activation, this sort of distinction has little meaning. Levine and Ursin (29) have provided an analogous definition of stress that includes three elements: stimulus input, a central processing system, and response output, with biological and psychological processes viewed as integral partsofageneralhomeostaticprinciple.Thepresenttheoryexpandsthe psychologicalstressmodelproposedbyLazarus (28,37) toinclude physiological stress and neuroendocrine and circulatory responses.

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Proponents of different psychological schools have debated the value of emotions and motivational states as scientific constructs. Being experiential, emotions and motivational states are not amenable to direct examination, and given two theories, one with and one without an untestable component, the law of parsimony would favor the simpler one. The behaviorist school posits that the study of the rules governing relationships between stimuli and responses is a sufficient and appropriate basis for experimental psychology. The same argument applies to all intervening variables and therefore to stress. One may question the scientific necessity of stress as an intervening variable. Does adding the word “stress” to hypoglycemia or hemorrhage enhance understanding of how these manipulations lead to responses of neuroendocrine effector systems? Nevertheless, one may conceptualize “hunger” more easily than “the collection of central neural and neuroendocrine mechanisms initiated by food deprivation that produce the search for and ingestion of food.” The term “stress,” as the term “hunger,” may provide a useful conceptual abbreviation. Moreover, since all people are hungry at some time or other, the experience leads to a sense of shared reality that seems to transcend simple stimulusresponse relationships; the same may hold true for stress. Unlike emotional and motivational intervening variables, the occurrence of stress does not imply a conscious experience. The present theory defines stress as a condition: Stressisacondition in whichexpectations,whethergenetically programmed, established by prior learning, or deduced from circumstances, do not match the current or anticipated perceptions of the internal or external environment, and this discrepancy between what is observed or sensed and what is expected or programmedelicits patterned, compensatory responses. Thefollowingdiscussionelaboratesonthemainelementsofthis definition.

Homeostats A determinant of whetheran intervening variableis a stress is the effort at a compensatory response. Stress depends on the organism’s sensing something that leads to a compensatory reaction. It matters little whether the reaction is rational or successful for the reaction to indicate stress. Whether the response is adaptive or maladaptive, however, depends on the success (or perceived success) and effects of the response. In stress the organism senses a disruption or a threat of disruption of homeostasis. This sensation requires a comparative process, where the brain compares available information with setpoints for responding. Consider the

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analogy of a thermostat. Feedback about temperature reaches a thermostat set for a certain temperature. A sufficiently large discrepancy between the measured temperature and the set temperature turns on the furnace, and sufficient reduction of the discrepancy shuts down the furnace, keeping room temperature within a certain range, the average temperature corresponding to the thermostat setting. The body has many such homeostatic comparators; they can be called “homeostats.”Eachhomeostatcomparesinformationwithasetpointfor responding, determined by a regulator (Figure 4-5). The homeostat uses one or more effectors to change values for the controlled variable. The loop is closed by monitoring changes in the levels of the controlled variable, via one or more monitored variables. Several treatments used in modem medicine entail artificial homeostats or effectors to correct or replace deranged stress systems. In patients with diabetes mellitus, the endogenous glucostatic system fails to regulate blood glucose levelsadequately.Animplantedglucosesensorcanmeasurelevelsofthe monitored variable, glucose, and regulate the rate of insulin injection. Analogously, to treat patients with orthostatic hypotension due to pure autonomicfailure,Polinskyetal. (38) developeda“sympatheticneural prosthesis,” consisting of a transducer to monitor arterial blood pressure and an injector to infuse norepinephrine, so that when the patient would stand, the

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monitor would sense the fall in blood pressure, and the pump would infuse norepinephrine to maintain blood pressure withinset a range. Theimplantabledefibrillatorconstitutesperhapsthemostextreme example of an artificial homeostat (39). The implanted defibrillator senses the lossofcardiacrhythm,diagnosesventricularfibrillation,anddeliversa defibrillatory shock. Stresssystemsrequiresensorsthatmonitorthecontrolledvariable faithfully. The organism responds not to the perturbation itself, not even to alterations in values of the variable that researchers may think the system is “designed” to control, but to changes in values of the variable that the sensor actually monitors. Understanding the function of any stress system requires elucidatingtherelationshipbetweenthesupposedregulatedvariable(the controlled variable) and the actually sensed variable (the monitored variable). In the human arterial baroreceptor reflex, stretch receptors in the walls of major arteries such as the carotid arteries sense pulse-related distortion of the vessel wall (Figure 4-6). Cardiovascular researchers have thought that the “purpose”ofthesystem is toregulatearterialpressure(hencethename “baroreceptor”), although pulse pressure and pulse rate also affect baroreceptor afferent activity (40). The afferent information to the brain leads to reflexive responses, including inhibition of sympathetic outflows, which, among other things, relaxes blood vessels and counters the initial perturbation of blood pressure. Under normal circumstances, the extent of receptor stretching, the monitored variable, faithfully indicates the extent of change in pressure, the presumed controlled variable. In arteriosclerosis, however, when thickening and rigidification of arterial walls decrease the extent of pulse-related distortion, even if the baroreceptors themselves functioned normally, the decreased distortion would attenuate the amountof baroreceptor stimulation. This would decrease the afferent baroreflex information, tending to increase sympathetic outflow and therefore blood pressure. In otherwords,allotherthingsbeingthesame, arteriosclerosis resets the functionof the barostatic systemin such a manner that blood pressure and sympathetic outflow increase. In fact, encasing the carotid sinus in a cast does increase blood pressure (41). Since in many populations, arterial rigidity increases with normal aging, this phenomenon may help to explain why blood pressure and sympathetic nerve activity tend to increase with age. Another key to understanding the function of homeostatic systems is to identifythehomeostatsthatactuallymediateobservedbiochemical, neurochemical, or physiological responses. The neuroendocrine response to water deprivation illustrates this point (Figure4-7). The response pattern in this setting does not result from the deprivation itself but from the deprivationinduced changes in levels of at least two monitored variables, serum osmolality andbloodvolume,eachofwhichahomeostatregulates.Cellsinthe

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Figure 4-6 The arterial baroreflex. The baroreflex exemplifies operation of a homeostatic system. Notethat this reflex includes multiple effectors, includes the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAS) arginine vasopressin (AVP), dopamine (DA), the endogenous digoxin-like substance (Endoxin), atrial natriuretic peptide (ANP), and the vagus nerve (X).

hypothalamus sense osmolality, and the main known effector used by the “osmostat” is vasopressin (arginine vasopressin, AVP, anti-diuretic hormone, ADH). Effective circulating blood volume is monitored not by volume sensors per se but by “low pressure” stretch receptors (i.e., low pressure baroreceptors) in the cardiac atria and to a lesser extent in the ventricular myocardium and other cardiovascular regions. The “volu~tat’~ also uses the AVP effector. AVP therefore servesasaneffectorfor both theosmostatandthevolustat.Sincewater deprivation tends to increase osmolality and decrease blood volume, and since in this setting the osmostat and volustat both direct increases in AVP release, AVP levels increase markedly during water deprivation (42,43). What happens to AVP levels when the perturbation tends to increase osmolality and blood volume concurrently? According to the homeostatic model in Figure 4-7, the osmostat would stimulate AVP release, whereas the volustat would inhibit AVP release. Depending on the gain of the two homeostats, and onthedynamicsofthemonitoredvariables, AVP levelsmightincrease, decrease, or not change at all. Thus, in baboons chronically ingesting hypertonic saline (44), and in dogs on a high-salt diet with constant water intake (45), circulating AVP levels do not change, despite the osmolar load. In humans, ingestion of oral hypertonic saline after dehydration transiently decreases plasma AVP levels from the high levels that result from dehydration alone (42). In general, hypervolemia shifts to the right the curve relating AVP levels to osmolality (46), that is, hypervolemia increases the setpoint of the osmostat. These results demonstrate thatin order to predict the response of an effectora to perturbation, one must take into account the effects of the perturbation on all homeostats that use theeffector.

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A tremendousarrayofhomeostaticsystemsdetectperturbationsof monitored variables (Figure 4-8). Arterial baroreceptors, as noted above, monitor distortion of arterial walls and use the sympathetic and parasympathetic effectors to regulate blood pressure acutely. Chemoreceptors in the macula densa of the kidney monitor electrolyte concentrations in the glomerular filtrate and use renin-angiotensin-aldosterone system ( M S ) effector to regulate sodium and potassium balances. Chemoreceptors in the carotid sinus region and in the brainstemmonitorarterialconcentrationsofoxygen,carbondioxide,and hydrogen ion, and use the phrenic and sympathetic nerves to regulate arterial oxygen,pH,andcarbondioxidelevels.Nociceptors in theskinsend information about pain via spinothalamic tracts and elicit sympathoneural, adrenomedullary,andpituitary-adrenocorticalactivationascomponentsof distress responses. Gastrointestinal distention by food stimulates local increases

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in bloodflowandproducesvagallymediatedparasympatheticactivation. Glucose and temperature sensors, located in the hypothalamus, elicit different efferent patterns, with hypoglycemia stimulating release of growth hormone and corticotropin (ACTH) from the anterior pituitary gland, cortisol from the adrenal cortex, glucagon from the pancreas, and epinephrine from the adrenal medulla, and inhibiting pancreatic release of insulin. Effectors for temperature regulation include cholinergic and noradrenergic nerve fibers in the skin that regulate sweating and vasomotor tone.

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According to the current definition, even a simple homeostatic reflex such as the arterial baroreflex may reflect stress, in that a perceived discrepancy between a setpoint for a monitored variable and information about the actual level of that variable elicits compensatory responses to decrease the discrepancy. Is stress,defined in thisway,toogeneraltobemeaningful,sincestress responseswouldencompassvirtuallyallphysiologicalandpsychological adjustments? The value of the definition will depend on the ability to generate hypotheses one can test by observation and experiment. One such prediction, about the homeostatic bases for AVP responses to water deprivation, was discussed above. Homeostatic systems seem to operate according to several principles, presented below; and from these principles one can derive many testable hypotheses. Given the multiplicity of homeostatic systems, predictions about patterns of responses to stressors that potentially affect many homeostats, each of which may have particular gains and time constants for several effectors, can require sophisticatedcomputermodeling (47). Choosingthiscomplexityseems preferable to the alternative, regressing to Selye’s doctrine of nonspecificity. An alternative theory distinguishes homeostatic responses from stress responses (48), with the latter implying maladaptiveness and therefore potential harm. Such a theory cannot define stress as a condition, since a condition should occur independently of the adaptiveness of the response. Defining stress in terms of maladaptiveness also risks the problem of circular reasoning that led to abandonment of Selye’s definition of distress.

Generators Values for monitored variables are generatedin different ways. Some, like blood glucose levels, are the complex product of ingestion, production by digestion of ingested carbohydrate, and endogenous factors such as insulin, glucagon, and epinephrine, which regulate glycogenolysis, gluconeogenesis, and hepaticsecretionofglucose.Others,likeheartrate,aredeterminedby spontaneousgeneratorswithinthetissueandareregulatedbyneuronal, hormonal, and local factors. Finally, others, like mean arterial blood pressure, may not be a single ‘‘controlled‘’ variable but one of several that produce the feedback to the homeostat. Values for effector system activities also are generated in different ways. In the case of the sympathetic nervous system,in addition to low tonic levels of pre-ganglionic and post-ganglionic nerve traffic, “pacemaker” neurons in the rostral ventrolateral medulla spontaneously fire rhythmically, some dependent and some independent of baroreceptor input (49-5 1).

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Principles of Horneostat Operation

Homeostaticsystemsoperateaccordingtoafewprinciples,which, despite their simplicity, can explain complex physiological phenomena and help toresolvepersistentlycontroversialissuesintheareaofstressand cardiovascular disease. In the analogy with a thermostat as a homeostatic system, the distinction between the monitored and the controlled variable might seem largely semantic. The distinction is important. The monitored variable is a tangible, measurable entity, such as the extent of cellular stretching or the concentration of hydrogen ions. The body does not directly sense the controlled variable, regulation of whichisthe“goal”ofthehomeostaticsystem. A controlledvariableisa theoretical construct that helps us to comprehend and to predict-that is, to ‘‘explain’’-phenomena. One should feel free to discard a controlled variable, if empirical observations disagree with predictions based on its regulation. In a homeostatic schema, therefore, the controlled variable appears in the assigned name of the homeostat itself(“osmostat,” “glucostat,” etc.). Thus, substantial progress has been made in identifyingthephysical location and regulation of brain centers mediating baroreflex regulation of the circulation. The central nervous pathways have been mapped out, and simple baroreflex arcs have been identified. Theseresults have helped to identify central neural sites and mechanisms of the baroreflex; they cannot identify with surety what and why the barostat is. Regulation by negative feedback Homeostatic systems always include regulation by negative feedback. Increases in values of the monitored variable result in changes in effector activity that oppose and thereby “buffer” changes in that variable. Thus, hypercortisolemia inhibits hypothalamo-pituitary-adrenocorticalsystem activity; stimulation of arterial baroreceptor afferents inhibits sympathoneural activity; increased cardiopulmonary filling inhibits vasopressin release; increases in the filtered load of sodium inhibit renin-angiotensin-aldosterone system activity; andatrialdecompressioninhibitsreleaseofatrialnatriureticfactor.This feedback regulation can be modulated at several levels and therefore can be quite complex. In homeostaticdiagrams,thesymbol “+” denotes a stimulatory relationship and “-” an inhibitory relationship. Each “-” changes the sign of the next relationship in the circuit, whereas each “+” does not affect the sign of the nextrelationship. Ina stablesystem(i.e.,asystemwherethemonitored variables are maintained within a certain “steady-state’’ range), all the loops must have at least one “+” and one “-.” For each perturbation of a monitored variable,

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the net effect of at least one effector must have a sign opposite to that of the perturbation. For instance, Figure 4-7 depicts two homeostatic loops, one for the sequence of relationships determining AVP responses to decreased blood volume and one for the relationships determining AVP responses to increased serum osmolality. Following the sequences of “+” and “-” signs, both circuits are stable, because decreased blood volume eventually increases AVP levels, tending to increase blood volume, and because increased serum osmolality eventually increases AVP levels, tendingto decrease serum osmolality. Ifaloophas “+” relationshipsbutno “-” relationships(apositive feedback loop), the system, if otherwise unchecked, will “explode,” because activity in the system will increase without restraint. The same would hold true for loops with an even number of “-” relationships. Positive feedback loops are unstable, and levels of the monitored value increase or decrease. If no other negative feedback can take effect, then no new apparent steady-state is attained, and the organism cannot tolerate such a condition for long. One must therefore suspect any hypothesis that includes a positive feedback loop, without a “-” relationship to enable attainment of a new steady-state. Physiological positive feedback loops can occur, such as in the “growth spurt” of adolescence, but these also incorporate negative feedback, so that a new apparent steady-state is attained, and the system does not “explode.” Positive feedback loops do occur in clinical medicine. When they do, theyalwayssignifyanunstablesituation.Forinstance,whenaninsulindependent diabetic contracts a bacterial infection, septicemia rapidly can ensue, the patient presenting with both hypotension and diabetic ketoacidosis. The fall in blood pressure disinhibits sympathetic outflow reflexively, and endotoxin increasescirculatingcatecholaminelevels (52,53). Catecholamines counter insulin effects in several ways (5435). This can worsen the ketoacidosis. Mechanisms of cardiac decompensation in heart failure probably involve several positive feedback loops. Ventricular chamber enlargement normally augments contractility and performance, according to Starling’s law of the heart (56,57). In patients with heart failure and cardiomegaly, for a given increment in chamber size, the increment in ventricular performance decreases; that is, the slope of the performance-volume relationship flattens. If the slope were to become negative, then with further enlargement of the ventricular chamber, ventricular performance would decrease rather than increase, resulting rapidly in myocardial depression and fatal pulmonary edema. Most patients with heart failure die before the descending portion of the Starling curve would apply. A major reason for this is the operation of other positivefeedbackloops, in whichthesympatheticnervoussystemfigures prominently.Forinstance,themaintenanceofventricularperformance in compensated heart failure depends not only on the Starling mechanismbut also on sympathetic neural outflow (58). In patients with heart failure, myocardial

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sympathetic outflow, as indicated by the spillover rate of norepinephrine into the cardiac venous drainage, increases markedly (59). High myocardial levels of catecholaminessuchasnorepinephrinepredisposetothedevelopmentof arrhythmias. Any arrhythmia in this setting would rapidly decrease cardiac output, reflexively evoking further increasesin cardiac sympathetically-mediated releaseofnorepinephrine,whichwouldfurtherincreasethelikelihoodof developing a fatal ventricular arrhythmia. The simultaneous occurrence of heartfailure and coronary ischemia causes another type of sympathetic positive feedback loop in heart failure. Heart failure recruitscardiacsympatheticoutflow,whichincreasesmyocardialoxygen consumption by increasing cardiac rate and contractility. This worsens the imbalance between oxygen supply and demand and can precipitate a lethal myocardial infarction or ventricular arrhythmia. Hypoxic ischemia also can evoke norepinephrine releaseby local effects at the sympathetic terminals(60).

Multiple eflectors Homeostatic systems generally use more than one effector. For instance, activationofthebody’sglucostatsrapidlyincreasesglucagonandgrowth hormone levels, augments activities of the adrenomedullary and pituitaryadrenocorticalsystems,andsuppressesinsulinrelease;andunloadingof cardiopulmonary baroreceptors increases skeletal sympathoneural outflow and renal release of renin, whereas cardiac release atrial of natriuretic factor declines. Natural selection would have favored the evolution of systems including multiple effectors. The redundancy comes at little cost, yet increases the range of control, enables a degree of control of regulated variables by compensatory activation when one effector malfunctions, and enables patterned activation of effectors to maximize adapativeness. Compensatory activation

Because of effector redundancy, disabling an effector compensatorily activates the others, assuming no change in homeostat settings (Figure 4-9). This enables partial or even complete maintenance of the monitored variable at the previous setting. The efficiency of the other effectors determines whether the compensatory activation actually normalizes values for the monitored variable. Examplesofcompensatoryactivationincludeaugmentationof sympathoneuralresponsivenessbyadrenalectomy,hypophysectomy,or thyroidectomy (6 1-63). Because of compensatory activation, blockade or destruction of a single effector to assess the contribution of the effector to a monitored variable may

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underestimate that contribution-or even fail to detect it-if effectors other than the blockedor destroyed one.

the homeostat uses

Range of control Consideragaintheexampleofthethermostat in controlofthe temperature of a house (Figure 4-10). During the winter, a furnace might serve adequately as a single effector, but in the summer this would not suffice. Havinganairconditioneraswellas a furnaceextendstherangeof environmental temperatures that the control system can regulate. A heat pump, attic fan, and functioning windows introduces economic benefits at relatively little cost. Because of compensatory activation, blockade or destruction of a single effector, to assess the contribution of the effector to a monitored variable, may

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Figure 4-10 A home heating system. Note multiple effectors regulating the monitored variable.

underestimate that contribution-or even fail to detect it-if the homeostat uses effectors other than the one blocked or destroyed. The multiplicity of effectors regulating blood pressure helps to explain inconsistent results of studies using sympatholytic procedures or adrenoceptor blockade to evaluate the sympathetic contribution to high blood pressure. Elucidating such a contribution requires either monitoring or control of the activities of the other effectors.

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Patterning Another consequence of multiple effectors is the potential for patterned effector responses. Patterning of neuroendocrine, physiological, and behavioral effectors increases the likelihood of adaptiveness to the particular challenge to homeostasis, providing another basis for natural selection to favor the evolution of systems with multiple effectors. In the analogy of the system regulating the temperature of the house, one can use one’s judgment or, nowadays, install a programmable computer, to maximize the control at the mimimum expense, by choosing among many patterns of effector activation and modifying their elicitation as circumstances change. Experimental evidence supporting this patterning (1 3,64-68) also argues against Selye’s doctrine of nonspecificity. This patterning is crucial not only for stress theory but also for elucidating the role of catecholaminergic systems in mediating the relationships between stress and cardiovascular disease. Patterning of autonomic responses to different stressors is discussed in Chapter 5. EfSector sharing Conversely,severalhomeostatscanregulatetheactivityofasingle effector system. A previous section discussed sharing of the vasopressin effector by the osmostat and volustat. Other examples of effector sharing abound in physiology. Both arterial hypotension and decreased cardiopulmonary filling stimulate sympathoneural activity; both hypoglycemia and emotional distress stimulate adrenomedullary activity; both exercise and hypoglycemia stimulate growth hormone secretion; and both decreased sodium concentration in the glomerular filtrate and decreased renal perfusion pressure stimulate activity of the renin-angiotensin-aldosterone system. Sharingoftheactivityof an effector by morethanonehomeostat increasesthelikelihoodofdrawingafalsenegativeconclusionaboutthe relationship between the state of activity of the effector and the extent of activation of any homeostat using that effector. For instance, whether borderline hypertensives have increased sympathetic nerve activity has incited debate for many years. Many homeostats share the sympathoneural effector. When the activity of one of them, the low-pressure barostatic system, is monitored by measurementsofcentralvenouspressure,thenexcessiveskeletalmuscle sympathetic activity fora given central venous pressure becomes obvious (69); in theabsenceofthismonitoring,thedistributionsofnerveactivities in hypertensive and normotensive groups overlap. Effector sharing alone cannot explain poor correlations between values for activity of the effector and values for a monitored variable, if the effector is the only one determining the level of the monitored variable. For instance, in

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Figure 4-7, even though two homeostats determine the activity of the same effector, changes in the function of Homeostat 1 do not affect the relationship between the activity of the effector and the activity of Monitored Variable 2. If the activity of the effector decreases, level the of Monitored Variable2 decreases, according to whatever defines the relationship between the two. In general, the presenceofasinglearrow in ahomeostaticschemaimpliesaconsistent relationshipbetweentheconnectedvariables,regardlessofthecomplex interactions among other variablesin the schema. Virtuallyeverymonitoredvariable,however,is in factsubjectto influences by more than one effector, as discussed above. The combination of multiple effectors and effector sharing can easily explain the notoriously poor correlations between values for activity of a single effector and of a single monitored variable-such as the correlations between sympathetic nerve activity and blood pressure in “resting” subjects. Blood pressure is only one of many factors determining sympathetic activity (effector sharing); and many systems besides the sympathetic nerve system contribute to blood pressure regulation (multipleeffectors).Inadequateconsiderationofthesetwoprinciplesof operation of homeostatic systems will lead to false-negative inferences. Interactions Among Homeostats

Homeostats can interact indirectly via the effectors they share. Increased activity of an effector activated by effects of a perturbation on one homeostat can alter values for a monitored variable regulated by another homeostat (Figure 411). These indirect interactions can explain many phenomenain clinical practice and provide a means to assimilate complex concepts of integrative medicine. The following provides a few examples. The chapter about autonomic systems in stress (Chapter 5 ) discusses some of these in more detail. Commonly in the practice of emergency medicine, a diabetic patient undergoingevaluationforgastrointestinalbleedingandhypotensionhas hyperglycemia. The patient may appear not to have complied with the prescribed insulin regimen. Instead, activation of the adrenomedullary hormonal system as part of the homeostatic regulation of blood pressure promotes hyperglycemia because of the effects of epinephrine on circulating glucose levels. Patients with autonomicfailuresyndromesoftenhavepost-prandialhypotension.One potential explanation for this phenomenon is that meal ingestion stimulates insulin release. Without reflexive sympathetically-mediated vasoconstriction, insulin might then induce systemic vasodilation and hypotension. Shoveling snow constitutes a well-known precipitant of angina pectoris in patients with coronary artery disease. Both isometric exercise and exposure to cold increase sympathetic nervous outflows, as part of responses to “central command” and thermostatic regulation. In this situation, diffuse sympathetic

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Figure 4-11 Interactions betweentwo

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homeostaticsystems, based on effector

sharing.

stimulation also increases myocardial oxygen consumption, and in the setting of limited ability to increase coronary blood flow, the oxygen consumption can exceed the supply, resulting in myocardial ischemia. Homeostat disruption Blockade of afferent information to or interference with the function of a homeostat increases the variability of levels of the monitored variable (Figure 412). Thus,baroreceptordeafferentiationincreasesthevariabilityofblood pressure (65), as does bilateral destruction of the nucleus of the solitary tract, the likely brainstem site of the arterial barostat (66,67). A more difficult issue is whether release of a monitored variable from homeostatic restraint increases the tendency for the variable to drift to a new level that may be pathophysiologic. In particular, researchers have debated for many years whether baroreceptor “debuffering” increases resting blood pressure (i.e., whether debuffering produces a form of neurogenic hypertension).Part of the problem here lies in the meaning of the term, “resting.” Many interacting systems determine blood pressure levels, and activities of these systems do not cease during life. Even if one were to avoid use of the term and were rigorously to control environmental conditions, organisms with impaired baroreflexes could have excessive classically conditioned sympathetic responses to seemingly neutral cues (68). Moreover, debuffering may decrease thresholds for arousal, vigilance, or rage (69-71), and the accompanying sympathetic activation would then increase blood pressure. In contrast with clinical hypertension, a largely statistical disease of modem man, hypotension due to traumatic hemorrhage has always posed an immediate and mortal threat. Natural selection must have favored the evolution

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TIME

TIME

Figure 4-12 Predicted effects of disruption of a homeostat (the arterialbarostat) on blood pressure. Blood pressurevariability increases markedly,and the mean value increases somewhat.

of systems to support blood pressure during emergencies.As Cannon (1,3,70) demonstrated, prominent among these systems is the sympathetic system, activation of which increases blood pressure. If the sympathetic system were an emergency system, then one would expect that release of the sympathoneural effectorfrombaroreceptorrestraintwouldbiasbloodpressureupwards. Conversely, baroreflexes often buffer hypotension more effectively than buffer hypertension (71). Interference with homeostatic regulation of blood pressure therefore increases the variability of blood pressure, augments hypertensive responses to various stressors, and produces acute hypertension.

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Resetting Homeostat resetting redefines homeostasis. Challenges to homeostasis mayormaynotrequirehomeostatresettingfortheorganismtorespond successfully. During orthostasis or performance of the Valsalva maneuver, as cardiac filling and output decrease, sympathetic vasomotor outflows increase reflexively; the resulting vasoconstriction maintains mean arterial pressure, without any obvious change in the functioning of the reflex. In contrast, during exercise, homeostatic resetting caused by altered “central command” releases skeletalsympathoneuraloutflowfrombaroreceptorrestraint,enabling sympathetically-mediated vasoconstrictor tone to counter effects of vasodilator substances that if unopposed would decrease blood pressure and flow to the brain. Short-termchanges in homeostaticsettingsduringstressgenerally enhance the long-term well-being and survival of the organism (responses during exercise provide an obvious example). When superimposed on a substrate of cardiovascularpathology,however,homeostaticresettingcancauseharm, because during many stresses (exercise and cold exposure are examples), the hemodynamic effects of homeostat resetting include increased cardiac work or afterload, due to global or patterned increases in sympathetic outflows. The resetting may then worsen a largely independent cardiac pathologic state. Homeostatic resetting in pathologic conditions can therefore produce unexpected clinical consequences. For instance, patients with chronic obstructive pulmonarydiseaseoftenhavedecreasedchemoreceptorresponsivenessto hypercarbia,thusdependinguponhypoxicdrivetoregulateventilation. Administering pure oxygen eliminates this drive, causing hypoventilation, accumulation of carbon dioxide,and possibly coma or respiratory arrest. The efficacy of nitroglycerine in angina pectoris may depend on baroreflex resetting. In healthy volunteers, nitroglycerine increases pulse rate reflexively as stroke volume falls (72). Since systolic blood pressure declines, whereas heart rateincreases,thepressure-rateproduct,anindexofmyocardialoxygen consumption,remainslargelyunchanged. In patientswithanginapectoris, nitroglycerine reduces the imbalance between myocardial oxygen demand and coronary arterial oxygen supply, relieving the chest discomfort. An explanation for this beneficial effect is that arteriosclerotic cardiovascular walls splint baroreceptors,preventingreflexivesympatheticcardiovascularstimulation during nitroglycerine-induced decreases in cardiac filling, thereby decreasing myocardial oxygen consumption.

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NON-AUTONOMIC STRESS SYSTEMS AND THEIR INTERACTIONS WITH CATECHOLAMINE SYSTEMS

Although the autonomic nervous system plays several major roles in maintaininghomeostasisduringexposureto a varietyofstressors, neuroendocrine and other non-autonomic effectors actin concert with autonomic effectors. This section briefly discusses some of non-autonomic effectors. Others are discussed in Chapter 5.

Hypothalamo-Pituitary-Adrenocortical System Activationofthe hypothalamo-pituitary-adrenocortical (HPA)axis releases hormones such as cortisol from the cortex of the adrenal glands into the bloodstream. Cortisol isa“glucocorticoid.”Exogenouslyadministeredcortisol increases blood levels of glucose; conversely, patients with adrenocortical failure due to Addison’s disease tend to have hypoglycemia. Cortisolalsoinhibitsdelayedinflammatoryresponses.Theantiinflammatory effects of glucocorticoids figure prominently in the stress theory of Selye, as previously noted. Glucocorticoids at high doses can improve the conditionofpatientswithinflammatorydiseases or shock.Conversely, adrenocortical failure, as in Addison’s disease, markedly increases susceptibility during exposure to a variety of stressors. The bases for the requirement of normal adrenocortical functionin order to weather acute stress remain obscure. Deficiency of circulating glucocorticoids increases capillary permeability, attenuates cardiac and vascular responses to catecholamines,andreducesbloodvolume,decreasingthethresholdfor circulatory collapse. Adrenalectomized animals failto maintain hepatic glycogen stores after brief starvation, rendering them hypersensitive to insulin. As with catecholamines, exogenously administered glucocorticoids affect virtuallyallbodyorgans;however,theseeffectsaremuchmoredelayed. Chronically elevated glucocorticoid levels can produce a form of diabetes mellitus.Theanti-inflammatoryeffectsincreasesusceptibilitytosome infections, such as tuberculosis. Other effects include redistribution of body fat, leading to central, or truncal, obesity and a moon-faced appearance; retention of sodiumandexcretionofpotassiumbythekidney,leadingtoincreased extracellularfluidvolume,hypertension,andhypokalemia;catabolismof proteins,leadingtomusclewasting;gastrointestinalbleeding;decreased sympathoneuraloutflows (73) andincreasedcardiovascularsensitivityto catecholamines (74); and several forms of psychiatric disturbance. Corticotropin, or ACTH (adrenocorticotropic hormone), regulates release of adrenocorticalglucocorticoids.Theanteriorlobeofthepituitarygland

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releases ACTH, a polypeptide consisting of 39 amino acids. The pituitary, a pea-sized gland, sits in a bony cavity called the sella turcica (from its shape similar to that of a Turkish saddle) at the end of a thin stalk (infundibulum) extending from the base of the brain. The pituitary gland is also known as the hypophysis, from the Greek words for a growth beneath the brain. Corticotropin-releasing hormone (75) importantly influences pituitary secretionofACTH.Corticotropin-releasinghormonereleaseinthe hypothalamus, the region of the brainstem giving rise to the pituitary gland, responds to several stressors. Other central neuropeptides (such as AVP, (76)), catecholamines in thebrain (77), andfeedbackinhibitionfromcirculating glucocorticoidsinteractcomplexlywithcorticotropin-releasinghormone in determining ACTHrelease. Intracerebroventricular administration of corticotropin-releasing hormone increases not only plasma levels of ACTH but also levels of epinephrine and norepinephrine (78,79). Simultaneous corticotropin-releasing hormone-induced activation of the body’s three main stress systems-hypothalamo-pituitaryadrenocortical, sympathoneural, and adrenomedullary-has led to speculation about corticotropin-releasing hormone being a “master stress hormone.” This would support Selye’sunitary theory of stress. hypothalamo-pituitary-adrenocortical and Activities the of catecholaminergicsystemsinteractatseverallevels(Figure 4-13). These interactionssuggestsharingofthe hypothalamo-pituitary-adrenocortical, adrenomedullary, and sympathoneural effectors by many homeostats. Physiologicalormetabolicstimulithatincreaseadrenomedullary secretion (e.g., hypoglycemia, hemorrhage, and surgery) often concurrently increase hypothalamo-pituitary-adrenocortical systemactivity (61 ,SO). Emotional distress also elicits combined adrenomedullary and hypothalamopituitary-adrenocortical activation. For instance, viewing Disney nature films decreases and viewing stressful (mainly anxiety-provoking) films increases urinary 17-hydroxycorticosteroid and epinephrine excretion ( S 1). During the mental challenge of playing a video game, responsesof arterial plasma levels of ACTH and epinephrine correlate strongly positively across individual subjects (82), even though mean ACTH levels remain unchanged. In theabsenceofafunctioningadrenomedullaryhormonalsystem, disruption of the hypothalamo-pituitary-adrenocortical axis compensatorily activates the sympathetic nervous system. Thus, adrenalectomized monkeys have exaggerated responses of plasma norepinephrine levels during surgical stress several months later, and the magnitude of this augmentation varies inversely with the amount of glucocorticoid pretreatment (61); and in rats, hypophysectomy produces large increases in plasma levels of norepinephrine and epinephrine (62).

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stlmulates sympathoneural and adrenomedullary outflows. Central NE promotes ACTH release. Cortlsol lnhlblts sympathoneural and adrenomedullary outflows.

P i t UI t a r y

SNS

Adrenals

R-Agonlstslnhlblt ACTHrelease. Hypophysectomy Increases sympathoneural and adrenomedullary outflows. Sterolds lnhlblt Uptake-2. Hypercortlsolemla responses.

augments R-adrenoceptor-medlated

Sterolds Increase adrenal PNMT acttvlty. Adrenalectomy augments sympathoneural responses. Chromaffm tlssue contams functlonal CRH receptors

Figure 4-13 Some interactionsbetweenthe hypothalamo-pituitary-adrenocortical and catecholamine systems. ACTH = corticotropin; CRH = corticotropin-releasing hormone; NE = norepinephrine; PNMT = phenylethanolamine-N-methyltransferase; SNS = sympathetic nervous system.

Administration of agonists at glucocorticoid receptors generally inhibits sympathoneural and adrenomedullary outflows, and conversely, administration of adrenoceptor agonists tends to inhibit hypothalamo-pituitary-adrenocortical systemactivity.Thus,administrationofcortisol or dexamethasone to rats decreases basal plasma levels of norepinephrine and especially of epinephrine (83,84). Dexamethasone can blunt acute plasma catecholamine responses (83), and hypercortisolemia abolishes a2-adrenoceptor blockade-induced increases in plasmanorepinephrinelevels ( 8 5 ) . Hypercortisolemiaalsoinhibits a2adrenoceptor blockade-induced norepinephrine releasein the brain (86). Intracerebroventricular administration of corticotropin-releasing hormone evokes large increases in plasma levels of ACTH and catecholamines and in directlyrecordedadrenalnerveactivity (87). Intracerebroventricular aadministration of the corticotropin-releasing hormone receptor antagonist, helical corticotropin-releasing hormoneg-41, does not affect basal plasma levels of catecholamines but attenuates plasma epinephrine responses to hemorrhage and to insulin-induced hypoglycemia(SS), consistent with a role of endogenous corticotropin-releasing hormone in mediating the adrenomedullary responses to these stressors. A subsequent study, however, failed to replicate the latter effect (62). Lewis rats have deficient corticotropin responses during inflammatory stresses,apparentlyduetodeficienthypothalamiccorticotropin-releasing hormone secretion (89). These rats also have low baseline plasma levels of epinephrine, compared with levels in histocompatible Fischer rats (90). Central noradrenergic receptors participate in regulation by hypothalamic corticotropin-releasinghormonesecretionandpituitaryACTHrelease.

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Activation of central oil-adrenoceptors stimulates release of vasopressin, which in turnfacilitatesACTHresponsestocorticotropin-releasinghormone (76,77,91-94). Glucorticoids, present at high local concentrations in the adrenal medulla because of the corticomedullary direction of blood flow, regulate activity of phenylethanolamine-N-methyltransferase(PNMT) and synthesis of the enzyme, thelatter by bindingto acorticosteroid-responsiveelement (CRE) in the promoter region of the PNMT gene. Thus, children with hypocorticotropic hypopituitarism have markedly reduced plasma levels of epinephrine, despite normal levels of norepinephrine (95). Patients with adrenocortical failure from Addison’s disease also have decreased plasma epinephrine levels (96). Sympatheticgangliaandadrenomedullarycellspossessfunctional corticotropin-releasing hormone receptors (97). ACTH (probably via adrenal corticosteroids) increases activities of dopamine-R-hydroxylase and PNMT (98), enhancing the capacity to synthesize norepinephrine and convert norepinephrine to epinephrine. ACTH administered at pharmacological doses can stimulate catecholamine release (99). Although it had been proposed that epinephrine stimulates pituitary release of ACTH(1 00), administration of the l3-adrenoceptor agonist, isoproterenol, if anything decreases circulating ACTH and epinephrine levels in humans (101-103). Hypercortisolemia augments R-adrenoceptor-mediated heart rate responses in rats (74), and glucocorticoids stimulate the transcription of genes coding for R2-adrenoceptors in hamster smooth muscle cells(104). Asnoted in Chapter 2, steroidsinhibitextraneuronaluptakeof catecholamines (105).

Vasopressin Water deprivation poses a distinct homeostatic challenge. Another stress system,theargininevasopressin(AVP)system, is themaineffectorfor maintaining total body water content. AVP, a peptide consisting of 9 amino acids, is synthesized as part of a larger precursor molecule in magnocellular cells of the paraventricular and supraoptic nuclei of the hypothalamus. Neurosecretory granules flow in the axoplasm to nerve terminals in the posterior pituitary; during the transport, AVP detaches from the precursor molecule. In the posterior pituitary, granules store AVP until AVP is released by neurosecretion from the nerve terminals into the bloodstream. AVP thereforeis a prototypical neurohormone. Increased serum osmolality, reflecting relatively inadequate serum water, potently stimulates AVP secretion (43). Decreased cardiac filling pressure, such as occurs during hemorrhagic hypotension, also stimulates AVP release.

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The interaction between the osmostat and volustat in regulating AVP levels was discussed above. Briefly, hypervolemia shifts to the right the curve for the relationship between AVP levels and osmolality (46); i.e., hypervolemia increases the set-point of the osmostat. AVP exerts an anti-diuretic effect (hence its other name, anti-diuretic hormone, or ADH) by stimulating specific AVP receptors (V2 receptors) on the abluminal membrane of renal tubular cells in the ascending loop of Henle and the collecting duct. Occupation of the V2 receptors increases generation of intracellularcyclic AMP, whichincreasesthepermeabilityoftheluminal membrane to water and promotes fusion of water-trapping endosomes with the luminal membrane. The endosomes take up water via protein-water channels, resulting in concentration of the urine. Consequently, AVP inhibition, such as produced by alcohol, evokes a diuresis, with the urine hypotonic with respect to plasma. By promoting excretion of concentrated urine, the renal actions of AVP increase retention of “free water” when water is available to drink. Free water retention, in concert with decreased delivery of water to diluting segments of the nephronduetodecreasedglomerularfiltration,explainshyponatremia in edematousstatessuchasheartfailure.Excessive ADH release in clinical pathologic states (syndromes of inappropriateADH secretion, SIADH) decreases serum osmolality and causes hyponatremia. As its name implies, exogenously administered vasopressin increases blood pressure, via peripheral vasoconstriction elicited by occupation of V1 receptors on vascular smooth muscle cells. Endogenous AVP probably does not participate in tonic blood pressure regulation in healthy humans; however, after sympathoneuralablation in laboratoryanimals,endogenous AVP does contribute to blood pressure (106). Intravenously administered AVP has been used clinically to ameliorate upper gastrointestinal hemorrhage due to variceal bleeding, by producing vasoconstriction and decreasing portal venous pressure. AVP also augments arterial baroreflex inhibition of sympathetic nerve activity, as discussed later in the section about AVP-catecholamine interactions, and augments baroreflex stimulation of cardiac parasympathetic activity. Studies about interactions between catecholamines andAVP have focused mainly on effects of catecholaminesin the brain on AVP release, on the relative rolesofthesympathoneuraland AVP systems in mediatinghypertensive responses to brainstem lesions, and on effects of AVP on baroreflex regulation of sympathoneural outflow. Stimulationofa-adrenergicreceptorsbyinjectednorepinephrine suppresses circulating AVP levels (107), probably because of use of the AVP effector by the high-pressure barostat, discussed below. In the brain, catecholaminergic pathways contribute to regulation ofAVP release. Central administration of 6-hydroxydopamine Causes adipsia and an

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inability to conserve administered fluids. Animals treated with 6hydroxydopaminedonothaveincreasedserumAVPlevels,despitethe dehydration (1 OS), although further hypovolemia resulting from intraperitoneal polyethylene glycol does evoke increasesin AVP secretion. Bilateral lesions of the nucleus of the solitary tract markedly increase AVP levels. Ganglion blockade alone does not attenuate the hypertension, whereas combined ganglion blockade and administration of an AVP antagonist abolishes the hypertension (1 09). Intravenous administration of clonidine can ameliorate both the hypertension and elevated levels of AVP resulting from bilateral lesions of the NTS in rats (1 lo), consistent for a role of central neural a2-adrenoceptors in determining the AVP response. Lesions of the A1 noradrenergic cells in the caudal ventrolateral medulla elicit fulminant hypertension, also due to sympathetic stimulation and AVP release (1 11,112).Ganglionicora-adrenoceptorblockadeabolishesand administration of a AVP antagonist attenuates A1 lesion-induced hypertension (109,110). Since systemic administration of the 6-hydroxydopamine attenuates A1hypertension,andAVP-deficientBrattlebororatscandevelopA1 hypertension, sympathoneural activation determines this form of hypertension, despite 100-fold increases in plasma AVP levels (1 13). The localization of parvocellular neurons projecting to medullary and spinal cord centers involved with sympathetic outflow and of magnocellular neurons contributing to AVP release suggests that the paraventricular nucleus (PVN) of the hypothalamus provides a site for interaction between AVP and peripheral catecholaminergic systems. Stimulation of the PVN increases blood pressure, the pressor effect apparently independent of AVP release, since PVN stimulation increases blood pressure even in Brattleboro rats (1 14,115). Acute sinoaortic denervation unmasks a stimulatory effect of parvocellular cells on blood pressure and on splanchnic, renal, and skeletal muscle vasoconstriction, whereas magnocellular stimulation in this setting exerts little effect on blood pressurebutcausesmarkedhindquartersvasodilation (1 16).Electrical stimulation of the circumventricular subfornical organ increases blood pressure by causingdiffusevasoconstriction,especiallyofthemesentericbed,and ganglion blockade abolishes and AVP blockade attenuates the responses (1 17). Surgicaldisruptionofcorticotropin-releasinghormoneandAVP pathwaystothemedianeminenceattenuateplasmaACTHresponsesbut augment plasma catecholamine levels during immobilization stress ( I 18). Conversely, chemical sympathectomy increases plasma AVP levels (106). In laboratory animals, circulating AVP inhibits renal sympathetic nerve activity indirectly, via a pathway from the area postrema to the nucleus of the solitarytract(119),suggestingeffectsofAVPonbaroreflexfunction. Stimulation by AVP of medullary centers regulating baroreflexes attenuates reflexive increments in regional sympathoneural outflows (120-123). In humans,

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AVPadministrationinhibitsdirectlyrecordedskeletalmusclesympathetic activity (124) and augments baroreflex inhibition of sympathoneural outflow (125). Concurrent sensitization of baroreceptor-sympathoneural reflexes may mask the pressor action of pharmacologic doses of AVP (124). Chemical sympathectomy markedly increases plasma vasopressin levels (106) and decreases blood pressure. Vasopressinergic inhibition after chemical sympathectomy produces profound, persistent hypotension. As noted in the following for the renin-angiotensin-aldosterone system, this finding illustrates how compensatory activation of alternative effectors can lead to underestimation of the role of a single effector system (in this case, the sympathetic nervous system) in determining “basal” levels of a monitored variable (in this case, blood pressure). Renin-Angiotensin-Aldosterone System

The body possesses impressively efficient means to preserve sodium. For this, the renin-angiotensin-aldosterone system is the most prominent effector. Dietary salt restriction stimulates renin-angiotensin-aldosterone system activity; saltloadingvirtuallyshuts it down.Activityofthesystemhascomplex, interacting determinants and effects (Figure 4-14). Reninisaglycoproteinsynthesized in andreleasedfrommodified vascular smooth muscle cells, juxtaglomerular cells, in the afferent arterioles to the renal glomeruli. Renin has no known activity of its own but catalyzes the conversionofalarge a - 2 globulin,angiotensinogen,toadecapeptide, angiotensin I. Angiotensin I also has no known physiological action; however, angiotensin-convertingenzyme(ACE)catalyzesitsconversiontothe physiologicallyactiveoctapeptide,angiotensin 11. Angiotensin I1 potently constricts blood vessels in all vascular beds, and exogenous angiotensin I1 increases blood pressure. On a weight basis, angiotensin I1 is 4-8 times as potent a vasoconstrictor as is norepinephrine in healthy individuals. Angiotensin I1 exerts little direct effect on the heart, and after bolus injection of angiotensin 11, heart rate decreases reflexively. This provided the basis for the first meansto test the gain of the arterial baro-cardiac reflex in humans (1 26). Angiotensin I1 also stimulates the adrenal cortex to release aldosterone, the main mineralocorticoid in humans. Aldosterone augments renal sodium retention (hence its designation as a mineralocorticoid) by stimulating exchange of sodium for potassium, so that hyperaldosteronism tends to produce sodium retention, expansion of extracellular fluid volume, hypertension, and potassium wasting. Angiotensinases rapidly destroy circulating angiotensin 11. One of these, aminopeptidase,cleavesanAspresiduefromtheN-terminalendofthe molecule. The metabolite, angiotensin 111, has about 40% the pressor activity of

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Figure 4-14 Overview of therenin-angiotensin-aldosteronesystem. AI1 = angiotensin 11; Aldo = aldosterone; ANP = atrial natriuretic peptide; AVP = arginine vasopressin; BP = bloodpressure;DA = dopamine; SNS = sympathetic nervous system.

angiotensin I1 and is equallypotentwithangiotensin 11 instimulating aldosterone secretion. Renin-angiotensin-aldosterone system activation increases blood pressure, bothbyangiotensin-inducedvasoconstrictionandbyaldosterone-induced sodium retention and expansion of extracellular fluid volume. Inhibitors of aldosterone, angiotensin-converting enzyme, or angiotensin I1 receptors are effective anti-hypertensive agents. Stimuli for release of renin include decreased renal perfusion pressure, sensed by the juxtaglomerular cells; decreased renal tubular concentrations of sodium, sensed by cells of the macula densa in the distal nephron near the juxtaglomerular apparatus; and decreased cardiac filling pressure, sensedby lowpressure baroreceptors in the heart. Thus, at least three homeostats regulate renin secretion. In addition, occupation of B-adrenoceptors by norepinephrine released fromsympatheticnervesterminatingatthejuxtaglomerularcellsand by epinephrine reaching those receptors via the circulation increase renin secretion (127-129). Angiotensin I1 inhibits renin secretion. The renin-angiotensin-aldosterone system interacts complexly with all three endogenous catecholaminergic systems (Figure 4-15). As noted above, stimulation of juxtaglomerular cell B-adrenoceptors, via neuronal norepinephrine orcirculatingepinephrine,evokesreninrelease.Conversely,exogenous angiotensin I1 augmentsreleaseofnorepinephrineduringsympathetic

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Brain

SN S Adrenals

Kidneys

Ref lexes

Angiotensin II stimulates sympathetic outflows. Angiotensin II augments NE release in vitro. Angiotensin II stimulates adrenomedullary secretion. Dopamine inhibits aldosterone secretion. Epinephrineandrenal release.

nerve stimulationevoke

renin

Angiotensin II decreases baroreflex-sympathoneural gain After chemical sympathectomy, the renin-angiotensinaldosterone system maintains blood pressure.

Figure 4-1 5 Some interactions between the renin-angiotensin-aldosterone and catecholamine systems.

stimulation (130-132), and application of angiotensin I1 to primary cultures of adrenomedullarycellsstimulatesrapidreleaseofcatecholaminesintothe medium (133). Whether endogenous angiotensin I1 influences adrenomedullary releaseofepinephrine in humansisunknown.Dopamineattenuates adrenocortical secretion of aldosterone in response to sodium depletion (134) or exogenous angiotensin I1 (135), via occupation of local D2 receptors. Since adrenocorticaldopamineproductiondependsimportantlyonuptakeand decarboxylation of circulating L-DOPA (1 36), the inhibitory effect of dopamine on aldosterone secretion probably dependson an autocrine-paracrine action. The brain contains all the elements of the renin-angiotensin-aldosterone system (137). Angiotensin 11-like immunoreactivity has been found in several brain regions, including the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, the subfornical organ, and the supraoptic nuclei and hippocampus; and angiotensinI1 receptors have been found in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, subfornical organ, and area postrema. In quietly resting, conscious animals, centrally administered angiotensin I1 increases sympathetic outflow, especially when unmasked by disruption of baroreflexes (1 38). Endogenous angiotensin I1 does not appear to exert a tonic influence on sympathetic outflow, since blockade of angiotensin receptors or angiotensin-converting enzyme fails to alter renal sympathetic activity (139). Animals that have received systemic angiotensin I1 infusion chronically develop aform of neurogenic hypertension (140).

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Thelocationofangiotensin I1 receptors in circumventricularorgans suggests that both circulating and central angiotensinI1 can reach the receptors. In the brain, exogenously administered angiotensin I1 elicits thirst (angiotensin I1 isoneofthemostpotentknowndipsogens),salthunger,secretionof vasopressin and ACTH, and sympathetic activation, and it appears to act in the nucleus of the solitary tract to decrease baroreflex sensitivity (141). All these effects are consistent with a homeostatic system to maintain extracellular fluid orbloodvolume.AngiotensinII-containingneuronsprojectfromthe paraventricular nucleus of the hypothalamus to the nucleus of the solitary tract, whereangiotensin I1 releasemayinhibitbaroreflexfunctiontoincrease sympathetic outflow and blood pressure. Destructionofsympatheticnerveterminalsbytheneurotoxin, 6hydroxydopamine, increases plasma renin activity, and whereas administration of an angiotensin-converting enzyme inhibitor produces little effect on blood pressure in intactanimals,administrationoftheinhibitortoanimalsafter destruction of peripheral sympathetic terminals produces immediate, marked hypotension (142). Thus,sympatheticdestructionactivatesthereninangiotensin-aldosterone compensatorily, and the compensatory activation masks the role of the sympathetic nervous systemin maintaining blood pressure. Associationsbetweensympatheticnervousandrenin-angiotensinaldosterone system activities result mainly from sharing of the effectors,by both the high-pressure arterial baroreflex system (the “barostat”) and low-pressure cardiopulmonary baroreflex system (the “volustat”). Consistent with this view, many studies have reported positive correlations between plasma levels of norepinephrine and renin activity across individuals, the relationship being especially apparent among groups of patients with essential hypertension (143148).

Endogenous Opioids The endogenous opioid system contributes to the experienceof pain and to stress-related analgesia. Activity of this system is linked closely with those of the hypothalamo-pituitary-adrenocortical and adrenomedullary hormonal systems (149). Martin hypothesized the existence of different receptors for opiates (1 50). Three types of receptors were suggested, based on in vivo observations: mu (p) (formorphine);kappa ( K , forketocyclazocine);andsigma ( G , forthe investigational drug SKF-10,047). In vitro bioassay evidence identified a fourth type of receptor, delta (6, for mouse vas deferens). The anesthetic, fentanyl, stimulates p receptors; whereas morphine stimulates p and 6 receptors. Pert and Snyder (15 1) first demonstrated the existence of opiate receptors in brian tissue and hypothesized that endogenous morphine-like

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determine the sensation of pain. The first identifiedclassofendogenousopioidsweretheenkephalins,methionineenkephalin and leucine-enkephalin, small peptides (5 amino acids each) with either methionine or leucine at the end of a chain with the first 4 amino acids being Tyr-Gly-Gly-Phe. Enkephalins are packaged together with catecholamines and released with them during adrenomedullary stimulation (1 52). Every known endogenous opioid peptide, collectively termed endorphins, contains the TyrGly-Gly-Phe sequence of amino acids. Narcotic activity appears to depend on the Tyr residue. Apituitaryhormoneofunknownfunction,R-lipotropin,or R-LPH, contains (but is not the source of) met-enkephalin. The opioid fragment of Rlipotropin is a 3 l-residue peptide, R-endorphin. R-endorphin is in turn a portion ofaprecursorpeptide,pro-opiomelanocortin(POMC),whichalsoisthe precursor of ACTH, melanocyte-stimulating hormone (y-MSH), and R-LPH. In the anterior pituitary, POMC gives rise to ACTH, as well as R-LPH, which is cleavedtoforma-LPHand R-endorphin.Assuggestedbythename, Rendorphin is an endogenous opioid neurotransmitter. The highest concentrations of R-endorphin in the body are in the pituitary gland. Corticotropin-releasing hormone increases plasma levels of both ACTH and R-endorphin. Many types of stress increase circulating levels of R-endorphin, and increases in plasma R-endorphin and epinephrine levels during real-life stress are highly correlated in humans (153). The role or roles of endogenous opioids in theregulationofautonomicoutflowsandcirculatoryparametersremain incompletely understood. Most reports have suggested indirect inhibitory effects of endogenous opioidson sympathetic outflow or neurotransmission. Studies about physiological roles of endogenous opioids have relied heavily on use of naloxone, which blocks effects of all endogenous opioids. Naloxone is a short-acting but very effective drug in the treatment of opiate overdose. Opioid antagonism by naloxone can reverse septic, hemorrhagic, or endotoxicshock (154), consistentwiththeviewthatendogenousopioids participate in the apparently paradoxical sympathoinhibition that occurs in these conditions. Opioids attenuate norepinephrine release from the locus ceruleus in the brainstem, and fentanyl produces a central vagotonic and sympatholytic effect, helping to explain the benefit of morphine in the prevention of sudden deathduetoventricularfibrillation in heartattackpatients(155).The relationshipbetweenendogenousopioidsandthefunctionofcentral adrenoceptors remains unclear. Pressor stimuli can induce analgesia (154, suggesting that input from arterial baroreceptors can release endorphins in the brain. High enkephalin concentrations in the dorsal columns of the spinal cord suggest involvement in the transmission of sensory information to the brain. Enkephalins in the spinal cord inhibit transmission of pain impulses. Injection

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+ Glucoreceptors

A

+ qGlucosek Figure 4-16 Overview of the glucostatic system. INS adrenomedullary hormonal system; HPA axis; X = vagus nerve.

=

= insulin; AHS = hypothalamo-pituitary-adrenocortical

of B-endorphin or fentanyl into the cerebrospinal fluid space produces analgesia, and both have been used to treat pain in patients with terminal cancer. Studies about opioid-catecholamine interactions have concentrated mainly on central neural mechanisms, discussed in the chapter about central functional neuroanatomy. In general, stimulation of popioid receptors on noradrenergic terminals inhibits norepinephrine release, both in the brain (157) and in the periphery (158). This inhibitory modulation seems related complexly to a2adrenoceptors (158,159), which exert similar actions in the brain and periphery (160). Thisinteractionmaydependonsharedlinkagetoanintracellular transduction pathway (1 57).

Insulin Insulin is the main effector for regulating cellular uptake of glucose. In response to meal ingestion, increased vagal outflow to the pancreas elicits increasedinsulinsecretion.Thislimitstheextentofhyperglycemiaupon digestion of dietary carbohydrate. Glucose counter-regulation depends on the complex interplay of insulin, glucagon, and epinephrine (Figure 4-16), with glucocorticoids, growth hormone, and other hormones playing minor roles. The effectors in glucose regulation interact in several ways. Exogenously administered insulin, with co-administered glucose to prevent hypoglycemia, increases skeletal muscle sympathetic outflows and plasma norepinephrine levels (1 6 1 - 163) and the spillover of epinephrine into arterial plasma (1 64).Glucagon injectionrapidlyincreasesplasmaepinephrinelevels,withoutconcurrent

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increases in plasma norepinephrine levels in healthy individuals (165). By a variety of mechanisms, epinephrine and glucocorticoids inhibit insulin secretion and effects. Hepatic sympathetic nerves also contribute to glucose releaseby the liver; however, relatively few studies have focused on the role of hepatic innervation in glucose regulation (1 66). Other Stress Effector Systems As with digestive processes, sexual activity declines during periods of distress. This is reflected by decreased circulating levels of gonadotropins and of gonadal steroids such as testosterone. Growth hormone is required for normal linear growth. Serum factors called somatomedins modulate effects of growth hormone on growth. As an anabolichormone,growthhormonestimulatesaminoaciduptake in some systems, and amino acids such as arginine stimulate growth hormone release. Growth hormone acts synergistically with insulin in stimulating amino acid uptake into cells. Pituitary release of growth hormone is regulated both by a hypothalamic growth hormone-releasing factor and growth hormone releaseinhibitory factor (somatostatin). Hypoglycemia is a potent stimulus for growth hormone release; conversely, growth hormone is a minor glucose counterregulatoryhormone.Thea2-adrenoceptoragonist,clonidine,increases circulating growth hormone levels, and failure of clonidine to do so appears to characterize patients with multiple system atrophy(167).

DISTRESS Distressisaformofstress,withadditionaldefiningcharacteristics: consciousness,aversiveness,observablesigns,andhomeostatresetting associatedwithpituitary-adrenocorticalandadrenomedullaryactivation. Sympathoneural outflows may increase, decrease, change in a heterogeneous manner among different vascular beds, or remain unchanged. Consciousness

The occurrence of stress does not require consciousness. Selye would have agreed, since he claimed that stress reactions can occur in anesthetized animals, in lower animals without nervous systems or undergoing mechanical damage to denervated limbs, and even in cells cultured outside the body ((6),p. 53). In contrast, distress does require consciousness, because distress entails not onlyachallengetohomeostasisbutalsoconsciousinterpretation by the

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organism of sensory information and simulation of future events that indicates that homeostatic mechanisms maynot suffice. This is a more generalized statement of the concept of psychological stress as the resultof a perceived inability to cope(37). The senseof inability to cope or of a lack of controllability is basic to psychological theories about feelings associated with distress (26,28,37). An organism experiences distress when it perceivestheinadequacy of compensatory adjustments to either a psychological or physiological stressor. One need not separate psychological and physiological models of stress, despite generally independent evolution of thetwo research traditions (26). The present stress model shares main elements with the psychological stress model proposed by Lazarus (37): appraisal processes based on afferent information, perception of threats to homeostasis, elicitation of compensatory response patterns, and continuous reappraisal of the success of the homeostatic effort. Theexistence,location,regulation,andpathologyofpsychological homeostats associated with the experience of distress are poorly understood. Fundamental questions remain about whether psychological stress can bring on physicaldisease in otherwisehealthyindividualsandaboutwhether physiological stress contributes to psychopathology. The present definition of distress intentionally avoids suppositions about harmful effects of repeated distress, enabling derivation of testable hypotheses about pathogenesis.

Aversiveness Distressedorganismsavoidsituationswherethesamedistressing experience may occur. Distress is therefore negatively reinforcing, motivating escape and avoidance learning. The experienceof distress would be expected to enhance vigilance behavior and long-term memory of the distressing event. These adaptive neurological adjustments may involve catecholamines in the brain, as discussed in the chapter about central neural regulation of autonomic outflows. Most higher organisms react instinctively not only to a stressor but also to symbolic substitutes that resemble the natural stimulus. Monkeys become visibly upset upon exposure to a snake, without ever having seen one before; rabbits freeze when a hawk-shaped shadow glides by; stickleback fish attack any red object in their territory; and mallards scurry to the water in response to a fox-like piece of red-brown skin dragged along the edge of the pond (1 68). Theplasticityafforded by learningdecreasesthelikelihoodof inappropriate instinctive responses to symbolic cues. One definition of learning is modification of behavior based on experience. According to this definition, learning requires memory. Even “primitive” animals have the capacity to learn to withdraw or escape from noxious stimuli, or to habituate after prolonged or

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Figure 4-17 Behavioralconditioningparadigms. repeated exposure to a stimulus. These forms of learning mirror each other, the former reflecting a sensitization and the latter a de-sensitization. The fact that “primitive” animals have these capabilities indicates the remarkably durable survival advantage of learning. Classical (or Pavlovian) conditioning represents an important refinement of these responses (169). Habituation and sensitization exemplify nonassociative learning, where the organism learns about single stimuli. In contrast, classical

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conditioning(andoperantconditioning,tobediscussedshortly)involves learning associations among stimuli (Figure 4- 17). In classical conditioning, repeated pairing of a neutral stimulus (e.g., a bell ringing) with an unconditioned stimulus (UCS) that elicits an instinctive unconditioned response (UCR-e.g., salivation at the presentation of meat powder to a hungry dog; limb withdrawal after a local shock) results eventually in the elicitation of the UCR (or components of it) by the previously neutral conditioned stimulus (CS). The CS elicits a conditioned response (CR). For instance, depending on the UCS with which the ringing is paired, the dog may salivate or withdraw a leg when thebell rings. Pavlov taught that the acquisition of conditioned reflexes requires cerebral cortices-the “crowning achievement in the nervous development of the animal kingdom”((169),p.1);however,eveninvertebratessuchastheseasnail, Aplysia, have the capacity to learn by classical conditioning (170). Althoughmostclassicalconditioningexperimentshaveinvolvedan external UCS, such as an electric shock to the skin, this does not imply that the UCS must be external. For instance, rats can acquire hyperglycemia as a CR after repeated pairing of a previously neutral cue with injections of insulin (171). Pavlov (( 169), p. 36) himself demonstrated classically conditioned nausea and vomiting after repeated pairing of a CS (approach of the experimenter) with an internal UCS (injected morphine). Moreover, although classical conditioning experimentsoftenhavefocusedonpresumablyinvoluntaryalimentary, glandular, or cardiovascular responses mediated by smooth muscle, Pavlov emphasized that conditioned reflexes include both external motor and internal secretory components (( 169), p. 17). Instrumental, or operant, conditioning, represents a more advanced form of learning that requires a cerebral cortex (172). In instrumental conditioning, the likelihood of a behavior increases when the behavior leads to positive reinforcement (reward) and decreases when the behavior leads to negative reinforcement (punishment). Conversely (but circularly), reinforcement can be definedas an eventthatstrengthenstheresponseitfollows(173).The conditioning is “operant,” in that the individual’s behavior operates on the environment, determining the occurrence of reinforcement; and the conditioning is “instrumental,” in that the learning is a means to an end, with the occurrence of reinforcement contingent on the behavior. Operant conditioning therefore differs from Pavlovian conditioning, where delivery of the reinforcement occurs independently of the individual’s behavior. Both forms of conditioning require remembering an association between reinforcement and behavior. In Pavlovian conditioning, behavior (the UCR and CR) depends on the reinforcement (the UCS), whereas in operant conditioning, reinforcement depends on the behavior.

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According to Hull’s drive-reduction theory (174), an individual acquires a behavior because the behavior reduces a drive. For instance, a hungry rat learns to press a bar in order to receive food pellets, since the reinforcement, food, reduces the drive, hunger. Drive-reduction theory encountered several criticisms, beyond the scope of this presentation. Discarding intervening variables such as ‘‘drives” from the mechanism of instrumental learning seems to necessitate a circular definition of reinforcement. In avoidance learning, a form of operant conditioning, the individual learns to avoid negative reinforcementby producing behaviors that decrease the likelihood of that reinforcement. According to the drive-reduction theory, the punishmentincreasestheexperienceoffearoranxiety,andlearningthe avoidance behavior reduces thedrive. This is wherethepresentviewofdistressentersthepicture.If an organismexperiencesdistressconsistently in agivensituation,subsequent perceptionofreexposuretothesituationelicitsdistressasaclassically conditioned response. Thus, in the morphine experiment described by Pavlov, when the experimenter entered the room, the dog became “restless,” not as a CR to morphine injection but as a CR to the experimenter. In anthropomorphic terms, the dog recognized that every time the experimenter entered the room, suffering followed, and this realization elicited a feeling of distress as a CR in response to the CS of the experimenter. Aversive CRs lead to at least three types of behavioral response. Oneis a rapid, involuntary, conditioned withdrawal response. The response may be so rapid that the individual may not have time to consider the significance of the CS. The rapidity of withdrawal responses helps to explain their endurance in evolution. A second response is escape, consisting of coordinated locomotor, autonomic, and experiential components expressed in a largely instinctively regulated pattern. A third is avoidance. The “drive” for acquiring avoidance behavior is the reinforcement provided by reducing the distress. Situationsevokingdistresstypicallyinvolveacomplexinterplayof classicallyandoperantlyconditionedbehaviors.Forexample,considera speeder who notices a red flashing light in the rear-view mirror. From prior experience, being caught speeding causes delay, confrontation, humiliation, and expense, all deliveredby a UCS in uniform. The light therefore acts as aCS and evokes distress. Virtually instantaneously, the speeder’s right foot withdraws from the accelerator. The leg muscles may tighten for a split second, as the speeder thinks about whether to “floor it” and escape. Attempting to deny the situation, the speeder may flip down the rear-view mirror, rendering the red light less glaring, or turn on the cruise control, rapidly adjusting the car speed to a rate within the legal limit, or just stare straight ahead. In preparation for the likely upcoming confrontation, the speeder may practice an excuse, based on mitigating circumstances. Withdrawal, escape, avoidance, and denial reduce the

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distress;conversely,distressreductionreinforcestheselearnedresponses. Nevertheless, one would not expect them to eliminate the distress, because the attempts at denial probably would be insufficiently convincing, and uncertainty probably would remain about whether the attempts at avoidance would work.

Communicated Signs A thirdcharacteristicofdistress, in additiontoconsciousnessand aversiveness, is instinctively generated and instinctively understood communicatedsignsthatindicatetheemotionalstateandintentofthe organism. Darwin (175) emphasized that the various outward manifestations of emotion provide important means of intraspecific communication with survival value for the species; and that physiological arousal, by intensifying emotions, furtheramplifiesthephysiologicalstressresponsesthataccompanythose emotions. This suggests a psychological positive feedback loop. The instability of such a loop can explain why fear, if not checked by some interposed negative feedback,degeneratesintoself-destructivepanicanddirectedangerintoa rampage. Perceptions of signs of distress by other members of the species elicit involuntary, instinctive responses. Lorenz (168) described the behavior of two fighting wolves after one submitted and extended its neckto the victor: A dog or wolf that offers its neck to its a d v e r s a r y ...w i lnl e v ebrbe i t t e n seriously ....Since the fight is stopped so suddenly by this action, the victor frequentlyfindshimselfstraddlinghis vanquished foe in anything but a comfortable position. So to remain, with his muzzle applied to the neck of the “underdog” soon becomes tedious for the champion and, seeing that he cannot bite anyway, he soon withdraws.... Whyhasthedogtheinhibition against biting his fellow’s neck? Why has the raven an inhibition against pecking the eye of his friend?...Should the raven peck, without compunction, at the eye of hisnestmate, his wife or his young, in the same way as he pecks at any other moving and glittering object, there would, by now, be

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no more ravens in the world. Should a dog or wolf unrestrainedly and unaccountably bite the neck of his pack-mates and actually execute the movement of shaking them to death, then his species also would certainly be exterminated within a short space of time ((176), pp. 188-191). This principle applies analogously in humans, where the fiercest combat usually ends abruptly when one side shows universally understood signs of surrender and submission. The communication value of external signs of distress helps to explain the continued elaboration of observable components of distress responses, despite the relative rarity of true “fight-or-flight” reactions in humans. Even in thewild,allsocialanimalscontinuallyelicitandinstinctivelycomprehend psychosocial cues (22). Alterations in sympathoneural activity often produce these external signs. For instance, sympathetic nerves to cutaneous blood vessels mediate facial blushing (177,178), indicating embarrassment or humiliation. In a confrontation between two people, if one turns pale, quivers, averts his eyes, mumbles, and exposes his palms, and the other flushes, stands erect, glowers, shouts, and clenches his fists, the former evinces signs of submission and capitulation, and the latter signs of dominance and triumph. In evolution, these signs may have beenby-productsofgeneticallydeterminedneurocirculatoryadjustments supporting fleeing and fighting. In modem society, they serve signal functions of their own. Crying in human newborns also exemplifies the communication value of distress responses. Studies of expression of common emotions in primitive cultures and in blind infants (179) suggest that newborns cry not because of an emotional experience but as part of an instinctive pattern (1 80,18 1). One may surmise the “goal” of the behavior from what stops the crying-warmth, nursing, and being held protectively. Birth removes the fetus from an environment that has maintained its temperature, supplied metabolic fuels, and sheltered it from physical trauma, The newborn now depends entirely on its interaction with its mother. This being a matter of survival, natural selection must have favored the development of expressions fostering this interaction. The mother’s response to the cry may also include substantial genetic “loading.” Thus, both the infant’s expressions and temperamental characteristics and the mother’s emotional experiences, expressive behaviors, and personality traits predict the infant-mother attachment during the first year of (1 life 82). In psychology, the issue of the relationship between emotional expression and emotional experience remains controversial (181). Eventually, the infant

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experiences distress when it cries. Distress, as all emotional experiences, can in turn motivate learning. Any parent can confirm that, at some point in an infant’s development, the infant cries not only from distress but as a learned behavior. Crying leads to positive reinforcement, in the form of parental provision of comfort and food. Neuroendocrine Pattern

A fourth characteristic of distress is patterned neuroendocrine activation thatincludesenhancedadrenomedullaryreleaseofcatecholaminesand adrenocortical release of steroids. Increased plasma epinephrine constitutes perhaps the most sensitive neurochemical index of this activation. The neuroendocrine pattern attending distress results from resetting of homeostats. Thus, stimulation of the “defense area” of the hypothalamus or elicitation of the “defense reaction” decreases the sensitivity of the cardiac limb ofthearterialbaroreflex (1 83-185);andelectricalstimulation in the paraventricular nucleus of the hypothalamus inhibits responses of single unitsin the nucleus of the solitary tract in response to input from arterial baroreceptors (1 86,187). Reversible resetting of homeostats during distress produces the associated neurocirculatory and neuroendocrine pattern that includes activation of the hypothalamic-pituitary-adrenocortical and adrenomedullary systems. The prominence of changesin pituitary-adrenocortical and adrenomedullary outflows during distress results from sharing of these effectors by so many homeostats that reset during distress. The neuroendocrine activation alone does not itself produce distress (188).Theexperienceofdistressrequiresbothphysiologicalarousaland appropriate cognitions by the organism (21). Although several emotions include distressing elements (e.g., fear, anxiety, panic, guilt), other emotions do not (e.g., libido, joy), yet adrenomedullary activation accompanies even positive emotional experiences (10). According to the present concept, adrenomedullary activation does not imply the experience of distress, because such an experience requiresappropriatecognitionsandbecausesympatheticactivationcan accompanyevennondistressingemotions;however,inorganismswith a functional adrenomedullary system, the absence of adrenomedullary activation excludes the experience of distress. Cannonviewedtheneuronalandhormonalcomponentsofthe sympathetic system to act as a unit in preserving homeostasis. Describing the pattern of neuroendocrine activation attending distress requires a distinction between the neuronal and adrenomedullary systems, because according to the present conception, it is specifically the adrenomedullary hormonal component that characterizes distress.

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Distress-associated resetting provides at least a theoretical basis for many psychosomatic concomitants of cardiovascular disease. For instance, resetting of arterial baroreflex function due to repeated “defense reactions” remains a viable mechanistic hypothesis for the pathogenesis of hypertension (1 89- 191). The many physiological, neurochemical, and psychological adjustments attendingdistressreflectstrategiesestablished by learning,memory,and instinct,which, in turn,enableanticipatoryresponses.Meanstomake adjustments even in anticipation of distress-evoking situations evolved, because the survival advantages of anticipatory changes outweighed the potentially deleterious effects of temporary redefinition of homeostasis. Cardiac output increases, blood flow is diverted to skeletal muscle, and vasoconstriction occurs in mesenteric and renal vascular beds, in order to meet the markedly increased demand for glucose and oxygen and to remove metabolic waste during the strenuous exercise associated with fighting or fleeing, without compromising blood flow to the brain or heart. Platelet aggregability increases; this enhances theabilitytoplugvascularholes.Bloodglucoselevelsrise,owingto glycogenolysis, and accelerated gluconeogenesis, increasing availability of this vital fuel. Sweating increases, as evaporative heat loss ameliorates increases in bodytemperatureresultingfromacceleratedmetabolism.Hyperventilation removes carbon dioxide generated from oxidative metabolism, counters effects ofproductionofacidicmetabolitesonbloodpH,anddecreasesserum potassium, countering acidosis and hyperkalemia produced by tissue trauma. Alertness, strength, and resistance to fatigue increase. Memory processes change tofacilitatelong-termrecallofthedistressingeventandacquisitionand retention of conditioned withdrawal, escape, and avoidance behaviors. The appearance and actions of the individual instinctively communicate information about the internal state. Levine and Ursin (29) and Weiner(27) have used the terms “distress” and “stress” largely interchangeably. The present conception considers the distinction to be more than semantic, viewing distress as a form of stress with additional, defining features. A second distinction of the present view from others is the emphasis on homeostat resetting, which always accompanies distress. Higher brain centers determine this resetting as part of the elaboration of coordinated behavioral,endocrine,andphysiologicalpatterns.Thus,homeostasisis redefined during distress. There are no “steady states,” not only because some effector systems are inherently oscillatory, but also because homeostatic settings are readjusted continually, such as during distress. The above theories do not emphasize such resetting. A major task for future research is to identify central neural processes underlying “homeodynamic” readjustments and their resultant response patterns. With repetition of exposure to a situation evoking distress, the organism habituates, in the sense that effector components whose expression depends on

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novelty or unpredictability recede; concurrently, however, the organism becomes hyperreactive to other potential stressors (8,192-194), a phenomenon called stressor-switch hyperresponsiveness, or dishabituation. Habituation to a stressor recalls the stage of resistance, the second phase of Selye’s General Adaptation Syndrome; however, in the stage of resistance, all the components of the unitary stressresponsewoulddiminish,notonlythosecomponentsdependenton novelty or unpredictability. As noted above, the occurrence of dishabituation refutes Selye’s doctrine of nonspecificity, since the stress response in this setting would depend on the type of stressor. The present conception of distress resembles that of Selye, but it also differs in severalregards.Bothviewsholdthatdistressisaversivetothe organism,butthecurrentviewdoesnotassumeanequivalencebetween noxiousness(i.e.,negativelyreinforcingproperties)andproductionof pathological changes. As noted above, Selye’s theory emphasized the nonspecificity of the stress response. According to the present conception, the elicitation of distress responses depends on the character, intensity, and meaning of the stressor as perceived by the organism and on the organism’s perceived ability to cope with it. Distress responses, as all stress responses, have a purpose, mitigating effects of a stressor in some way. This applies not only to neuroendocrine aspects of those responses (such as the glucose counter-regulatory actions of pituitary-adrenocortical and adrenomedullary stimulation during insulin-induced hypoglycemia) but also to psychological aspects (such as conditioned aversive and instrumental avoidance learning). In this sense the present conception agrees with that of Gray(195): Fear or anxiety that is associated with real or perceived threat constitutes psychological stress.This“stress”orso-calleddefense response is composed of a set of relatively well-defined biological changes ...These changes help to promote the readiness and execution of behaviors that will ultimately increase the probability of survival of the organism. (p. 39) Gray, however, does not distinguish stress as an experiential entity from stress as a stereotyped biological pattern, just as Selye sometimes defined stress as a condition and sometimes as a response pattern. According to Selye, the General Adaptation Syndrome consisted of a series of well-definedstages:alarm,resistance,andexhaustion;however,

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experimental results have not consistently confirmed either the habituation or exhaustion of adrenomedullary responses after chronically repeated episodes of distress (9,193). The present theory does not depend on these stages. The present theory views distress as a consciously experienced condition. Neither adrenomedullary nor pituitary-adrenocortical activation implies the experience of distress. Since Selye never developed a clear distinction between stress (which could be conscious or unconscious) and distress, his theory did not consider whether the experiential requirement might distinguish them. According to the present conception, distress responses evolved and are expressed even in higher organisms, including humans rarely exposed to truly “fight-or-flight’’agonisticencounters,becauseoftheimportanceofthose responses in instinctivecommunication.Selyedidnotconsiderthe communication aspect of distress. Finally, the present theory does not assume that distress causes disease. Distress, while unpleasant, is not by definition pathologic. Selye characterized distress as unpleasant or harmful(4), without separating these two very different characteristics. He never incorporated the relationship between distress and disease explicitly in his theory; he appears to have added distress as a concept long after he proposed maladaptation from excessive or inappropriate stress responses or the operation of “conditioning factors.” Thus, the index to his treatise about stress and diseases of adaptation (5) does not include an entry under “distress”; and his book for laypeople, Stress Without Distress (4), does not elaborate on the relationship between distress and disease. PerhapsSelyerecognizedtheparadoxofstressassimultaneously homeostaticandpathologic.Ratherthanconcludingthattherelationship between stress and disease was a matter for research, he simply defined a new term, distress, to denote stress that causes disease. As suggested above, he seems to have developed this idea rather late in his career. Writers about stress have also generally not recognized this paradox of Selye’s theory and have either assumed the linkage between stress and psychiatric and physical disease or else adopted the term, distress, without explaining its meaning specifically (196198). Stress theorists have argued that because of modem societal constraints on emotional expression, people repeatedly suppress behavioral responses during emotionaldistresswithouttheabilitytosuppressthephysiologicaland biochemical concomitants, resulting in psychological or physical pathology: “Distress or end-organ dysfunction can occur as a result of the accumulation of many unresolved ‘fight or flight’ responses”(( 196), pp. 170-17 1). Folkow (1 99) similarly has suggested that chronic, frequent repetition of even mild “defense reactions” can produce high blood pressure. More generally:

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Limbic-hypothalamic patterns are basically designedtoprotecttheindividualand species from adverse environmental influences in primitive life ...Thanks to our more advanced neocortex, man differs here from animals mainly in two ways. First, we learntocopewithsomeenvironmental stimuli and thus delimit undue emotional engagements; second, when once elicited we can often suppress the behavioural nk.... li As we cannot suppress the autonomic-hormonal links, however, they then occur more or less “invain,”andsuchsociallyenforced dissociationsof per se normalresponse patterns may not in the long run be healthy. ((1991, P. 61) This notion is a founding, and unproven, tenet of psychosomatic medicine. Weiner (30) seems to have adopted Selye’s circular argument that stress is harmful when it causes disease: The linear relation between stressful experience and disease, which Selye described,occurswhentheexperienceis injurious, unavoidable, or incontrollable. In most other instances, however, when it is not, little or no organ damage occurs. ((30), p. 11-2) Theassertionthatstressfulexperienceprobablyleadstodiseaseonly in predisposed individuals seems to add another layer of circularity. Henry(200)offeredtheconceptofstages in thebiologicchanges attendingdistress.Whileagreeingthatdifferentstressorselicitdifferent neuroendocrine responses, he proposed that distress produces neuroendocrine alterations that occurin a sequence. A challenge perceived as easy to handle will elicit an active coping response and release the of neurosympathetic system’s norepinephrine. Testosterone will rise as the subjectsavorssuccess.Withincreasing anxiety this active coping shifts to a more

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passive mode and the behavior becomes less assuredastheanimallosescontrol.The norepinephrinelepinephrineratio decreases as epinephrine, prolactin, renin and fatty acids rise.Astheoutcomebecomesstillless cdeiarsntgtardieonsws s , adrenocorticotropichormoneandcortisol levels arise. Thus, the effort required on the onehandandthedegreeoffrustration conflictanduncertaintyontheother, determinetheratioofcatecholaminesto corticoids. With severe emotional trauma, brain dysfunction may occur. These effects can be lasting, and corticoids paradoxically return to normal as the behavior changes to thatofpost-traumaticstressdisorder. Repressionanddenialset in andthe organism responds with decreased concern of impaired attachment and increased irritability ((200), p. 66). The present view does not necessarily disagree with the notion of a neuroendocrine sequence in distress. This is a testable but as yet untested hypothesis. Thepresentconceptionimpliesnonecessarylinkbetweenstressor distress and the long-term developmentof physical disease. This does not mean that acute distress, by evoking neuroendocrine activation, cannot evoke severe and even fatal cardiovascular events. For instance, a large plasma epinephrine response during forced exercise in a patient with coronary heart disease can augment myocardial oxygen consumption, platelet aggregability, and ventricular irritability, resulting in angina pectoris, myocardial infarction, or sudden death. Nor does this suggest a lack of reasonableness for the assertion that chronic emotional distress has pathological consequences. Rather, the present conception views the long-term pathologic effects of distress as a matter for experimental testing, especially using longitudinal controlled studies. STRESS IN EVOLUTIONARY PERSPECTIVE

The current theory of stress and distress relies on concepts Darwin introduced: Autonomic changes that accompany emotional experiences and their behavioral manifestations evolved, because they were advantageous in natural selection,withoneadvantageofautonomicarousalrapidoranticipatory

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adjustmentsandanotherprovisionofuniversallyunderstoodmeansof intraspecific communication. Darwinintroducedthenotionthatemotionalexpressionsandtheir autonomic accompaniments evolved. Based on numerous interviews, readings, andobservations,Darwinsuggestedtheinheritanceofnotonlyphysical characteristics but also of emotional behaviors. In fact, he used the latter to support his theory of the descent of man:

I have endeavored to show in considerable detail that all the chief expressions exhibited by man are the same throughout the world. This fact is interesting, as it affords a new argument in favor of the several races being descended from a single parent-stock, which must have been almost completely human in structure,andtoalargeextent in mind, before the period at which the races diverged from each other. (( 175), p. 359) The naturalistic studies of the ethologists, Lorenz and Tinbergen, largely confirmed Darwin’s views about the evolution of instinctive behaviors. Indeed, Darwin provided much of the conceptual foundation for the field of ethology, the branch of zoology that deals with instinctive animal behaviors. In the preface to an edition of Darwin’s classic, The Expression of the Emotions in Man and Animals (originally published in 1872, a century before Lorenz received the Nobel Prize in Physiology and Medicine), Lorenz wrote: The adaptation of the behavior patterns of an organism to its environment is achieved in exactlythesamemannerasthatofits organs,thatistosayonthebasisof information which the species has gained in the course of its evolution by the age-old method of mutation and selection. This is true not only for relatively rigid patterns of form or behavior, but also for the complicated mechanisms of adaptive modification,amongwhicharethose generally subsumed under the conception of learning. ((175), p. xii) Darwin himself wrote:

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My object is to show that certain movements were originally performed for a definite end, and that, under nearly the same circumstances, they are still pertinaciously performed through habit when not of the least use. That the tendency in most of the following cases is inherited, we may infer from such actions being performed in the same manner by all the individuals, young and old, of the same species. ((175), 1965, P. 42) As far as we can judge, only a few expressive movements ...are learnt by each individual ...The far greater number of the movements of expression, and all the more important ones, are, as we have seen, innate orinherited;andsuchcannotbesaidto dependonthewilloftheindividual .... ((175), p. 351-352) Darwin recognized that the autonomic concomitants of emotion have provedadvantageousnotonlyinpreparingtheorganismforemergency responses, but also for providing the basis for visible signs that serve important, universally understood communication functions within the species: The movements of expression in the face and body, whatever their origin may have been, are in themselves of much importance for our welfare. They serve as the first means of communication between the mother and herinfant;shesmilesapproval,andthus encourages her child on the right path, or frownsdisapproval.Wereadilyperceive sympathy in others by their expression; our sufferingsarethusmitigatedand our pleasures increased; and mutual good feeling is thusstrengthened.Themovementsof expression give vividness and energy to our spoken words. They reveal the thoughts and intentionsofothersmoretrulythando

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words, which may be falsified. ((175), 1965, p. 364) Research on primates in the wild (22,23) has suggested that in everyday life, most “stress” system activation accompanies instinctive social behaviorse.g., dominance displays, sexual pursuit, and submissive escape-rather than mitigating threats to physiological or metabolic homeostasis. Behavioralevolutionrequiresageneticsubstrate.Severalstrainsof laboratoryanimalshavegeneticdifferences in activitiesofmajoreffector systems. For instance, spontaneously hypertensive and borderline hypertensive rats of the Okamoto strain have excessive responses of renal sympathetic nerve activity or plasma catecholamine levels during various forms of psychological stress (201,202). “Lewis”rats have a genetic deficiency of ACTH responses after injection of substances evoking inflammation (89) and have low plasma levels of epinephrine at rest (62). Plasma catecholamine levels differ in rats inbred for differences in response to stress (203). “Brattleboro” rats lack hypothalamic production of vasopressin. In humans,studiesofidenticaltwinshaveindicatedrelativelyhigh heritability of levels of various neurochemicals, including catecholamines (204206). Monozygotic twins tend to have similar rates of directly recorded skeletal musclesympatheticnervetraffic(207)andsimilarcardiovascularstress responses (208). Lacey and Lacey (209) elaborated a principle of autonomic response-stereotypy, in whichindividualsrespondwith a consistent physiological activation pattern across stressors. Thus, rates of directly recorded skeletal muscle sympathetic traffic have remarkable intraindividual reproducibilityafteradecadebetweenmeasurements,despitesubstantial interindividual variability (2 10). Considering the genetic component of stress responses, the same selective pressures that determined the evolution of physical characteristics should have determined the evolution of stress responses. More generally, the ethologist Richard Dawkins has presented a comprehensive theory about the evolution of behavior (21 1). The following propositions summarize his “selfish gene” theory: (1) The fundamental unit of selection is neither the species nor the individual but rather the gene. A gene is any portion of chromosomal material thatpotentiallylastsforenoughgenerationstoserveasaunit of natural selection. A gene is not a single physical piece of DNAin a chromosome but all replicas of that piece, distributed throughout the world. Groupsof genes can be selected as units. (2) “Survival of the fittest” means survival of the stable. Selection has favored genes that cooperate within a body, so that it is usually convenient to consider the body as an integral agent for preserving and propagatinggenes-a “survival machine.”

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(3) In animals,behavior,mediatedbymuscles,evolvedbecause it enabledrapidmovement.Generatingcomplex,timedmovementsrequires coordination by a computer, the brain, the unit of which is the neuron. The genes control behavior indirectly, like a computer programmer. They set up the machine but cannot control it because of time-lag problems. Genes work by controllingproteinsynthesis,whichispowerfulbutslow.Theyprovide strategies, programmed behavioral policies. An evolutionarily stable strategy is one which, if most members of a population adopt it, cannot be bettered by an alternative strategy. (4) Genes predict behavioral strategies by incorporating a capacity for learning, which requires memory and feedback. Learning can occur by trial and error. Simulations represent vicarious trial-and-error predictions of future events. The evolution of the capacity to simulate may have culminated in subjective consciousness. From the selfish gene theory, one may hypothesize that natural selection favored the evolution of stress responses, because they constitute the body’s mainmeansforpreservingastableinternalenvironment.Thecontinual adjustments in activities of homeostatic systems reflect genetically determined algorithms, learning by combinations of classical and operant conditioning, and conscious simulations of possible future events. The mystery and the challenge for stress research is not to explain why stress responses evolved but how they work. Research has begun to explore the molecular events underlying classical conditioning, such as in Aplysia (1 70), and the genetic instructions dictating these events. Ascending the phylogenetic scale, organisms have depended increasingly on complex, energy-requiring systems and on close coordination of behavioral, neuroendocrine, and physiological responses. For instance, reef corals, relatively simple animals, live a fragile existence, surviving only in unusual,suitable niches within a small range of salinity, turbulence, and temperature. Although theybenefitfromthelackofenergyexpendituretomaintaincellular temperature, they cannot live in water colder than 18O C. More versatile coldblooded reptiles and other lower vertebrates survive a larger range of external temperature by instinctively using both the sun and shade and probably by adjusting cardiovascular system performance, but this mechanism requires more organization and more energy. Warm-blooded mammals require and use much more fuel thando reptiles or fish, simply to maintain body temperature. As in reptiles, mammals possess notonlyphysiologicalbutalsoinstinctivebehavioralmeanstoregulate temperature. Ecological niches determine the adaptive value of this inheritance. For instance, llamas, having evolved in a cold, mountainous, treeless climate, do not instinctively seek shade from the sun. Humans spend most of their lives

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wrapped in protectiveclothingor in environmentswheretheexternal temperature itself is regulated. Other stress responses are also phylogenetically very old. Even relatively simple organisms such as Aplysia have withdrawal or escape responses to physical or chemical manipulation. Mechanisms for preserving body water, ionic composition, and supplying essential nutrients (oxygen and glucose) must also have developed early in evolution. The remarkably large repertoire of glucose counterregulatory systems indicates the importance of appropriate adjustments in blood glucose levels in different situations, including exercise, emotion, and the postprandial state. Many behaviors increase glucose utilizationin different organs, and therefore, a variety of means to maintain glucose levels evolved with those behaviors. Since all cells require glucose, these situations often call for generalized metabolic responses, elicited by hormones reaching all tissues of the body. Conversely, cellular glucoprivation poses a generalized threat, where no patterned neural response or readjustment of blood volume distribution can suffice. Glucopenia therefore evokes marked hormonal responses, including large, rapid increases adrenomedullary secretion of epinephrine. Generalized threats suchas glucopenia often elicit emotional distress. In insulin-induced hypoglycemia, the patient’s anxious, pale, and sweaty appearance constitutes an important clinical sign. Drugs that block effects of epinephrine mask this protective response and can render the patient and those caring for him or her unaware oflife thethreat. Agonistic behavior, such as attack and dominance displays, also includes strong genetically determined components and evolved. Aggression facilitates predation, reproduction, social organization, and the divisionof ecological space (176). Sinceuncheckedaggressionwouldalsothreatengenepropagation, instinctivemeanstolimitintraspecificaggressionhavealsoevolved,as discussed above. Theassumptionofanuprightposture-orthostasis-hasposeda relatively recent challenge in evolution. The ability of snakes to maintain blood pressureduringorthostasisillustratestheinterplaybetweenecologyand physical, physiological, and behavioral characteristics of a species (212). In climbing snakes, the heart is located relatively close to the head, and the thin tail minimizes pooling of blood during climbing. In contrast, in sea snakes, the heart is located in the center of the body. Exposure of sea snakes to orthostatic stress in a tilting tube causes their blood pressure to fall, whereas climbing snakes in the same situation maintain their blood pressure, both because of the above physical features and because of active muscle-pumping behavior. In mammals, internal sensations and perceptions of changes in the body’s orientation in space during orthostasis lead to patterned neural discharges that result in constriction of arterioles in the legs and gut, increased pulse rate, and increased total peripheral resistance to blood flow, all tending to redistribute

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blood volume towards the heart and brain. Skeletal muscle pumping contributes to this redistribution, Ordinarily, these rapid and effective concerted neural responses, mediated mainly by the sympathetic nervous system, counter the stressor unconsciously. The importance of these mechanisms in human well-being is illustrated by several clinical autonomic disorders, discussed in detail later in this book, and the effects of weightlessnessin space flight. Possibly because of the relative recency of assuming the upright posture in human evolution, one effector system, the sympathetic nervous system, dominates regulation of blood pressure during orthostasis. Sympathetic neurocirculatory failure therefore always is associated with orthostatic hypotension. Weightlessness is obviously a novel stressor in human evolution. Several manifestationsof“spacesickness”resultfromthelackofevolutionof physiologicalandneuroendocrinemechanismstocountertheabsence of gravitational force. During exposure to zero-gravity, the absence of orthostatic pooling of blood increases venous return to the heart, in turn altering activities of several systems that maintain cardiac filling. Excretion of water and salt increases,probablyduetodecreasedrenalsympatheticactivity,decreased activity of the renin-angiotensin-aldosterone system, increased atrial natriuretic factor release by the heart, and decreased vasopressin release by the pituitary gland. Blood volume falls and becomes dissociated from cardiac filling. A new stateofequilibriumoccurs,andsympathoneuralactivity,asindicatedby norepinephrine levels, becomes about normal during prolonged space flight (213,214), despite hypovolemia. When the astronaut returns to earth, orthostatic pooling of blood combines with the relatively low blood volume and possibly with resetting of cardiopulmonary baroreflexes to evoke symptomatic orthostatic hypotension. Catecholaminergic systems also seem to have evolvedin a sequence, with dopamine the most primitive catecholamine. For instance, sea anemones contain the catecholamine precursor, L-dihydroxyphenylalaine (L-DOPA) but do not contain catecholamines or the enzyme catalyzing the conversion of L-DOPA to catecholamines(215).Inmostinvertebrates,dopamineisthedominant catecholamine; concentrations of norepinephrine, when detected, are less than those of dopamine, and epinephrine is absent (216). In organs or plasma of amphibia,epinephrine is thedominantcatecholamine;inreptiles,either norepinephrine or epinephrine may predominate; and in mammals norepinephrine predominates. Hart et al. (217) reported that of 3 1 animal groups,thelampreyhadthehighestbasalcirculatingconcentrationsof dopamineandepinephrine;sharksanddomesticanimalshadthehighest concentrations of norepinephrine; and the eel and lumpfish had the lowest concentrations of norepinephrine.

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Autocrine/paracrine systems can theoretically meet the needs of simple organisms that lack mechanisms of neurocirculatory regulation, whereas more sophisticated organisms use hormones to coordinate organ functions, and in the most complicated organisms, including humans, autonomic nerve networks enable complex central neural regulation of regional resistances to blood flow and of glandular secretion. The regulation of nerve networks by the brain also fosters a close association between learned skeletal muscle movements and autonomic outflows to smooth muscle that support those movements. These principlesmayhelptofacilitatecomprehensionoftheevolutionof catecholamine systems. The autocrine/paracrine catecholaminergic systems still appear to operate, at least in the kidneys, adrenal glands, and gut. In the kidneys, locally formed dopamine contributes to regulation of sodium balance (218,219). In the adrenal cortex, locally formed dopamine inhibits aldosterone secretion. In both organs, however,morepowerfulhormonalandneuronalsystemsnowseemto predominate.Inrabbitmyocardium,nestsofchromaffincellshavebeen observed at all ages studied, even in the fetus (220). In the gastrointestinal tract, dopamine,whichcan be formedlocallyfromL-DOPA (221), stimulates bicarbonate secretion (222,223) and may constitute a catecholaminergic effector forthe“brain-gutaxis” (224). Ruminantshaveveryhighpulmonary concentrations of dopamine (225), forunknownreasons.Thesourceand significance of scattered “APUD” (amino precursor uptake and decarboxylation) and enterochromaffin cells of the gut,“SIF” (small intensely fluorescent) cellsin sympathetic ganglia, and mast cells in the lungs remain mysterious. Perhaps they constitute remnants of ancient autocrine/paracrine aminergic systems. Dopamineconcentrationsinplasmaareremarkablylow,and concentrations of the inactive conjugate dopamine sulfate exceed those of unconjugateddopaminebyabout 50 fold.Sincetheconjugationcauses circulating concentrations of free dopamine to be far lower than required to produce physiological effects, and since dopamine injection in humans rapidly increases plasma levels of dopamine sulfate (226), one may speculate that conjugation inactivates dopamine escaping from organs into the bloodstream, localizing changes in tissue function due to alterationsin release of dopamine as an autocrine/paracrine agent. In the gut, sulfation may provide a “gut-blood barrier” for ingested catecholamines(227). Selective factors favoring the evolution of coordination of activities of hormonal stress systems may explain the architectural arrangement of the adrenal cortex and medulla. In mammals, the adrenal cortex envelops the medulla. The two components of the adrenal gland have entirely different embryological sources. Adrenal medullary cells arise from ectodermal sympathetic neuroblasts that migrate anteriorly to penetrate the fetal adrenal, of mesodermal origin. Since adrenal blood flows in a corticomedullary direction, this arrangement produces

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very high local concentrations of adrenocortical compounds in blood passing throughtheadrenalmedulla.Glucocorticoidscontributeimportantlyto regulation of adrenomedullary epinephrine synthesis. Since angiotensin I1 is formed in the adrenal cortex, and since angiotensin I1 stimulates catecholamine secretion in cultured adrenomedullary cells (228), high local concentrations of angiotensin I1 may also contribute to adrenomedullary secretion. The sympathetic nervous system is immature at birth (220). From the concept that ontogeny recapitulates phylogeny, this immaturity may indicate relatively late development of the sympathetic nerve network in evolution. Maturation of the sympathetic nervous system after birth allows a degree of plasticity of sympathoneural development based on experiences of the individual early in life. In contrast, as noted above, the adrenal medulla forms in utero in mammals, and low and unchanging basal tissue concentrations of epinephrine persist in sympathetically innervated organs throughout the lifespan. Primitive Specificity A major thesis in this book is that activities of stress effector systems are coordinated in relatively specific patterns, including neuroendocrine patterns. These patterns, produced by the actions of different homeostats, serve different homeostatic needs. For each stress, neuroendocrine and physiological changes are coupled with behavioral changes. For instance, the regulation of total body water in humans depends on an interplay between behavior (the search for water and drinking), an internal experience or feeling (thirst), and the elicitation of a neurohormonal response pattern (in this case dominated by vasopressin, the antidiuretic hormone; and to a lesser extent angiotensin, a potent stimulator of drinking).Evokedchanges in homeostatfunctionoftenproducenotonly neuroendocrine and physiological effects but also behavioral responses; however, becauseoftraditionalboundariesamongphysiology,endocrinology,and psychology,interactionsproducingintegratedpatterns of responseremain incompletely understood. For instance, studies about vasopressin and activity of the renin-angiotensin-aldosterone system during blood volume depletion rarely have included controls for or monitoring of thirst and salt hunger. This situation developed partly because of the long-held view that acts of skeletal muscle-the provinceofneurologyandpsychology-mediatethe voluntary, conscious responses of the organism to the external environment, whereas autonomic and endocrine changes-the province of physiology and endocrinology-mediatetheinvoiuntary,unconsciousresponsesofsmooth muscleandglandstomaintaintheinternalenvironment.Findings in neuroendocrinology refute this distinction. Conclusive evidence has accrued that the external environment, via the central nervous system-in particular, the

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hypothalamus-affectsautonomicandendocrineactivity.Biofeedbackand conditioning studies have suggested learned modifications of some autonomic functions (171,229). The state of physiological arousal affects behavior by, among other things, intensifying emotions (21) and communicating external signs of internal states. Finally, recent findings involving circumventricular organs,sitesinthebrainthataredevoidofablood-brainbarrier,have introduced the possibility that hormones can reach central neural sites, eliciting various behaviors and altering autonomic and neuroendocrine activity. Folkow (1 9 1) has argued that limbic-hypothalamic patterns, protecting the individual during exposure to adverse environmental conditions, are always expressedasatriadofcloselylinked,situation-specific,somatomotor behavioral, visceromotor autonomic, and hormonal changes. One may speculate thatpatternsofbehavioral,experiential,neuroendocrine,andautonomic activities during stress intertwined so tightly in evolution that they are now expressed as units, since, as noted above in the discussion of Dawkins’s “selfish gene” theory, groupsof genes can be selected as a unit. Thenotionofstressor-specificresponsepatternsdisagreeswiththe theories of both Cannon and Selye. Cannon, largely ignoring other systems, asserted that sympathico-adrenal activation meets most or all important threats to the internal environment. The amazing feature of the role played by the sympathico-adrenal system its is applicabilitytothewidespreadrangeof possibledisturbancesthatwehavejust noted. As stated earlier, the system commonlyworksasaunit.It is very remarkable indeed that such unified action can be useful in circumstances so diverse as low blood sugar, low blood pressure, and lowtemperature ....Theappearanceof inappropriate features in the total complex of sympathico-adrenal function is made reasonable, as I pointed out in 1928, if we consider,first,thatitis,onthewhole,a unitary system; second, that it is capable of producing effects in many different organs; andthird,thatamongtheseeffectsare differentcombinationswhichareofthe utmost utility in correspondingly different conditions of need ((3), pp. 298-299).

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According to Cannon, the neuronal and hormonal components of the system function as a unit. The present conception emphasizes the separate regulation of sympathoneural and adrenomedullary responses. Differentialregulationofthesympathoneuralandadrenomedullary systems during different forms of stress supports the concept of primitive specificity and argues against Selye’s doctrine of nonspecificity. Selye, like Cannon, overemphasized responses of a single system-in Selye’s case, the pituitary-adrenocorticalsystem.Thisactivationproducesthetriad of thymicolympathicdegeneration,adrenalhypertrophy,andgastrointestinal ulceration but only provides a glimpse at the spectrum of systemic responses to stress. Deriving a concept based on heterogeneous neuroendocrine responses during stress has required measures of several endogenous substances indicating activitiesofdifferentstresssystems,anddescriptionsofassaysforthese measurements appeared only long after Cannon and Selye promulgated their unitary theories. SUMMARY ANDCONCLUSIONS

Hans Selye popularized stress as a scientific and medical concept. His theory was founded on the doctrine of nonspecificity, which stipulates that various stimuli elicit the same stress response, consisting of enlargement of the adrenalglands,thymicolymphaticinvolution,andpepticulceration.High circulating levels of adrenal corticosteroids produce all these effects. The General AdaptationSyndromehadcharacteristicstages:alarm,resistance,and exhaustion. Several major problems with Selye’s stress theory, including the circularities, inconsistencies, and especially the doctrine of nonspecificity, have led to its abandonment by many researchers. According to the present conception, stress is a type of intervening variable. It is a condition where expectations-whether genetically programmed, established by prior learning, or deduced fromcircumstances-do not match the current or anticipated perceptions of the internal or external environment, and this discrepancy between what is observed or sensed and what is expected or programed elicits patterned compensatory responses. The body has many homeostatic comparators, which generically can be called “homeostats.” All share several characteristics. Homeostatic systems are subject to negative feedback regulation. They usually include more than one effector, allowing for a degree of compensatory activation of effectors, extending ranges of control, and enabling elaboration of relatively specific patterns of effector responses. Compensatory activation can obscure relationships between effector system activity and values for levels of any single monitored variable. Disruption of a homeostatic system increases the variability of the monitored variable and tends to resultin drifting of the absolute value to a new level.

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Homeostaticsettingscanchange,includingwhenthechallengeto homeostasisreachesconsciousness.Thisresettingredefineshomeostasis continually in life. Distress is a consciously experienced form of stress, characterized by specific behavioral and autonomic communicated signs, pituitary-adrenocortical and adrenomedullary activation due to homeostat resetting, and a negative feeling that motivates escape behavior or avoidance learning. Charles Darwin introduced the notion that emotional expressions and theirautonomicaccompanimentsevolved.Theprocessdeterminingthe phylogenetic development of physiological and even psychological patterns of response has been essentially the same as the process that has determined the development of anatomic patterns-that is, natural selection. As homeostatic systems evolved, so did mechanisms regulating them. Activitiesofthebody’sstresssystemsareregulated in primitively specific patterns. Many of these patterns, which are at least partly inherited, can be understoodteleologicallyonthebasisofpreservationoftheinternal environment and natural selection in evolution. The physiological, biochemical, experiential, and behavioral components usually are closely linked. The scientific worth of the homeostat theory andits medical applications willdependontheabilitytogeneratehypothesesthatobservationand experiment can test. Future studies in this area should focus on examining further the notion of stressor-specific patterns of central neurotransmitter release and regional neuronal activation and on altered responsiveness of organisms with specific genetic changes. Meanwhile, the present theory may spur attempts to elaborate concepts that both incorporate the specific and nonspecific elements of stress responses and yield testable hypotheses. This could reconfirm stress as a legitimate subject for scientific inquiry.

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216. Welsh JH. Catecholamines in the invertebrates. In: Eichler 0, Farah A, Herken H, Welch AD, eds. Handbook of Experimental Pharmacology. XXXIII. New York: Springer-Verlag, 1972:79-109. 217.Hart BB, Stamford GG, Ziegler MG, Lake CR, Chernow B. Catecholamines: study of interspecies variation. Crit Care Med 1989; 17:1203-1222. 218. CareyRM,SiragyHM,Felder RA. Physiological modulation of renal function by the renal dopaminergic system. JAuton Pharmacol 1990; I O (Suppl. I):s47-s51. 219. Siragy HM, Felder RA, Howell NL, Chevalier RL, Peach MJ, Carey RM. Evidence that intrarenal dopamine acts as a paracrine substance at the renal tubule. Am JPhysiol 1989; 257:F469-F477. 220. FriedmanWF,PoolPE, Jacobowitz D,SeagrenSC,BraunwaldE.Sympathetic innervation ofthe developing rabbitheart. Biochemical and histochemical comparisons of fetal, neonatal, and adult myocardium. Circ Res 1968; 23:2532. 221. Vieira-Coelho MA, Soares-da-Silva P. Dopamine formation, from its immediate precursor 3,4-dihydroxyphenylalanine, along the rat digestive tract.Fundam ClinPharmacol 1993; 7:235-243. 222. Flemstrom G , SafstenB,Jedstedt G. Stimulation of mucosal alkaline secretion rat duodenum in by dopamine and dopaminergic compounds. Gastroenterology 1993; 104:825-833. 223. KnutsonL,Knutson TW, Flemstrom G. Endogenousdopamine and duodenal bicarbonatesecretion inhumans.Gastroenterology 1993; 104:1409-1413. 224. Glavin GB.Dopamineand gastroprotection. Thebrain-gut axis. Dig Dis Sci 1991; 3611670-1672. 225. JuorioAV,Chedrese PJ. Theconcentrationofdopamineandrelated monoamines in arteries and some other tissues of the sheep. Comp Biochem PhysiolC 1990; 95:35-37. 226. Ratge D,Kohse KP, Steegmuller U, Wisser H. Distribution offree and conjugatedcatecholamines between plasma, plateletsanderythrocytes: Different effects of intravenous and oral catecholamine administrations. J PharmacolExpTher 1991; 257:232-238. 227.Cuche JL, Brochier P, Klioua N, Poirier MF, Cuche H, Benmiloud M, Loo H, Safar M.Conjugated catecholamines inhumanplasma:Where are theycoming from?JLabClinMed 1990; 116:681-686. 228. Zimlichman R, Goldstein DS, Zimlichman S, Keiser HR. Angiotensin I1 increases cytosolic calcium and stimulates catecholamine release in cultured bovine adrenomedullarycells.CellCalcium 1987; 8:315-325. 1969; 229. Miller NE.Learning of visceral and glandularresponses.Science 1631434-445.

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5 Autonomic Systems in Stress Cannon and Selye viewed stress responses in terms of only one effector system-in Cannon’s case the “sympathico-adrenal” system and in Selye’s the pituitary-adrenocortical system. Predictably, both concluded that acute exposure toanyofseveraldifferentstressorswouldproduceessentiallythesame neuroendocrine response. In contrast, according to the present conception, the body’s homeostats interactcontinuouslytomaintaintheinternalenvironment,viaprimitively specific patterns of response. As noted in the chapter about stress, multiple effectors tend to evolve over time. Effector redundancy enhances survival, by extending the range of control and by enabling compensatory activation of alternative effectors when one effector fails; and this redundancy comes at the relativelysmallcostofever-increasingcomplexityofregulation.Effector redundancy, in turn, could have provided a basis for the evolution of adaptively advantageous, stressor-specific patterns. This chapter presents patterns of effector system responses upon exposure to different physiological, metabolic, and psychological stressors. These patterns relatedirectlytoclinicalevaluationschemes,putativepathophysiological mechanisms, and rational treatments for neurocardiologic disorders. Differences in relative extents of activation of the adrenomedullary hormonalsystemandsympatheticnervoussystemduringdifferentstress responsesironicallyprovidesomeofthemostconvincingevidencefor distinctive neuroendocrine stress response patterns. This is ironic, because it was Cannon who was so instrumental in describing and studying these components and yet who most forcefully advocated the combined and undifferentiated activationofthe“sympathico-adrenal”system in responsetostress (1,2). Compensatory activation of other vasoactive systems after destruction of the sympathetic nervous system helps to explain why many workers, including Cannon, erroneously concluded that the sympathetic nervous system acts only as an “emergency” system. Muchofthefollowingdiscussiondwellsonneuroendocrineand circulatoryvariables;however,asemphasized in thechapteraboutstress, distinctions among experiential, behavioral, neuroendocrine, and circulatory facets of stress responses largely reflect separate investigative traditions in 279

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psychology,endocrinology,andcardiologyandnotintrinsicallyseparate processes. VEGETATIVE FUNCTIONS AND THE PARASYMPATHETIC SYSTEM

No generallyacceptedchemicalmethodmeasuresparasympathetic “activity” (if there is such an entity). Thisis because of the very rapid metabolic breakdown of acetylcholine, the parasympathetic neurotransmitter. (Recall that the discovery of the “Vagusstoff” by Loewi required the use of a bioassay preparation.) Studies have instead used indirect chemical measures, such as blood levels of pancreatic polypeptide, insulin, or gastrin, or physiological measures, such as salivation, gastric acid secretion, or pupillometry, Valsalva heart rate ratios, or power spectral analysis of heart rate variability (3). Digestion and Excretion

The “cephalic” phaseof digestion After a meal, increased vagal parasympathetic nervous system activity contributes to the “cephalic” phase of digestion, augmenting release of gastrin and insulin and increasing gut motility (Figure 5-1). Whereas vagal outflow to the gut increases after a meal, cardiac parasympathetic activity appears to change relativelylittle (4), possiblybecausehemodynamicchangesproduce counterbalancing reflexive parasympathetic nervous system inhibition. Salivation depends not only on secretion but also on myoepithelial cell contractionandlocalvasomotorchanges.Secretionandmyoepithelialcell contractioninvolveincreasedoutflowsofboththeparasympatheticand sympatheticnervoussystems,exemplifyingasituationwheretheusual antagonism between the two branches of the autonomic nervous system does not occur. Parasympathetic cholinergic stimulation, such as elicited by citric acid applied to the tongue, increases secretion of watery, Na+-rich saliva, and sympathetic noradrenergic stimulation, such as elicited by fructose applied to the tongue, increases secretion of amylase-rich saliva. Sympathetic stimulation is thought to increase secretion via occupation of both l3- and a-adrenoceptors and motor activity via occupation of a-adrenoceptors (5,6). In addition, a2adrenoceptor occupation attenuates and a2-adrenoceptor occupation augments parasympathetically-mediatedsalivation (7). Administration of the ~ 2 adrenoceptor antagonist, yohimbine, increases salivation (8). This appears to result partly from augmented parasympathetic outflow from the brainstem(9). Multiple central neural sites project to the salivary glands, based on studies using the pseudorabies virus technique (IO). These sites participate

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Figure 5-1 Neuroendocrineresponsestomealingestion.

Note theimportantrole = epinephrine.

of the vagus nerve (X). SNS = sympathetic nervous system; EPI

in other aspects of autonomic nervous fimction, as discussed in the chapter about central functional neuroanatomy. Thus, in the medulla, sites projecting to the submandibular gland include not only the superior salivatory nucleus but also the “reticular formation,” nucleus of the solitary tract, spinal trigeminal nucleus, and deep cerebellar nuclei. In the pons, they include the locus ceruleus andsubceruleusandparabrachialcomplex; in themidbrain,theEdingerWestphalnucleus,deepmesencephalicnucleus,andcentralgrey; in the hypothalamus, the lateral, perifornical, and paraventricular nuclei; and in the forebrain, the substantia innominata, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Increased parasympathetic nervous system activity results in meal-related increases in insulin levels. Hyperinsulinemia after meal ingestion results not only from effects of elevated glucose levels but also from afferent information from the gut to the nucleus of the solitary tract and then to the paraventricular nucleus of the hypothalamus, increasing vagal efferent activity to the pancreas (1 1). Increasedvagaloutflowcontributestothegastro-colicreflex,where increased peristalsis and the urge to defecate follow ingestion of a large meal. Conversely, parasympatholytic drugs decrease intestinal peristalsis and are used clinically for abdominal cramping. Vagalstimulationalsoincreasespancreaticsecretionofinsulin. Teleologically, this effect makes sense, because meal ingestion increases the

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need subsequently to remove glucose from the circulation into cells and store metabolic energy. Insulin, gastrin, pancreatic polypeptide Parasympathetic stimulation elicits increased release of insulin, gastrin, and pancreatic polypeptide. Thus, surgical vagotomy has for many years been used to decrease gastric acid release. Urinary excretion Bladder atony constitutes a sign of parasympathetic failure. Patients with bladder atony typically have overflow incontinence and may have to selfcatheterizetoobtainrelief.Cystometrographicevaluationcanconfirmthe presence of atonic bladder from the relationship between vesicular pressure and volume during instillation of saline. Defecation Parasympatholytic agents classically induce constipation. In patients with chronic primary autonomic failure, loss of parasympathetic function can lead to severe constipation. Sleep Arterialbaroreflex-cardiacgainincreasesduringsleep (12). Since atropinization virtually abolishes reflexive bradycardic responses to infused vasoconstrictors (1 3), the increased baroreflex-cardiac gain probably results at least partly from increased parasympathetic cardiac “tone.” Sexual activity Sympatheticnoradrenergic,parasympatheticcholinergic,andnonnoradrenergicnon-cholinergic(probablynitricoxide-mediated)neuronal outflows all contribute to sexual function in men. Classically, parasympathetic activation plays a major role in initiating and maintaining penile erection, and sympatheticactivationplaysamajorrole in ejaculation.Consideringthat vasodilator effects of acetylcholine depend importantly on local generation of nitric oxide, and that penile erection results from engorgement of veins in the corpus cavernosum, penile erection could depend on release of nitric oxide as a neurotransmitter or as an intra-cellular messenger consequent to acetylcholine release.

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Figure 5-2 Homeostatic adjustments to orthostasis. Becausethesympathetic nervous system (SNS) is a key effector for both the barostat and volustat, this system dominates the neuroendocrine response toorthostasis.Othereffectors include arginine vasopressin (AVP), atrialnatriureticpeptide (ANP), the renin-angiotensinaldosterone system (RAS), the adrenomedullary hormonalsystem (AHS), and the vagus nerve (X). HR = heart rate; CO = cardiac output; SV = stroke volume; TPR = total peripheral resistance; BP = blood pressure.

STRESSES ASSOCIATED WITH SYMPATHONEURAL ACTIVATION

Patterned responses of regional sympathetic nervous system outflows redistribute blood volume or alter glandular secretion. The organism often remains unaware of these automatic adjustments.

Orthostasis When a person stands up, dependent pooling of blood rapidly decreases cardiac filling and stroke volume. Low-pressure baroreceptors in the heart and high-pressure baroreceptors in the carotid arteries and aorta virtually immediately sense the perturbation (Figure5-2). Proprioceptive, vestibular, and intrinsic skeletal muscle inputs signaling the change in body position also rapidly reach the central nervous system. Thus, at least five homeostats regulate the neurocirculatory response to orthostasis: the arterialbarostat,thecardiopulmonary“volustat,”homeostatsmonitoring proprioception and vestibular variables, and homeostats monitoring input from “ergoreceptors” activated by changes in skeletal muscle tension. Figure 5-1, depicting only volustat- and barostat-mediated changes, therefore oversimplifies the situation, despite the complexity of the depicted circuitry.

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The main effector mediating reflexive adjustments of blood volume distribution and total peripheral resistance during orthostasis is the sympathetic nervous system. In humans, other effectors, such as the renin-angiotensinaldosterone and vasopressin systems, normally play only minor roles. Thus, orthostaticintoleranceinvariablyattends,andconstitutes a cardinal manifestation of, sympathetic neurocirculatory failure. Peroneal sympathetic nervous activity increases virtually instantaneously in response to orthostasis in humans (14), and plasma levels of norepinephrine double within a few minutes (1 5). Duringorthostasis,sympatheticnervousactivationmaintainsmean arterial pressure by several mechanisms. Release of norepinephrine constricts several vascular beds, and regional and total body vascular resistances increase. Decreased splanchnic and limb venous capacitance augments the amount of cardiac filling for a given amount of gravitational pooling of blood. Increased cardiac inotropy augments the stroke volume for a given amount of cardiac filling; increased cardiac rate augments the cardiac output for a given stroke volume. Increased total peripheral resistance increases the mean arterial pressure for a given cardiac output. The neurogenic vasoconstriction during orthostasis occurs by at least three reflex mechanisms: supraspinal arterial and cardiopulmonary baroreflexes affecting sympathetic vasomotor outflows to skeletal muscle and other vascular beds; spinal reflexes elicited by altered cardiopulmonary baroreceptor activity, affecting subcutaneous blood flow; and a local veno-arteriolar axon reflex elicited by venous distention (16). Reflexive adjustments in behavior also help to maintain mean arterial pressure during orthostasis. The main behavioral response to orthostasis is leg muscle pumping. This enhances venous return to the heart. Skeletal muscle veins possess little or no sympathetic innervation, and so muscle pumping during orthostasis contributes importantly to the venous capacity. The ancient Romans recognized the role of leg muscle pumping in maintaining blood pressure during orthostasis, in their practice of crurijkgium. In people tortured bycrucifixion,smashingtheshinboneshastenedcollapseanddeath (17). Muscle pumping probably also prevents orthostatic hypotension in climbing snakes. Water snakes, which appear to lack this capacity, develop orthostatic hypotension when tilted in a tube; climbing snakes do not(1 8). Central neural pathways participating in sympathetic adjustments during orthostasis include brainstem interconnections between the fastigial nucleus of the cerebellum and several brainstem cell clusters (19,20). The fastigial nucleus receives input from the vestibular apparatus, and, as discussed in detail earlier, the nucleus of the solitary tract receives afferent input from carotid and aortic baroreceptors.

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Orthostasis ordinarily does not elicit distress. Adrenomedullary secretion increases but generally not to an extent that would produce hemodynamic or behavioral effects (21,22), whereas plasma norepinephrine levels and rates of traffic in sympathetic nerves supplying skeletal muscle in the legs normally increase markedly. During orthostasis, activationof the renin-angiotensin-aldosterone system plays only a minor role in the vasoconstrictor response. Thus, blockade of angiotensin I1 generation or effects does not produce orthostatic hypotension in salt-replete subjects (23). Levels of plasma renin activity, angiotensin 11, and aldosteroneincreaserelativelylittleandslowly,comparedwiththe sympathoneuralresponses;andintheabsenceofbaroreflexregulationof sympathetic post-ganglionic outflows, such as in patients with quadriplegia from injury to the cervical spinal cord, orthostatic hypotension occurs despite (24). marked stimulation of the renin-angiotensin-aldosterone system When hypotension attends orthostasis, activities of the adrenomedullary hormonal system, renin-angiotensin-aldosterone system, and vasopressin system increase substantially (2 l ,22,25). Since patients with pure autonomic failure have tilt-induced increases in circulating vasopressin levels (26), and patients with quadriplegia have tilt-induced increases in plasma renin activity (24), the increases in vasopressin levels and plasma renin activity do not require an intact sympatheticneuroeffectorapparatus.Neithervasopressinnorthereninangiotensin-aldosterone system can compensate for sympathetic neurocirculatory failure in maintaining blood pressure during orthostasis. Evaluations of patientswith suspected dysautonomias often include headup tilting,toproduceorthostaticstresssemi-quantitatively.Theextentof reflexive forearm vasoconstriction, measured by impedance plethysmography, and reflexive cutaneous vasoconstriction, measured by laser-Doppler flowmetry, provide simple, non-invasive means to examine sympathetic neurocirculatory reflexes. As noted above, altered proprioceptive input contributes to the integrated neurocirculatory response to head-up tilting. Lower body negative pressure (LBNP) does not entail such a manipulation, in applying controllable intensities of orthostatic stress. Lower body negative pressure at a low intensity (about -15 cm H20) decreases central venous pressureby about 2 mm Hg and has been thought to unload cardiac “low pressure” mechanoreceptors selectively; however, even low-intensity LBNP also unloads arterial baroreceptors (27). Many studies have shown thatin humans, LBNP increases ratesof sympathetic nerve traffic to skeletal muscle and increases forearm vascular resistance. LBNP also increases renal and forearm norepinephrine spillover and vascular resistance (28,29). Increases in plasma epinephrine levels also occur, especially during LBNP sufficient to decrease blood pressure. Whether LBNP increases spillover of norepinephrine into arterial plasma has been unclear (29,30) and appears to

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depend also on the occurrence of hypotension. Whether LBNP increases cardiac norepinephrine spillover is unknown. Heart transplant recipients not only have blunted responses of plasma norepinephrine levels during exposure to LBNP but also have absent responses of plasma renin activity and vasopressin levels 1). (3 These findings indicate that the renin and vasopressin responses to LBNP depend importantly on afferent neuralinformationfromthehearttothebrain,whereasextra-cardiac baroreceptors contribute to sympathoneural responses to LBNP. The results also are consistent with the view that input from cardiac baroreceptors exerts more influence on activities of the renin-angiotensin-aldosterone and vasopressin systems than does input from arterial baroreceptors. Thus, decreases in cardiac fillingelicitespeciallylargeincreases in plasmareninactivity(32);atrial stretching increases cardiac sympathetic outflow (33), whereas vasoconstriction decreasescardiacsympatheticoutflow(34);andinhibitionofcardiac baroreceptorafferentactivity by applicationofLBNPincreasesskeletal sympathoneuralactivityandregionalvascularresistancemorethandoes inhibition of carotid arterial baroreceptor afferent activity by application of negative pressure at the neck (35,36). Systemicadministrationofthedirect-actingvasodilator,sodium nitroprusside, at a dose that produces mild hypotension unloads both cardiac andarterialbaroreceptors.Thisevokeslargeincreases in peronealmuscle sympathetic outflow and plasma norepinephrine levels but relatively small increases in epinephrinelevels(37,38),indicatingselectivestimulationof sympathoneural outflows. Orthostasis decreases sodium excretion by several mechanisms. Renal bloodflowdecreasesreflexively,decreasingglomerularfiltrationof Na'. Increasedsympatheticallymediatedreleaseofnorepinephrineaugments reabsorption of filtered Na'. Decreased renal perfusion pressure and increased adrenoceptor occupation augments activity of the renin-angiotensin-aldosterone system, leading to increased exchange of Na' for K'. In response to decreased atrialstretching,secretionofvasopressin,thebody'smainanti-diuretic hormone, increases, and secretion of atrial natiuretic peptide (ANP) decreases. The anti-natriuresis subacutely increases extracellular fluid volume and cardiac filling for a given amount of hydrostatic pooling of blood. These processes may explainthecommonclinicalfindingthatinpatientswithorthostatic hypotension due to sympathetic neurocirculatory faillure, the blood pressure increases as the day goes on.

Exercise Many homeostatic systems interact in maintaining appropriate delivery of metabolic fuels and removing metabolic waste during exercise. These include

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CEKTRAL COMMAND

Metabostat W Barostat

Volustat ,Thermostat AFFERENTS

Glucostat Oxistat ,pH-stat bOsmostat

-,Carbistat HOMEOSTATS

Sympathetic

Nervous

System

Parasympathetic Nervous System Adrenomedullary Hormonal System

Insulin Vasopressin Endogenous Opiates Growth Hormone P i t u i t a r y - A d r e n o c o r t i cSayl s t e m EFFECTORS

Figure 5-3 Some neuroendocrine responses to exercise. Note involvement of numerous homeostats and effector systems.

chemoreceptor systems, respondingrapidly to changes in arterial concentrations ofoxygen,carbondioxide,andhydrogenion;low-andhigh-pressure baroreceptorsystems;proprioceptorsystems;inputfromskeletalmuscle “metaboceptors,” and glucostatic, osmostatic, and thermostatic systems. The neuroendocrine, physiological, and experiential aspects of exercise therefore are very complex (Figure 5-3), and effector activities change dynamically. Alterations in sympatheticnervoussystemoutflowsduringexercise (Figure 5-4) result partly from “central command” by the cerebral cortex, partly from reflexive effects of hemodynamic changes, and partly by stimulation of metaboceptors in the exercising muscle. Increasedcardiacoutput is thehemodynamichallmarkofisotonic exercise. Rhythmic contraction of skeletal muscle during isotonic exercise acts as a pump, increasing venous return to the heart. Products of skeletal muscle

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Figure 5-4 Effects ofbicycle exercise onestimatedratesof different processes related to cardiac sympathetic nervous function. The more than 15-fold increment in norepinephrine spillover exceeds by far the less than 3-fold increase in turnover of vesicular norepinephrine stores.

metabolism act locally to dilate blood vessels, redistributing blood flow to the exercising muscle. This dilatory response may result not only from direct effects of cellular metabolites on vascular smooth muscle cells but also indirectly from pre-synaptic modulation of norepinephrine release. Parasympathetic inhibition combines with sympathetic stimulation to increase heart rate during exercise. As exercisecontinues,bodytemperaturetendstoincrease,and temperature-sensitive cells in the anterior hypothalamus activate cholinergic fibers to sweat glands and inhibit sympathetic cutaneous vasoconstriction. The resulting flushing and sweating limit further increasesin core temperature. The tendency for skeletal vasodilation to decrease filling pressures and total peripheral resistance releases sympathetic nervous system outflows from inhibition by low- and high-pressure baroreceptors, increasing renal, arterial, and especiallycardiacspilloversofnorepinephrine (39). Regionalchanges in sympathetic nervous system outflows contribute importantly to the redistributions of blood volume during exercise. As vasodilator metabolites accumulateandoxygendebtincreasesduringprolongedexercise,the

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neuroendocrine pattern changes,in order to balance the increased skeletal muscle flow against the tendency to decrease blood pressure. Beyond an "anerobic threshold,"accumulationoflactateprobablyleadstofurthersympathetic nervous system enhancement by recruiting a chemoreceptor homeostatic system that uses the sympathetic nervous system effector. Duringsevereexercise,adrenomedullarysecretionofepinephrine augmentscardiacrateandcontractilityaswellasvenousandrenal vasoconstriction,andtherenin-angiotensin-aldosterone,vasopressin,and pituitary-adrenocortical systems arerecruited. At least until the anerobic threshold, the plasma norepinephrine response toisotonicexerciseexceedstheepinephrineresponseandvarieswiththe workload or oxygen consumption. The requirement for supplying glucose to exercising muscle appears to determine the epinephrine response. Thus, infusion of glucose during exercise attenuates the plasma epinephrine response without greatly affecting the plasma norepinephrine response(40)"also confirming the importanceofglucosemetabolisminregulationoftheadrenomedullary hormonal system. Isometric handgrip exercise increases the rate of sympathetic nerve traffic in non-exercisingperonealmusclebutproducesrelativelysmall,delayed increases in plasma norepinephrine levels, compared with the rapid, often large hemodynamic changes. Plasma norepinephrine and epinephrine levels both increase,asdoestotalperipheralresistance.Attheinitiationofisometric handgrip exercise, cholinergically mediated vasodilation probably occurs in the non-exercising forearm (41). Post-Prandial State

Sympathetic nervous system outflowsto most vascular beds increase after a meal, for at least three reasons. First, splanchnic pooling of blood decreases cardiac filling and stimulates sympathoneural outflows reflexively. Second, increased vagal outflow and post-prandial hyperglycemia stimulate insulin secretion, and insulin increases sympathoneural outflows, both by actions of insulin in the brain and by reflexive responses to insulin-induced vasodilation. Third, the act of eating itself may increase sympathetic outflows (42). The postprandial state therefore represents a situation where sympathetic nervous system outflows to several regions increase concurrently with increased parasympathetic nervous system outflows. In adipose tissue, one might expect sympathetic inhibition after meal ingestion, since this would promote storage of metabolic fuel; however, meal ingestionactuallyincreasesnorepinephrinespilloverintoveinsdraining epigastricfat (43). Perhapsdiffusesympatheticactivationtomaintain cardiovascularhomeostasisaftermealingestionoverridestheexpected

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inhibition. If so, then after meal ingestion, adipose tissue sympathetic outflow may depend on a balance between barostatic and metabostatic influences. Because the liver removes most of the catecholamines in portal venous blood, catecholamine levels in the systemic circulation only distantly reflect changes in splanchnic sympathetic outflow. Post-prandial increases in plasma norepinephrine levels therefore indicate sympathetically-mediated release of norepinephrine in organs other than mesenteric organs. Effects of eating on entry ofnorepinephrineintothesplanchnicvenousdrainage(splanchnic norepinephrine spillover) are unknown. In response to oral glucose administration, plasma epinephrine levels tend to, decrease(44).Thepost-prandialstatethereforeconstitutesanunusual situationwherevagalparasympatheticandsympatheticneuronaloutflows increase (45,46), while adrenomedullary hormonal outflow if anything decreases. Inrats,hyperglycemiaduringexerciseorduringhypoxiaattenuatesthe adrenomedullary response to these stressors, but not to handling (47,48). The latterindicates a degreeofstressor-specificity,wheretheabilityof hyperglycemia to suppress adrenomedullary activation depends on the stress producing the activation. The basis for this stressor-specificity may be that the centralactivation in responsetohypoxiaandexercisehasametabolic component that the activationin response to handling does not (48). Post-prandial redistribution of blood flow to the gut can contribute to post-prandial angina pectoris in patients with coronary artery disease and postprandial orthostatic hypotension in elderly people.

Altered Temperature Thesympatheticnervoussystemendowsmammalswith a most remarkableabilitytomaintaininternaltemperature.Withoutanintact sympatheticnervoussystem,theycannotsurviveeitherhotorcold environments. Intolerance of heat or cold therefore occurs frequently in patients with sympathetic failure.

Heat On January 23, 1774, five men entered a room that was heated with dry air to the temperatureof boiling water. In this room, where an egg roasted solid in 20 minutes, and where exhalation on a thermometer decreased the level of mercury by several degrees, the almost incredible ability of the human body to maintain internal temperature by perspiration and evaporative heat loss was demonstrated for the first time(49). Cutaneoussympatheticactivityrespondsmarkedly to changes in environmental temperature. Eccrine glands, which receive both sympathetic

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noradrenergic and sympathetic cholinergic innervation, underlie thermoregulatory sweating. These glands deliver watery sweat directly to the skin surface. During exposure to environmental heat, eccrine sweat secretion can exceed 1 literperhour.Sympatheticcholinergicactivationmediates thermoregulatory sweating. Thermoregulatorysweatinginvolvesdiffuseeccrinesecretion,with hypotonic sweat secreted onto the skin of the upper trunk and face. Eccrine glands in the palms and soles are especially responsive to emotional stimuli (50). Those in the lips, forehead, and nose respond to ingestion of spicy foods (gustatory sweating). Thus, patients with lesions of sympathetic innervation of the face have decreases in facial sweating and flushing in response to thermal and emotional stimuli but not in response to gustatory stimuli (5 1). Apocrine glands, localized in humans to the axilla, areola, and pubic and perineal skin, secrete mainly into pilosebaceous units rather than directly to the skinsurface.Theyfunctiononlyafterpuberty.Thesecretionisathick proteinaceous fluid released at the free end of the secreting cell. Functions of the apocrine secretion remain obscure and may be related to a form of sexual signalling. Sympathetic noradrenergic stimulation of apocrine glands is thought to contribute to emotional axillary sweating. Sympathetic noradrenergic outflow probably plays a relatively little role in thermoregulatorysweating.Forinstance,patientswithdeficiencyof dopamine-B-hydroxylase, who produce little if any endogenous norepinephrine, experience normal sweating (52). Although intracutaneous administration of epinephrine or other agonists at B2-adrenoceptors increases local sweating (53), circulating catecholamines probably produce only small effects,in the absence of experienced anxiety (54). Alterations in sympathetically mediated release of norepinephrine do help to counter thermal stress, by shifting blood volume distribution to the skin. Whentheseresponsesproveinadequate,adrenomedullaryhormonal system outflow increases. Thus, thermostatic failure elicits concurrent anxiety and epinephrine-induced tachycardia: [At 260°] I sweated, but not very profusely. For seven minutes my breathing continued perfectly good; but after that time I began to feelanoppression in mylungs,attended with a sense of anxiety; which gradually increasingforthespaceofaminute, I thought it most prudent to put an end to the experiment, and immediately left the room. My pulse, counted as soon as I came into the cool air, was found to beat at the rate of

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144 pulsations in a minute, which is more ...(49). than double its ordinary quickness The mammalian thermoregulatory system is organized hierarchically, with the hypothalamus regulating coordinated changes in autonomic outflows. Twohypothalamicmechanismsseematworkhere: aheat-dissipating mechanism in the anterior hypothalamus (medial preoptic nucleus), involving sensationofbloodtemperatureandelicitingsweatingandcutaneous vasodilation; and a heat-producing mechanism in the posterior hypothalamus, elicitingcutaneousvasoconstriction,cessation of sweating,andshivering. Anteromedial hypothalamic neurons respond briskly to alterations in local or skin temperature, and medial preoptic lesions appear to render mammals into ectotherms, with behavioral but without visceral means to control temperature (55). Anterior hypothalamic damage can cause hyperpyrexia, whereas posterior hypothalamiclesionsusuallyproduceaconditionwherebodytemperature approaches that of the environment (poikilothermia).

Cold In response to decreases in environmental temperature, activation of hypothalamic and cutaneous temperature sensors elicits cutaneous vasoconstriction, and piloerection-mediated importantly by the sympathetic nervous system-and by behavioral responses including shivering and actively seeking warmer conditions. Cold exposure stimulates sympathetic activity in the skin, skeletal muscle, spleen, and heart, with smaller or absent effects on sympathetic activity in the kidney or gut (56). This pattern shunts blood to vital organs and decreases evaporative heat loss. Shivering markedly increases total body metabolic activity. A recent study examined the relative roles of skin temperature and blood temperature to the sensory experience and neurocirculatory responses to cold in humans (57). Whereas input from cutaneous temperature sensors and from sensors detecting blood temperature contributed about equally to the sensory experience,coretemperaturewasthemaindeterminantoftheplasma catecholamine responses. Cannon first showed that exposure to cold increases adrenomedullary secretion, as indicated by the denervated heart model (58). Since physiological increases in circulating epinephrine levels increase metabolic activity in humans (59), theadrenomedullaryresponse is homeostatic. As previouslynoted, however, exposure to mildly decreased environmental temperature stimulates sympathetic nervous system outflows relatively selectively, with adrenomedullary hormonal system activation occurring only when alterations in cutaneous vascular resistance fail to prevent hypothermia. Thus, exposure to

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Figure 5-5 The cold pressor test. The pressor response to cold exposure depends on sharing of the sympathetic nervous effector by two homeostats.

cold air or i.v infusion of chilled salineincreases plasma norepinephrine but not epinephrine levels in humans, until core temperature falls(60). In the cold pressor test, the subject voluntarily immerses a hand in icecold water for 1-3 minutes. This rapidly increases blood pressure, via substantial sympathetic nervous system activation (Figure 5-5). The stimuli and responses involve not only cold, however, but alsopain, novelty, and numbness. Accordingly,mechanismsoftherapidregionalandsystemic hemodynamicchangesprobablychangedynamically.Theincreases in sympathoneural outflow proportionately exceed the accompanying increases in plasmanorepinephrinelevels,perhapsbecausetheshorttimeperiodof immersion and regional vasoconstriction do not allow plasma norepinephrine levels toreach plateau concentrations. Nevertheless, antecubital venous levels of norepinephrine usually increase during the test. Plasma epinephrine levels also tend to increase but to a proportionately much smaller extent than do plasma norepinephrine levels (22). Exposure of the face to cold water stimulates trigeminal nerve endings andelicitsthe“divingreflex”(Figure 5-6). Inthedivingreflex,both sympatheticandparasympatheticoutflowsincrease.Reflexiveapnea accompanies vagal bradycardia and cutaneous, splanchnic, skeletal muscle, and

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Figure 5-6 Autonomic responses to immersion of the face in cold water (the divingreflex).Severalhomeostatsdetermineincreases in outflows of the sympathetic nervous system (SNS). The diving reflex also includes prominent vagal activation (X). Heartrate (HR) decreases, andtotalperipheral resistance (TPR). increases. CO = cardiac output; MAP = mean arterial pressure.

renal sympathetically-mediated vasoconstriction, decreased venous capacitance, and coronary vasodilation. As cold immersion continues, hypoxemia, acidosis, andhypercarbiadevelop.Thesestimulatechemoreceptors,augmentingthe reflexive sympathetic stimulation; however, acidosis may attenuate cardiovascular effects of catecholamines, limiting the sympathetically-mediated pressor response (6 1,62). Humans sometimes survive prolonged immersion in ice-cold water, such as in near-drownings in partially frozen lakes, due to decreased total body,brain, and cardiac metabolism and probably catecholamine-mediated redistribution of blood flow towards the heart and brain. The record for the longest survival of out-of-hospital cardiac a r r e s t 4 hours-belongs to a 41 year-old man who fell overboard into icy water near Bergen, Norway ((63), p. 176). Mental Challenge or Active Attention

Laboratory stressors such as the Stroop color-word conflict test, forced mental arithmetic, or playing a video game involve a complex interplay of problem-solving,skeletalmusclecontraction,verbalization,novelty,and emotional distress related to harassment. In this setting, antecubital venous

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plasma levels of epinephrine increase proportionately more than do levels of norepinephrine; however, changes in norepinephrine levels in antecubital venous plasma can be insensitive to responses of norepinephrine spillover into arterial plasma. Both arterial norepinephrine levels and norepinephrine spillover into arterial plasma increase substantially during exposure to laboratory mental stressors, and cardiac norepinephrine spillover increases markedly (64-66).

Altered Dietary Salt Intake The renin-angiotensin-aldosterone system dominates the complex pattern of neuroendocrine responses to alterations in dietary salt intake (Figure 5-7). Homeostats monitoring cardiac filling, arterial blood pressure, renal perfusion, and the amount of sodium filtered by the kidney all use the renin-angiotensinaldosteroneeffector.Theprominenceofthissystemfitswithaldosterone functioning as the main salt-retaining hormone of the body. By exchange Na' of for K+ in the kidneys, aldosterone participates importantly in homeostasis of all these monitored variables. Salt deprivation also leads to salt-seeking behavior and a preference for salty food, and aldosterone can act in the brain to increase salt appetite (67,68). Central neural pathways mediating salt hunger involve the anterior nucleus of the solitary tract and medial parabrachial region, since lesions in either region virtually abolish salt deprivation-induced increases in salt intake in rats (68). Deprivation of salt, without concurrent deprivation of water, would not be expected to stimulate an osmolar homeostat. Accordingly, vasopressin levels change relatively little in this situation (69). Conversely, dietary salt loading, whichonewouldexpecttoincreasebothcardiopulmonaryfillingand osmolality, results in competition between the volustat and osmostat and results in no net effect of chronicdietary salt loading on plasma vasopressin levels (70). Plasma norepinephrine levels and peroneal sympathetic nerve traffic increasemodestlyduringdietarysaltrestriction.Theincreases in plasma norepinephrine levels during dietary salt restriction do not result from increased releaseofnorepinephrineintotheextravascularcompartmentbutfroma decreased volume of distribution of plasma norepinephrine (71,72). Dietary salt loading markedly suppresses renin-angiotensin-aldosterone systemactivity,withlargedecreases in levelsofplasmareninactivity, angiotensin 11, and aldosterone. Plasma norepinephrine levels tend to decrease slightly, and plasma epinephrine levels remain unchanged. Probably because of increased cardiac filling, dietary salt loading also increases plasma levels of atrial natriuretic peptide. Dietary salt loading also increases urinary excretion of dopamine and endogenous L-DOPA (73). In humans, increased L-DOPA spillover into arterial plasma does not explain the increased excretion of L-DOPA and dopamine

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Figure 5-7 Neuroendocrineresponsestoaltered saltintake.Thereninangiotensin-aldosteronesystem ( M S ) dominates the response. Aldosterone (Aldo) is the main salt-retaining hormone in humans. AVP = arginine vasopressin; ANP = atrial natriuretic peptide; DA = dopamine; EPI = epinephrine; AI1 = angiotensin 11; JG = juxtaglomerular; ECF = extracellular fluid; BP = blood pressure; SNS = sympathetic nervous system.

during salt loading (74), suggesting that ingestion of a high-salt diet may enhance basolateral membrane uptake of L-DOPA by proximal tubular cells (Figure 5-7). In the adrenal cortex, where circulating L-DOPA also seems to provide a major source of local dopamine production (75), dopamine inhibits angiotensin 11-induced secretion of aldosterone. Increased or decreased cardiacjilling Application of lower body positive pressure (LBPP), assumption of the head-downreverseTrendelenbergposition,head-outwaterimmersion, weightlessnessduringspaceflight,autotransfusion,andrapidintravenous administration of salineallincreasecardiacfilling.Stimulationof cardiopulmonary mechanoreceptors in these situations reflexively attenuates renal sympathetic outflow, decreases secretion of vasopressin, inhibits reninangiotensin-aldosteroneactivity,andincreasescardiacsecretionofatrial natriuretic factor. These changes increase leg vein distensibility, decrease total peripheral vascular resistance, evoke diuresis and natriuresis, and increase pulse of the initial perturbation on cardiac filling. rate, all of which buffer the effects

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Figure 5-8 Activation of the renal L-DOPA-dopamine (DA) natriuretic system duringsalt loading. Not shown are natriuretic effects of DA in thetubularlumen. Aldo = aldosterone; AI1 = angiotensin 11. Renal sympathoinhibition contributes importantly to the diuresis and natriuresis evoked by increased cardiacfilling (76). Thus, surgically denervated kidneyshaveattenuatednatriureticresponses to stimulation of theatrial receptors. Residual natriuretic responses in denervated kidneys reflect one or more of the above-noted humoral mechanisms.

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The cardiac sympathoneural response to alterationsin cardiac filling is Ushaped:Bothseverecardiacunderfillingandoverfillingincreasecardiac sympathetic nervous system outflow, whereas mild increases in filling decrease cardiacsympatheticnervoussystemoutflow.Thepatternofautonomic activation attending congestive heart failure exemplifies responses to cardiac overfilling in humans. Acute,mildcentralhypervolemiaproducedbybloodtransfusion in healthy humans normally produces only small effects on central blood volume, cardiac output, and left ventricular stroke work; however, in the setting of ganglionblockade,transfusionsubstantiallyincreasesvaluesforallthese parameters, indicating that the normal response includes reflexive venodilation and reflexively decreased myocardial contractility(77). Head-out water immersion redistributes blood volume to the chest and evokes a prompt, marked diuresis and natriuresis. Large and consistent decreases in urinary norepinephrine excretion occur(78). Since renal denervation abolishes natriuresis in this setting (79), renal sympathoinhibition probably is the main determinant of the natriuresis attending immersion. The immersion increases plasma levels of atrial natriuretic peptide, tends to decrease vasopressin levels, increasesurinaryexcretionofprostaglandins,anddecreasesplasmarenin activity. The increased atrial natriuretic peptide secretion may act directly in the kidney to induce a natriuresis or indirectly via vagal afferents or in the central nervous system to augment the reflexive renal sympathoinhibition. Saline infusion evokes a natriuresis by several mechanisms, including renal vasodilation due to sympathoinhibition, decreased activity of the reninangiotensin-aldosterone system, increased release of atrial natriuretic peptide, and stimulation of the renal L-DOPA-dopamine system. Most studies have failed to distinguish responses to intravascular volume loading from responses to the increased filtered load of Na'. Blockade of dopamine receptors or of the enzymatic conversion of L-DOPA to dopamine in the kidneys usually interferes with acute natriuretic responses to infused saline; however, the literature on this point is not entirely consistent. The body's responses to the weightlessness of space flight demonstrate the actions of reflexive adjustments that evolved to counter effects of gravity during upright posture. In zero-gravity conditions, astronauts commonly note periorbitalfullness,nasalcongestion,anddistendedneckveins,reflecting redistribution of blood from the legs to the upper body and possibly reflexive sympathoinhibition. Upon return to earth, cardiac filling pressures and stroke volume suddenly decrease, resulting in poor tolerance of orthostasis, despite sympathetic stimulation. Reversal of these effects can take several days or even weeks. One would predict that the sudden increase in central blood volume upon exposure to weightlessness would elicit reflexive sympathoinhibition and that after prolonged exposure, the natriuresis would decrease blood volume and

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normalize cardiac filling (80). Preliminary and as yet unpublished observations from the Neurolab space shuttle mission have not enabled firm conclusions about skeletal muscle sympathetic nerve traffic. The decrease in plasma volume couldmaintainplasmanorepinephrinelevels,despitesympathoinhibition. Prolonged head-down bed rest, a model of weightlessness, produces persistent decreases in urinary norepinephrine excretion (81). In humans,blooddonationprovidesausefulmodelforstudying responses to small decreases in blood volume and thereby in cardiac filling. After donation of about 1 unit of whole blood (480 ml, 7 mVkg), increments in plasma levels of norepinephrine exceed those of epinephrine, and levels of vasopressin, atrial natriuretic peptide, and renin activity remain unchanged (82). Heart rate stays about the same, and blood pressure if anything increases. Blood losssufficienttodecreasebloodpressurerecruitsactivitiesofseveral neuroendocrine systems, including the adrenomedullary hormonal system and hypothalamo-pituitary-adrenocorticalsystem. One would predict that patientswith sympathetic neurocirculatory failure shouldhaveafall in bloodpressureafterblooddonationandshouldbe susceptible to hypotension in response to bleeding. These hypotheses do not appear to have been tested. Waterdeprivationbothincreasesplasmaosmolalityanddecreases effectivecirculatingbloodvolume.Thesestimulisynergisticallyincrease secretion of vasopressin, which dominates the neuroendocrine response pattern in this setting, consistent with vasopressin acting as the foremost hormone promoting retention of “free water.” Although angiotensin I1 and arginine vasopressin both participate in central neural mechanisms eliciting thirst and water intake, the exact central neural mechanisms relating increased serum osmolality and decreased cardiac filling to thirst and drinking are incompletely understood.Waterdeprivationwithouthypotensiondoesnotstimulate sympathoneural outflows (83), and increased vasopressin levels and reninangiotensin-aldosterone system activity help to maintain blood pressure in this setting (84). STRESSES ASSOCIATED WITH ADRENOMEDULLARY ACTIVATION

In response to most local or mild stressors, sympathoneural elicitation of patterned alterations in glandular activity or distribution of blood flow might suffice, without distracting the organism. Adrenomedullary hormonal, rather than sympathetic neuronal, responses counter most effectively stressors that require compensatory adjustments throughout the body. One may view the sympathetic neuronal effector as a homeostatic “housekeeping” system and the adrenomedullary hormonal effector as a “distress” system. In general, stressors that pose immediate threats to life or that compromise distribution or utilization

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of essential nutrients evoke marked increases in adrenomedullary secretion, while sympathetic nervous traffic may increase markedly, change little, or even decrease. Hemorrhagic Hypotension

Throughout mammalian evolution, traumatic hemorrhage has posed a threat to survival. The blood volume depletion during hemorrhage decreases input from cardiac baroreceptors, eliciting reflexive stimulation of effector systems that tend to restore cardiac filling (Figure 5-9). The pattern of neuroendocrine responses to bloodlossdependsonwhethersympatheticnervoussystemactivationto redistribute blood flow maintains blood pressure and cerebral perfusion. In conscious animals,two distinct phases of neuroendocrine responses occur during acute hypovolemia (85). Initially, unloading of cardiac baroreceptors reflexively increases peripheral resistance, via increased overall sympathetic nervous system outflows and renin-angiotensin-aldosteronesystem activation. These responses compensate for the decreases in stroke volume and cardiac output, maintaining blood pressure. In humans, non-hypotensive blood loss increases plasma levels of norepinephrine but not of epinephrine, plasma renin activity, or vasopressin (82). These findings agree with those from studies of laboratory animals about predominantly sympathoneural activation during non-hypotensive hemorrhage but disagree about effects of non-hypotensive hemorrhage on renin-angiotensinaldosterone system activity. A fall in blood volume beyond a critical amount-about 30% of blood volume-ushers in a second phase, characterized by sympathoneural inhibition, markedlyincreasedepinephrineandvasopressinlevels,continuedreninangiotensin-aldosteronesystemactivation,and,often,relativeorabsolute bradycardia. The multiple effector systems, and their dynamic interactions, rendertheneuroendocrineresponsepatternhighlycomplex(Figure 5-9). Increased vasopressin levels during hypotensive hemorrhage produce an antidiuresisandpossiblyvasoconstriction;andaugmentedrenin-angiotensinaldosterone system activity increases angiotensin I1 production and aldosterone secretion, contributing to vasoconstriction and anti-natriuresis. In humans, blood loss with hypotension increases levels of epinephrine, plasma renin activity, norepinephrine, and vasopressin (82). These findings agree with studies of laboratory animals about predominantly sympathoneural activation during non-hypotensive hemorrhage but adrenomedullary hormonal system activation during hypotensive hemorrhage (85). Across several species, marked adrenomedullary activation in response to hypotensive hemorrhage contrasts with variable sympathoneural responses (86-88). In dogs, temporary, bilateral, functional adrenalectomies producedby diversion of the adrenal venous

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MILD

HYPOTENSIVE

Figure 5-9 Neuroendocrineresponsesto mild hemorrhageandhemorrhagic hypotension. RAS = renin-angiotensin-aldosterone system; AVP = arginine vasopressin; ANP = atrial natriuretic peptide; Op. = endogenous opioid; AHS = adrenomedullary hormonal system; X = vagus nerve; HPA = hypothalamo-pituitaryadrenocortical axis; TPR = totalperipheralresistance; CO = cardiac output; SV = stroke volume; H R = heartrate; BP = bloodpressure; SNS = sympathetic nervous system.

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-

Glucoreceptors

Insulin

+,

Baroreceptors

-

-

c

-

IHemorrhagel

Figure 5-10 A mechanisticexplanation for hemorrhage-induced hyperglycemia. The adrenomedullaryhormonalsystem is activatedbyhypotensive hemorrhage and shared by the glucostat. EPI = epinephrine.

effluentsabolisheshemorrhage-inducedincreases in aorticcatecholamine concentrationsandaugmentsincreases in hepaticvenousnorepinephrine concentrations (89)-an example of compensatory activation. Hyperglycemia often accompanies hemorrhagic hypotension (Figure 5 10).Thehyperglycemiaresultsfrombothadrenomedullarysecretionand increased hepatic sympathetic nervous system activity (89). Hyponatremia also can accompany hemorrhagic hypotension, as well as other clinical disorders involving decreased venous return to the heart or decreased ejection of blood into the arterial circulation. The hyponatremia probably reflects high vasopressin levels and increased retention of‘‘free water,” rather than loss of Na’ (Figure 5 11). Renal sympathoinhibition during hypotensive hemorrhage (87) depends oncardiacvagalafferents(90).Severalmechanismsexplainthisvagallymediated sympathoinhibition. Increased vagal afferent activity appears to be responsible for the large increments in circulating vasopressin levels, by central pathways that include the A1 cells of the caudal ventrolateral medulla (91), and vasopressininhibitsrenalnervetraffic,bothdirectlyandviaaugmented baroreflex inhibitory control of renal nerve activity (92). Plasma levels of the endogenous opioid, R-endorphin, also increase during hypotensive hemorrhage,

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i Osmoreceptors

Serum Sodium

Volustat

Cardlopulmonary Baroreceptors

+

+

+

& Hemorrhage

Figure 5-1 1 A mechanistic explanation for hemorrhage-induced hyponatremia. The arginine vasopressin (AVP) effector activated by hypotensive hemorrhage is shared bythe osmostat. RAS = renin-angiotensin-aldosterone system; ANP = atrial natriuretic peptide; SNS = sympathetic nervous system; DA = dopamine; Endoxin = endogenous digitalis-like substance.

and vagal afferent stimulation may inhibit renal sympathoneural outflow by a mechanism involving release of endogenous opioids (93-95). A serotonergic mechanismalsomayparticipate (96). Therenalsympathoinhibition in hemorrhagichypotensioncontrastswiththeprogressiverenalsympathetic stimulation in hypotension evoked by infusion of a vasodilator, indicating that the sympathoinhibition does not resultfrom hypotension itself. BecauseepinephrinestimulatesR-adrenoceptorsonskeletalsmooth muscle cells, the adrenomedullary activation decreases total peripheral resistance, and in the absence of reflexive sympathetic nervous system stimulation in the heartandothervascularbeds,bloodpressurefalls,evokingfurther

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adrenomedullarystimulation.Thehomeostaticcircuitsduringhypotensive hemorrhage therefore include the potentialfor several positive feedback loops. Thepatternofneuroendocrineresponsestohemorrhagedependson previousexposuretostressors.Forinstance, in rats,priorimmobilization augments plasma epinephrine responses and attenuates corticotropin responses to hemorrhage (97). The exaggerated adrenomedullary response might increase the likelihood of a positive feedback loop and cardiovascular collapse. Generalanesthesiabluntshemorrhage-inducedincreases in plasma catecholamine levels (98). This calls into question the applicability to conscious individuals of neuroendocrine findingsin many studies (89).

Glucoprivation Glucose is so important in the body economy, and so many situations alter glucose utilization, that a large number of neuroendocrine systems regulate levels of this vital fuel and react rapidly to glucoprivation. Hypoglycemia poses a metabolic threat toall cells. In contrast with mild hemorrhage, where regionally selective increasesin sympathetic nervous system activity to redistribute blood volume can effectively counter mild challenges to cardiovascular homeostasis, even mild hypoglycemia necessitates global-i.e., hormonal-responsestocounterthechallengetometabolichomeostasis. Adrenomedullary hormonal system activation, insulin dissipation, and glucagon secretion dominate bodily responses to hypoglycemia (99). Glucagon deficiency increases dependence on epinephrine for glucose counterregulation, illustrating the principle of compensatory activation, and glucagon itself rapidly increases plasma epinephrine levels (1 00), illustrating direct interactions among effectors. Other hormones, such as growth hormone, cortisol, l3-endorphin, vasopressin, renin, and prolactin, play minor or as yet unknown roles in glucose counterregulation. Hypoglycemia elicits hunger. The central mechanisms are unknown. Parasympathetic stimulation to the gut appears to constitute the final pathway forthisresponse(101-104);vagalactivation in turnstimulatesgastric production of acid and pepsin and increases intestinal motility. Decreases in blood glucose levels too small for the individual to notice increase circulating epinephrine levels,with little if any concurrent sympathetic nervous system activation as indicated by circulating norepinephrine levels (105). Selective adrenomedullary activation during hypoglycemia constitutes key evidence for differential regulation of sympathetic nervous system and adrenomedullaryhormonalsystemoutflowsduringexposuretodifferent stressors. This contrasts with Cannon’s concept of the sympathico-adrenal system. Ironically, it was Cannon who first demonstrated that hypoglycemia evokes adrenomedullary activation (1 06). The denervated heart preparation

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Figure 5-12 Neuroendocrine responses to glucoprivation.INS = insulin; AHS = adrenomedullary hormonal system; X = vagus nerve; HPA = hypothalamo-pituitaryadrenocortical axis; GH = growth hormone.

Cannon used did not allow assessment of the effects of hypoglycemia on regional sympathoneural activity. A central neural “glucostat” determines the neuroendocrine response to glucoprivation. Thus, intra-carotid injection of glucose attenuates and ganglion blockade or spinaltransectionabolishestheadrenomedullaryresponseto hypoglycemia (107,108). In contrast, responses of circulating glucagon levels during hypoglycemia do not appear to depend on central nervous connections. Although lower brainstem centers can initiate adrenomedullary hormonal system responses to hypoglycemia, the hypothalamus normally plays a critical role. Stimulation of the lateral hypothalamic area increases directly recorded adrenal nerve activity, as does intracerebroventricular 2-deoxyglucose, which causes cellular glucoprivation. Lateral hypothalamic lesions virtually abolish the stimulatory effect of 2-deoxyglucose on adrenal nerve activity (109), implying that the pathway by which the central nervous system senses glucoprivation and produces adrenomedullary activation includes this region. Hypoglycemia appears to evoke selective secretion of epinephrine from the adrenal medulla. Adrenomedullary epinephrine content decreases by about 70% three hours after insulin injection into fasted Sprague-Dawley rats, whereas the norepinephrine content remains unchanged(1 IO). The bases for this selective epinephrine secretion are unknown. Acuteglucoprivationelicitsonlysmallandvariableincreases in sympathetic neuronal outflows. In humans, insulin or 2-deoxyglucose increases

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skeletal muscle sympathoneural activity; however, whether these effects result from central neural glucoprivation or from reflexive sympathetic responses to systemic vasodilation and splanchnic sequestration of blood remains unclear (1 1 1). Plasma norepinephrine levels generally increase only slightly after administration of insulin or 2-deoxyglucose(1 12). In adrenalectomized patients, insulin-inducedhypoglycemiafailstoincreaseplasmanorepinephrine concentrations (1 13), indicating a mainly adrenomedullary source of the small increment in plasma norepinephrine during hypoglycemia. Analogously, during glucopeniainducedby2-deoxyglucose in healthyvolunteers,plasma dihydroxyphenylglycollevelsdecreaseratherthanincrease,andprofound stimulation of adrenomedullary secretion, indicated by marked increases in plasma epinephrine levels, can account completely for the increases in plasma norepinephrine levels (1 14). Neuroendocrine responses to glucoprivation, to arteriolar vasodilation, and to decreased cardiac filling therefore differ substantially. Mild hypoglycemia stimulatesadrenomedullarysecretionselectively;mildblood loss or vasodilation do not. Severe hypoglycemia and hemorrhagic hypotension both profoundly stimulate adrenomedullary outflow, with relatively small increases orevenwithdecreases in renalsympatheticnervoussystemoutflow.Even severevasodilator-inducedhypotensionevokesreflexiverenalsympathetic nervous system stimulation. Alterations in the activity of different homeostats that use the sympathetic nervous and adrenomedullary hormonal effectors can explain these differences.

Asphyxiation Interference with respiration produces asphyxiation, manifested by the biochemical triad of decreased arterial p02, increased pC02, and decreased pH. Each of these probably serves as a monitored variable in homeostatic regulation of ventilation. Most research on this topic has been based on animals during general anesthesia, inadvertent asphyxiation in infants, or apneic episodes in patients with sleep-apnea syndrome. In all these settings, other factors probably influence the results. Asphyxiation always stimulates adrenomedullary secretion drastically. Since anoxia of denervated adrenal glands promptly releases catecholamines (1 1 9 , the adrenomedullary activation during asphyxiation occurs even without increased adrenal nervetraffic. Hypoxiaaloneproducesonlysmallincreasesinplasmalevelsof catecholamines and directly recorded peroneal sympathetic nerve traffic (1 161 18). Reflexive ventilatory stimulation, by decreasing p c 0 2 and increasing pH, restrainsthesympathoneuralresponse(119).Hypoxiadoesaugmentthe sympathoneural response to exercise (120,12 1).

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Hypercarbia in the presence of normal or even increased blood oxygen tension increases sympathetic nerve traffic and plasma levels of norepinephrine and epinephrine (122). Acute hypoxemia and acute respiratory acidosis act synergistically to increase plasma levels of both norepinephrine and epinephrine (1 23) and to increase sympathetic nerve traffic (1 17,119). Mildacidosisdoesnotaffectplasmalevelsofcatecholaminesbut augmentscatecholamineresponsestoexercise.Severeacidosisattenuates contractileresponsestocatecholamines(61,124),probablyincreasingthe likelihood of a neurocirculatory positive feedback loop and cardiovascular collapse. Ventilatory stimulation by metabolic acidosis produces Kussmaul’s sign in diabetic ketoacidosis. of asphyxiationacts Thus,eachofthethreebiochemicalfacets synergistically with the others to stimulate sympathetic nervous system and adrenomedullary hormonal system outflows. Vascular chemoreceptors, located especially in the carotid bodies adjacent to the carotid sinuses, respond to decreased arterial pOq,, increased pC02, and decreased arterial blood pH. Chemosensitive cells near the ventral surface of the medulla respond to the same stimuli. Increased baroreceptor afferent stimulation decreases respiration as well as total peripheral resistance, and chemoreceptor afferent stimulation increasestotal peripheral resistance as well as respiration. Circulatory Collapse and Shock

Cardiac arrest profoundly stimulates adrenomedullary hormonal system activity, as indicated by drastically increased plasma levels of epinephrine (125). Cardiovascular collapse also markedly increases plasma levels of ACTH and vasopressin. Since in dogs, bilateral adrenalectomy decreases by about 70% the response of plasma norepinephrine levels during cardiac arrest (126), most of the norepinephrine response probably arises from the adrenomedullary stimulation. The standard treatment for sudden cardiac collapse due to ventricular fibrillation is external direct current electrical shock. In humans undergoing evaluationforimplantationof an internaldebrillator,externalshockitself evokesrapid,markedincreases in plasmaepinephrinelevels;arterial norepinephrine levels increase to a much smaller extent (127). As discussed in more detail in the chapter about autonomic systems in cardiovasculardiseases,myocardialinfarctionincreasesplasmalevels of epinephrine and norepinephrine, especially in patients with infarction-related ventricular fibrillation; and the plasma catecholamine levels correlate positively with both the extent of the infarction and with poor prognosis (128). Not only circulatory but also endotoxic or anaphylactic shock markedly increases plasma catecholamine levels. In both settings, larger proportionate increments in plasma epinephrine than norepinephrine levels occur (129-13 1).

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Pain Cannon was one of the first to describe adrenomedullary activation attending pain (132). According to Cannon, activation of the sympathico-adrenal system during pain would facilitate fight-or-flight behaviors that throughout evolutionhavebeenassociatedwiththeexperienceofpain(1).Thus, sympathico-adrenal activation would not relate directly to pain. As discussed below, however, catecholaminergic systems probably participate in several ways in coordinated responses to pain. Novel, painfil stimulation evokes distressand struggling. In terms of the homeostat theory, these are associated with resetting of multiple homeostats, resulting in changes in values for many neuroendocrine parameters (Figure 513). In rats, subcutaneous injection of formalin, which produces painful tissue trauma, elicits large increases in arterial plasma levels of ACTH, epinephrine, and norepinephrine. Levels of adrenocortical steroids also increase substantially, while levels of gonadal steroids fall. Circulating levels of the endogenous opioid, R-endorphin, increase during pain. Exaggeration of experienced pain and of neuroendocrine activation in humans treated with the opiate antagonist, naloxone, demonstrates compensatory activation (1 33). Strenuous exercise typically increases pain thresholds, probably because of release of endogenous opiates (134). This explains why, for instance, foot blisters produced by friction during running or skating hurt noticeably more after the exercise. High circulating levels of epinephrine may also ameliorate pain, since third molar extraction elicits correlated increases in plasma levels of epinephrine andR-endorphin,andinjection of epinephrineattenuatesthe&endorphin response (1 33). Activationofdescendingcatecholaminergicpathwaysinhibits transmissionofnociceptorsignaling,probably by occupationof a2adrenoceptorsoncells in thedorsalhorn.Drugsthatactascentral 9adrenoceptor agonists therefore are being developed for the treatment of chronic pain (135). In contrast, peripherally administered agonists at a-adrenoceptors (in particular, a1-adrenoceptors) worsen hyperalgesia associated with peripheral nerve injury (136). Nerve growth factor is neurotrophic both for sympathetic nerves and for dorsal root ganglion cells. Thus, patients with mutation of the gene for the trk A nerve growth factor receptor have congenital insensitivity to pain (137). Overexpression of nerve growth factor in glial cells enhances neuropathic pain following chronic sciatic constriction injury in mice (138). As discussed in Chapter 9 about mysterious or controversial entities, whether patients with reflex sympathetic dystrophy (complex regional pain syndrome, type I) have abnormal sympathetic innervation or function remains in dispute (139-141). In

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+I

+I

-I

&&+,

Steroids

5-13 Homeostatic responses to adrenomedullaryhormonal system; HPA axis; SNS = sympathetic nervous system. Figure

=

painful stimulation. AHS = hypothalamo-pituitary-adrenocortical

rats, neuropathic pain from chronic constriction injury increases expression of nerve growth factor in dorsal root ganglia(142).

Distress William Harvey recognized the link between the central nervous system, emotions, and the heartin his De Motu Cordis, when he wrote: “Every affection of the mind that is attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart.” Physiological responses during emotional distress always include changes in cardiovascular function. Sympathetic nervous and adrenomedullary hormonal activation underlie pressor and tachycardia responses. Nevertheless, as discussed below, distress can also evoke vasodepression, when adrenomedullary and vagal activation coincide with sympathoinhibition. Evidence presented in the following suggests that emotional distress evokes predominantly adrenomedullary hormonal system activation, whereas as

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noted in the foregoing, performance of attention-requiring but non-distressing tasks elicits predominantly sympathetic nervous system activation. Just as no unitary neurocirculatory or neuroendocrine response pattern occurs during different forms of physiological stress, no unitary neurocirculatory or neuroendocrine response pattern occurs during different forms of emotional distress. The following discussion develops the theme that the neurocirculatory and neuroendocrine patterns during “fight” differ from those during “flight,” “fright,” and “defeat,” just as the behavioral patterns differ, even though all four contain an element of distress. Aggression (Anger/Rage/Frenzy) vs. Fear (Amiety/Terror/Panic) Cannon used the phrase,“fight-or-flight,” to refer to situations that would elicit essentially the same activation of the “sympathico-adrenal” system. In contrast, observations dating back at least to the time of Darwin disagree with this notion. Terror does share several features with rage-tremor, hyperventilation,tachycardia,diaphoresis,andpiloerection.Despitethese similarities, behaviors obviously distinguish fear and aggression, and one would expect that the different behavioral responses would require appropriate, different neuroendocrine and neurocirculatory supportive responses. From the concepts introduced in the chapter about stress, one may hypothesize that behavioral, neuroendocrine, and circulatory changesin distress evolved together. Inhisclassicbook, The Expression of theEmotions in Man and Animals, Darwin (143) described the main signs that distinguish extreme fear (terror) from extreme anger (rage). The following discussion considers four such differences-the state of effective skeletal muscular tone, the state of cutaneous vascular smooth muscle tone, the state of gastrointestinal smooth muscle tone, and the state of glandular myoepithelial activity. The trembling associated with fear represents a form of ineffective skeletal muscle contraction that contrasts with the more obviously purposeful, concerted, yet largely involuntary skeletal muscle contraction that produces the clenched fists, grimacing, and upright or advancing posture associated with anger. One may speculate that trembling provided an evolutionary advantage as a form of skeletal muscle “idling” prior to“flight-or-flight’’ behavior. Trembling also communicates extreme emotional intensity. Of course, humans shake during both terror and rage. Thus, the words, “agitate,” “quiver,” and“quake”implybothshakingandastateofemotionalupset,without necessarilyindicatingfearoranger;however, in theabsenceofsignsof purposeful skeletal muscle contraction, and in the presence of other signs discussed below, trembling probably mainly indicates intense fear. Classical writers most commonly use trembling for this purpose.

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And among these nations shalt thou have no repose, and there shall be no rest for the sole of thy foot; but the Lord shall give thee there a trembling heart, and failing of eyes, and languishing of soul. And thy life shall hang in doubt before thee; and thou shalt fearnightandday,andshalthaveno assurance of thy life (Deuteronomy 28, 6566). Then the king’s countenance was changed, and his thoughts troubled him, so that the jointsofhisloinswereloosed,andhis knees smote one against another...(Daniel 5, 26)

I shudder at the word(Virgil, The Aeneid 11, 204). Less than a drop of blood remains in me that does not tremble;I recognize the signals oftheancientflame(Dante,Purgatorio, XXX, Line 46). How all the other passions fleet to air, Asdoubtfulthoughts,andrash-embrac’d despair And shuddering fear, and green-ey’d jealousy (Shakespeare, The Merchant of Venice, 111, 2, 100). Distilled Almosttojellywiththeactoffear (Shakespeare, Hamlet I, 2,204). What man dare,I dare: Approach thou like the rugged Russian bear, The arm’d rhinoceros,or the Hyrcan tiger, Take any shape but that, and my firm nerves Shall never tremble (Shakespeare, Macbeth 111, 4, 99).

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Darwin also associated terror with muscular weakness, in contrast with the association between rage and contraction of skeletal muscle: We m a y i n f e r that fear was expressed from an extremely remote period, in almost the same manner as it now is by man; namely, by trembling, the erection of the hair, cold perspiration, pallor, widely opened eyes, the relaxation of most of the muscles, and by the whole body cowering downwards or held motionless ...((l43), p. 360). The excited brain gives strength to the muscles, and at the same time energy to the will. The body is commonly held erect ready for instant action, but sometimes it is bent forward towards the offending person, withthelimbsmoreorlessrigid.The mouthisgenerallyclosedwithfirmness, showing fixed determination, and the teeth areclenchedorgroundtogether.Such gestures as the raising of the arms, with the fists clenched, as if to strike the offender, are common. Few men in a great passion, and telling some one to begone, can resist acting as if they intended to strike or push the man violently away ((143), p. 239). Thetremblingassociatedwithextremefearmayresultfromhigh circulating epinephrine levels, since epinephrine infusedi.v. (144) or released by i.v. yohimbine (145) elicits trembling in humans. Patients who have panic reactions to i.v. yohimbine have both marked trembling and large increases in arterial plasma epinephrine concentrations. The state of contraction of cutaneous vascular smoothmuscle-i.e., pale or red skin color-also differentiates terror from rage. In many animal species, includinghumans,thecolorredsignifiesaggressivefeelingandintent (146,147). When enraged, we “see red,” and our “blood boils,” but when we surrender, we wave a white flag. The English adjectives, “pale”, “wan”, and “pallid,” denote not only whiteness but feebleness or weakness; and “sanguine” denotesnotonlybloodinessbutconfidence,and“ruddy”denotesnotonly redness but vigor. We “seethe” with anger but “freeze” and turn “pale as a ghost” with fright.

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These cutaneous manifestations reflect alterationsin autonomic outflows. Expression of fear in humans decreases skin temperature, whereas expression of angerincreasesskintemperature (148). During rage reactions, cholinergic stimulationprobablycontributestotheflushing,whereasduringfear, cholinergic inhibition and sympathetic nervous system and adrenomedullary hormonal system activation probably contribute to the pallor(149). The state of contraction of gastrointestinal smooth muscle constitutes a third general distinction between terror and rage. The Old Testament contains a unique “trial by ordeal” (Numbers 5, 2728), carried out to test a woman accused by her husband of adultery. Failure to digest a type of potion, the “water of bitterness,” would produce abdominal distention and indicate guilt. Since adrenomedullary activation during intense fear can cause a form of ileus (recall that gastrointestinal relaxation assessed by bioassay was the initial means used by Cannon to demonstrate adrenomedullary secretion during emotion (1 SO)), the biblical test may have had a rational basis. The 23d Psalm includes: “He sets a table for me in the presence of my enemies.” Perhaps the psalmist was referring to fear interfering with digestion, since the ability to eatin the presence of one’s enemies would require a sense of calm confidence. Shakespeare similarly recognized the effects of emotional distress on the gastrointestinal system when he wrote, “Unquiet meals make ill digestions” (The Comedy of Errors, V.i.73). In the film, Shoah, Franz Suchomel, former SS Unterscharfuhrer at the Treblinka death camp, recalls with sardonic detachedness the “death panic” of Jews in the tunnel to the gas chambers: In the “funnel” the women had to wait. They heardthemotors of thegaschambers. Maybe they also heard people screaming and imploring. As they waited, “death panic” overwhelmed them. “Death panic” makes people let go. They empty themselves, from thefrontortherear. So often, where the women stood, there were five or six rows of excrement .... When this “death panic” sets in, one lets go. It’swellknownthatwhensomeone’s terrified, and knows he’s about to die...(( 15 1) p. 1 18). The preceding biblical quotation about king Belshazzar’s reaction to the handwriting on the wall-“the joints of his loins were loosed’’-probably also refers to gastrointestinal “letting go” evoked by terror. Whether adrenomedullary

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activation plays a role in the defecation attending extreme fear is unknown. Maudsley “stress-susceptible” rats, inbred based on defecation during emotional distress, have decreased, not increased, basal plasma levels of catecholamines (1 52). Gastrointestinal “letting go” more likely reflects intense vagal stimulation as part of a “giving up” reaction, discussed later. The state of contraction of glandular myoepithelial cells provides a fourth physiological difference between terror and rage. Darwin wrote that during terror, Thesalivaryglandsactimperfectly;the mouth becomes dry, and often is opened ...One of the best-marked symptoms is the trembling of all the muscles of the body; and this is often first seen in the lips. From this cause, and from the dryness of the mouth, the voice becomes husky or indistinct, or may altogether fail. “Obstupui, steteruntque comae, et vox faucibus haesit” ((143), p. 291). Anxiety-provoking situations generally inhibit salivary secretion (153), explaining a component of stage fright in musicians. In contrast, increased drooling during rage recalls anticipatory salivation before predatory attack. To “spit in another’s face” signals aggression bothin cats and humans. Thepatternofadrenomedullaryhormonalsystemandsympathetic nervous system activation provides a fifth distinction between rage and terror ”between “fight” and ‘‘fright.” In general, situations producing panic or anxiety increase plasma epinephrine levels proportionately more than they increase plasma norepinephrine levels. For instance, in subjects with acute flight phobia, actual flying increases heart rate, blood pressure, perceived anxiety, and plasma epinephrine levels, whereas plasma norepinephrine levels remain unchanged (1 54). In professional hockey players and in neuropsychiatric patients, selective increases in norepinephrine excretion accompany aggressive, active emotional displays; whereas selective increasesin urinary epinephrine excretion accompany tense and anxious but passive emotional behaviors(155). Studies of laboratory animals confirm this view. Dogs exhibiting anger haveprominentincreases in plasmanorepinephrinelevels,whereasthose exhibiting fear (indicated by cowering posture and trembling) have prominent increases in plasmaepinephrinelevels (156). In cats,defensivebehavior associatedwithexposuretoadogelicitspredominantlyadrenomedullary activation, whereas exposure to another cat elicits both sympathoneural and adrenomedullary activation (1 57,158). In rats, passive avoidance is associated

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with larger responses in plasma epinephrine levels than in norepinephrine levels (159,160). Adrenomedullary activation during fright may intensify but probably does not cause emotional experiences. Patients with pheochromocytomas, with high circulating catecholamine levels due to release by the tumor, do not have excessive anxiety; and epinephrine when administered exogenously amplifies emotional experiences (161) but does not elicit any specific emotion. Moreover, plasma epinephrine levels required for healthy people to discriminate between infusions of epinephrine or saline exceed those typically noted in situations eliciting emotional distress (144). Several studies have supported a closer link between adrenomedullary hormonalsystemand hypothalamo-pituitary-adrenocortical responsesthan between adrenomedullary hormonal system and sympathetic nervous system responses during distress. Public speaking markedly increases plasma levels and urinaryexcretionofepinephrineandcortisol,withonlysmallchanges in norepinephrine levels (1 62). In humans playing a video game, responses of arterial ACTH levels correlate positively with responses of epinephrine levels but not of norepinephrine levels (66). In rats, passive avoidance elicits large plasma epinephrine and corticosterone responses but small plasma norepinephrine responses (159). The central neuroanatomy of “fight-or-flight” behaviors includes pathways from the limbic system to the hypothalamus and lower brainstem. In 1892, Goltz reported that decortication in dogs exaggerates attack behavior. Cannon and Britton (163) later confirmed this finding, naming the phenomenon “sham rage.” Bard (164) identified the posterior hypothalamus as the most rostral portionoftheneuraxisrequiredforelicitationofshamrage.Electrical stimulation along a pathway including the amygdala, basal nucleus of the stria terminalis, perifornical lateral hypothalamus, and periaquaductal gray region evokes defensive behavior (165). As discussed in the chapter about central neuroanatomy, Smith and co-workers proposed that cells in the “HACER” region of the perifornical hypothalamus determine alterationsin neurocirculatory function during the defense reaction. The role of higher cortical and limbic system structures in the central neuroanatomy of distress remains less clear. Consistent with cortical inhibition of defensive attack behavior, in cats prefrontal cortical electrical stimulation suppresses hypothalamically-mediated defensivebehavior;however,in psychiatric patients, prefrontal lobe destruction ameliorates aggressive behavior; and until the introduction of the major tranquilizers, lobotomy was an accepted neurosurgical method for controlling intractable patients. Although portions of the limbic system may trigger or otherwise influence “defensive attack” by naturalstimuli,limbicstructuresarenotnecessary,whereastheposterior hypothalamus is.

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Central pathways mediating defensive attack behavior differ from those mediating predatory behavior. Predatory attack may not be associated with the experience of distress, in contrast with defensive attack; purely aggressive behavior can even be associated with decreased adrenomedullary secretion of epinephrine (166). Descending pathways for defensive attack behavior traverse the central gray and those for predatory behavior traverse the ventral tegmental area, following the two main portions of the medial forebrain bundle (1 1). Whether the central neuroanatomy of “fight” differs from that for “flight” remains unknown. Activity vs. Passivity

As theintensityoftheemotionincreases,thetendencytoevince locomotor activity increases, independent of the quality of the emotion itself. Thus,thecontinuumoffearrangesfromboredomtounexpressedbut experienced anxiety to visible, trembling terror to uncontrollable panic and headlong flight; and the continuum of anger ranges from boredom to unexpressed angertovisibleragetouncontrollablefrenzy.Thecirculatoryand neuroendocrinepatternsaccompanyingfear or angerprobablydepend importantly on the extent of expression of the locomotorbehaviors-i.e., on the amount of activityor passivity. As the intensity of fear increases, any of several reaction patterns can occur: The organism may tremble but otherwise remain attentive and motionless (the “freezing” or “fright” reaction); it may attack defensively (the “defense reaction”);itmaysuddenlyattempttoflee; or itmaysuddenlylose consciousness in a “playing dead”or “defeat” reaction. Species vary instinctively in their tendencies for these behaviors. The triggers and mechanisms causing abrupt shifts among these reaction patterns remain mysterious. Little is knownabouttheneuroendocrineandcirculatorypatterns associated with active and passive fear. As noted above, passive avoidance is associated with larger plasma epinephrine and smaller plasma norepinephrine responses than is active avoidance (159). In cats, different cardiovascular patterns occurduringimmobileconfrontation,“non-supportivefighting”involving defensive movements of the forelimbs to ward off an aggressor, and “supportive fighting,” where all four limbs areused to attack (167). In contrast with defense reactions elicited by hypothalamic stimulation, naturally-occurring defense is not accompanied by large increases in blood pressure, because during immobile confrontation, bradycardia and decreased cardiac output counter renal and splanchnicvasoconstriction.Duringactualfighting,markedskeletal vasodilationoccurs.Whetherimmobileconfrontationdiffersfromactual fighting in termsofsympatheticnervoussystemactivity or plasma catecholamine levels remains unknown.

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Frankenhaeuser (168) proposed a higher threshold for norepinephrine As responses than for epinephrine responses during psychosocial stimulation. discussed above, the higher norepinephrine threshold may reflect the greater amount of skeletal muscle contraction associated with more intense emotional experiences. Fainting, Defeat, and Giving Up Darwinrecognizedthatextremefearcanevokesuddenlossof consciousness in lower animals and in humans:

A terrified canary-bird has been seen not only to tremble and to turn white about the baseofthebill,buttofaint;and I once caught a robin in a room, which fainted so completely, that for a time I thought it dead ((143), p. 77). Psychological theorists have viewed fainting asan expression of helpless defeat, when the individual perceives the fhtility of either fightingor fleeing in an emotionally distressing situation, and the central nervous system directs a physiological response pattern resembling primitive “playing dead” reactions (169). Many situations in modem-day life, such as undergoing blood sampling at the doctor’s office, receiving an injection of dental anesthetic, witnessing a traumatic automobile accident, or receiving tragic news in public, can cause distress without the possibility of coping by fighting or fleeing. Standing for a long period, warm external temperature, and delayed ingestion of a meal increase the likelihood of developing vasodepressor syncope, possibly because they tend todecreaseeffectivearterialfillingandthereforerequiresympathoneural activation to maintain venous return to the heart. A section in the chapter about autonomic failure syndromes discusses the physiology and neurochemistry of neurocardiogenic syncope in detail. Briefly, a neuroendocrinepatternincludingsympatheticnervoussysteminhibition, adrenomedullaryhormonalsystemandparasympatheticnervoussystem stimulation, and release of endogenous opioids and vasopressin may trigger vasodepressor syncope, via multiple neurocirculatory positive feedback loops. One may ask what survival advantage a “giving up” or defeat reaction would have provided in evolution. Predators may instinctively avoid eating an animal they havenot killed, since eating any discovered carcasses would pose an infectious or toxic threat to health.Thus, when attacked opossums enter a deathlike trance, the predator may shake the animal but may eventually lose interest inthepreythatlooksandfeelsalreadydead.Withinaspecies,including

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humans, combat usually ends abruptly when one of the combatants displays a defeat reaction. This allows the “underdog” to survive. A defeat reaction may arousealtruisticbehaviorinothers.Finally,“givingup”maysacrifice consciousness to allay pain and suffering. In rats, chronic repetition of exposure to distressing, inescapable stimuli, suchasimmobilizationandelectroconvulsiveshock,doesnotleadto recrudescent pituitary-adrenocortical activation and does not attenuate acute responses of plasma catecholamines (170,17 1). These findings do not support the notion that repeated exposure to a stressor leads ncessarily to a “defeat reaction” (1 72) or a “stage of exhaustion” (1 73). Applying the same hypothesized mechanisms triggering neurocardiogenic syncope during acute distress to “giving ,p” during chronic distress, “giving up” might be characterized experientially by atypical depression and resignation, behaviorally inaction, by inattentiveness, and blunted affect, neuroendocrinologically by increasedvagaloutflow,sympathoinhibition, increasedsecretionofepinephrine,ACTH,R-endorphin,vasopressin,and pancreaticpolypeptide,andhemodynamically by intolerance to exercise or orthostasis. According to this view, the long-term consequence of “giving up” would not be hypertension but, if anything, hypotension. In 1942, Cannon described“voodoodeath,”whichmayexemplifyadefeatreaction,where depression, failure to care, and bradycardia culminate in vagal cardiac arrest (1 74).Theinterplayofparasympathetic,endogenousopioid,pituitaryadrenocortical, and catecholaminergic systems in this phenomenon is unknown. Novelty vs. Predictability

Hypothalamo-pituitary-adrenocortical(HPA) activation seems especially prominent in distressing situations that the organism perceives as novel. When no coping behavior is possible, novel or threatening conditions are associated with both HPA and adrenomedullary hormonal system activation (175-177). Thus, rats exposed to repeated predictable or unpredictable noise have decreases in plasmacorticosteronelevelswithrepeatedregularbutnotirregular presentations of the stimulus; plasma epinephrine responses are abolished, regardless of the irregularity of the presentations, and plasma norepinephrine responses are attenuated partially after repeated irregular presentations ( 1 60). Analogously,ratsundergoingunpredictableshockhavehigherplasma corticosteroid levels and more extensive gastric ulcers than do rats receiving predictable shock (178,179). Glucocorticoid responses to an aversive stressor depend on stressor controllability when the animals are highly prepared to escape but not when they areunprepared-i.e., controllability and preparedness both appear to influence the HPA response (1 80). Most evidence supports the view that repeated exposure to distressing stimuli attenuates responses of ACTH

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and corticosterone levels in rats, with generally maintained responses of plasma levelsofcatecholamines (97,176,181). EarlyclinicalstudiesaboutHPA activation in stressful situations did not take into account separately the factors of novelty, predictability, and controllability. During repetition of exhausting bicycle exercise, physiological and performance measures are reproducible, whereas responses of ACTH, cortisol, and vasopressin levels diminish with increasing experience (1 82). Chronic, repeated exposure to a distressing stimulus augments plasma catecholamine responses to a novel distressing stimulus-a phenomenon called “stressor shift hyper-responsiveness” or “dishabituation” (97,17 1,183). The response to either a physiological or psychological stimulus evoking distress of the organism. therefore depends importantly on the previous experiences Dominance vs. Submissiveness Subordinate baboons in the wild have higher plasma concentrations of cortisolthandodominantanimals.Thechronichypercortisolemia in subordinate animals has been proposed to produce resistance to suppression of the HPA axis by exogenous glucocorticoids such as dexamethasone. Actual position in thedominancehierarchyappearsnottobeasimportanta determinant of basal cortisol levels as are aspects of the individual’s personality, includingsocialskillfulness,outletsforfrustration,affiliations,andthe correctness of perceptions about predictability and control in confrontational situations (1 84,185). Analogously, subordinate rabbits have increased ACTH and corticosterone levels (1 86). This line of research has so far not considered the relationship between dominancehbmissiveness and either sympathetic nervous system or adrenomedullary hormonal system activity. SUMMARY AND CONCLUSIONS

Patterns of neuroendocrine stress responses depend on the character and intensity of the stressor, on the organism’s perceived ability to cope with the stressor, and on the history of the organism with respect to the stressor and other stressors. Dynamic aspects are especially apparent in the effector patterns elicited by hemorrhage, depending on the absence or presence of hypotension, and by exercise, as vasodilator metabolites accumulate, fatigue develops, and the anerobic threshold is passed. The neuroendocrine response patterns described earlier reflect different relative contributions of many effector systems (Table 5-1). The brain coordinates dynamically activities of these systems, using multiple homeostats to maintaintheinternalenvironment.Othersystemsbesidesthesympathetic nervoussystem,adrenomedullaryhormonalsystem,hypothalamo-pituitary-

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adrenocortical axis, and parasympathetic nervous system participate in stress responses. These include the L-DOPA-dopamine autocrine-paracrine system, the renin-angiotensin-aldosterone system, and neuropeptidergic systems involving atrial natriuretic peptide, arginine vasopressin, and endogenous opioids. Patternsofneuroendocrineresponseshaveadegreeofprimitive specificity that one can comprehend in terms of the evolution of adaptively advantageous adjustments. During orthostasis or cold exposure, sympathetic nervous system activation predominates; during manipulations of dietary salt intake, renin-angiotensin-aldosterone responses predominate; during manipulations of water availability, arginine vasopressin responses predominate; andduringmanipulationsofglucoseavailability,responsesofinsulin, glucagon, and adrenomedullary secretion predominate. Small amounts of acute blood loss elicit mainly unconscious sympathetic nervous system responses, which maintain cardiac output and cerebral perfusion by redistributing blood volume; large amounts of acuteblood loss, sufficient to decrease blood pressure, elicit a verycomplex and dynamic pattern of neuroendocrine responses. Stresses associated with adrenomedullary hormonal system activation usually elicit distress. Stressors that pose global, metabolic challenges or are perceived as threats to well-being elicit adrenomedullary hormonal system activation, even when the intensity of the stressor is mild. Adrenomedullary hormonalsystemactivation isprominent in hypotensivehemorrhage, hypoglycemia,asphyxiation,circulatorycollapse,andemotionaldistress. Stresses eliciting adrenomedullary hormonal system activation typically also elicit hypothalamo-pituitary-adrenocorticalactivation, as indicated by circulating levels of corticotropin or glucocorticoids, and increases in release of endogenous opioids, as indicated by plasma levels of &endorphin, with small increases or even decreases in sympathetic nervous outflows. Sympathetic nervous system activation is prominent in orthostasis, mildmoderateexercise,thermoregulation,andthepost-prandialstate.Stresses associatedwithsympatheticnervoussystemactivationoftenincludea component of activemovement.Patternedsympatheticnervoussystem activation during stress produces adaptive shifts in the distribution of blood volume or in glandular secretion. When these changes suffice to maintain homeostasis, they are not consciously experienced, but when the organism senses that these responses are not or will not mitigate effects of the stressor, the situationreachesconsciousness,andadrenomedullaryhormonalsystem activation ensues. The character and intensity of neuroendocrine and circulatory patterns during emotional distress depend on the perceptions of the organism, both about thestressorandabouttheavailablerepertoireofcopingresponses. Hypothalamo-pituitary-adrenocortical and adrenomedullary hormonal system activationaccompaniesunanticipateddistress.Atleastthreepatternsof

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Table 5-1 Summary of Autonomic and Neuroendocrine Responses to Stressors.

Stressor Water Dep. Glucopriv.

Homeostat(s) Effector(s)

Osmostat Volustat Glucostat

AVP > SNS, RAS INS, AHS, Glucagon > PACS, X, CH, etc. SNS > AVP, M S , AHS, X, PACS AHS, M S , AVP, PACS, X > SNS SNS, THY > M S , PACS

Hemorrh. Hypotens. Cold

Volustat Barostat Barostat Volustat Thermostat

Calorie Bal.

Metabostat

Pain Asphyxia

Exercise

Nocistat Oxistat pH-stat Carbistat Multiple

Orthostasis

Volustat

Distress

“Fight”

SNS > M S , AHS, AVP, X SNS > AHS

“Flight”

AHS, SNS

Dec. Bld. Vol.

THY,Leptin, SNS, INS, X, PLP, CCK, etc. Opioid, AHS > SNS SNS, AHS > PACS

SNS > AHS, PACS, AVP, X, CH, etc.

“Fright” AHS, X > SNS “Faint/Defeat”AHS, X, PACS Opioid > SNS

Neurobehavioral

Water-seeking, Thirst, Drinking Hunger, Anxiety Hunger, Anxiety, Thirst, Orthostatic, Anxiety, Pica Shivering, Heat-seeking, Piloerection, Vasoconstriction Satiety, Somnolence, Hunger Escape, Avoidance, Anxiety Hyperventilation, Panic

Skel.Musc.Contraction, Locomotion Hyperventilation, Thirst, Sweating Musc.Pumping,Alertness Rage, Skel. Musc. Contraction Skel. Musc. Contraction, Anxiety Trembling, Terror Prostration, Denial, Somnolence

Abbreviations: Dep. = deprivation; Bld. Vol. = blood volume; Hemorrh. = hemorrhage; Bal. = balance; AVP = arginine vasopressin; SNS = sympathetic nervous system; M S = renin-angiotensin-aldosterone system; INS = insulin;

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AHS = adrenomedullary hormonal system; PACS = pituitary-adrenocortical system; X = vagus nerve; CH = growth hormone; THY = thyroid; Skel. Musc. = skeletal muscle.

experiential,behavioral,neuroendocrine,andphysiologicalresponsesoccur during emotional distress-anger, which can develop into rage and fighting; fear, which can develop into terror and flight; and passivity, which can develop into “giving up,” vasodepression, and vagal cardiac arrest. Physiological distinctions between fear and anger reflect differential changes in contractionofskeletalmuscle,cutaneousvascularand gastrointestinal smooth muscle, and glandular myoepithelium. The extent of skeletal muscle contraction, and the extent of recruitment of sympathetic nervous system activation to redistribute blood flows appropriately, generally varieswiththeintensityoftheemotionalexperience.Adrenomedullary hormonal system activation accompanies fear and sympathetic nervous system activationanger.Whentheorganismperceivesafailuretogaincontrolor cope, a combination of vagal parasympathetic nervous system stimulation, high plasmaepinephrine,argininevasopressin,andf3-endorphinlevels,and sympathetic nervous system inhibition can trigger neurocirculatory positive feedback loops, precipitating cerebral hypoperfusion and loss of consciousness. As studies assess activities of several stress systems concurrently, clearer depictions of primitively specific patterns should emerge, enabling identification of central neural mechanisms determining the elaboration of those patterns and ultimately of genetic bases for stressor-specificity of neuroendocrine responses.

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Clinical Evaluation of Neurocardiologic Disorders Theclinicalevaluationof apatientwithaknownorsuspected neurocardiologic disorder, dysautonomia, or derangement of catecholaminergic function (Table 1-1) begins with and depends crucially on a carefully obtained medicalhistory.Theastutecliniciancancullkeydifferentialdiagnostic informationbyintelligentquestioning.Thephysicalexaminationincludes measurements of pulse rate and blood pressure with the patient supine and also standing, in order to detect orthostatic hypotension and diagnose sympathetic neurocirculatory failure. Neurologists and cardiologists should recognize the importance of these simple measurements. Theevaluationusuallyalsoincludesanyof a largevarietyof physiological, neuropharmacological, neurochemical, or nuclear imaging tests. Availabilityofthesetestsvarieswidelyamongmedicalcenters(l),and selection of appropriate testing depends on the individual case.

MEDICAL HISTORY (Table 6-1) Hypertension

Most patients with persistent high blood pressure have “essential,” or primary, hypertension, which elicits no or non-specific symptoms. Nevertheless, the medical history can reveal relevant information about the risks of morbid consequences of primary hypertension and about potentially curable forms of secondary hypertension. Chronic high blood pressure increases the risk of stroke, heart failure, and kidney failure. Accordingly, in obtaining the medical history of a hypertensive individual, one should ask about other risk factors with which hypertension may interact.Theseincludegender,age,familyhistory,diabetesmellitus, hypercholesterolemia, cigarette smoking, and probably obesity and sedentary lifestyle. Medications probably constitute the most common cause of secondary hypertension, and the medical history in a patient with high blood pressure must carefully review all prescription and non-prescription drugs. These include 335

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Table 6-1 Medical History in Neurocardiology Patients

History of the Present Illness

Hypertension Orthostatic or Post-Prandial Presyncope Libido and Sexual Function Gastrointestinal Function UrinaryFunction Sweating Symptoms of Central Neurodegeneration Trends during the Day Treatments and Responses to Treatments

Allergies and Drug Sensitivities “Alternative” Treatments Past History

Hospitalizations Operations Injuries and Disabilities Chronic Medical Conditions (e.g., Hypothyroidism, Diabetes, Asthma,Chronic Obstructive Pulmonary Disease, Hypertension, Peptic Ulcer Disease, Hepatitis, Seizure Disorder, Chronic Fatigue Syndrome, Anemia, Bleeding Diathesis) Family History

Premature Deaths Diseases that Run in the Family Risk Factors Personal and Social History

Marital Status Employment Status Smoking, Coffee, Alcohol Illicit Drugs Special Diet Chronic Psychiatric Conditions (e.g., Depression, Schizophrenia, Panic/Anxiety)

Clinical

337

Review of Systems

General: Weight, Fatigue, Appetite, Fever, Muscle Strength, Mobility, Heat- or ColdIntolerance, Loss of Consciousness, Facial Appearance Skin: Edema, Altered Hair Pattern, Altered Skin Coloration HEENT: Visual Changes, Altered Hearing, Senses of Smell and Taste Respiratory: Shortness of Breath, Cough Cardiac: Chest Pain or Pressure, Palpitations, Heart Murmur, Orthopnea Gastrointestinal: Difficulty Swallowing, Abdominal Pain, Altered Bowel Habit, Fecal Incontinence Genitourinary: Nocturia, Urinary Incontinence Neurological: Limb Weakness or Numbness, Symptoms of Transient Cerebral Ischemia, Tremor, Paresthesias, Allodynia, Gait, Balance, Speech

oralcontraceptives,adrenocorticalsteroids,monoamineoxidaseinhibitors, anorecticagents,“dietarysupplements,”cyclosporin,erythropoeitin,and nonsteroidal anti-inflammatory drugs. Obese women older than 35 years old who have taken oral contraceptives for more than five years have an especially high frequency of hypertension from oral contraceptive use. Chronic treatment with prednisone elicits hypertension as part of iatrogenic Cushing syndrome. Patients taking monoamine oxidase inhibitors, effective drugs in the treatment of depression, can have paroxysmal pressor responses to over-the-counter sympathomimetic amines as well as to tyramine in some foodstuffs. Individuals wishing to lose weight can have hypertensive responsesto thyroid hormone or amphetamines. Some “herbal” or “natural” remedies contain yohimbe bark, which releases norepinephrine from sympathetic nerve terminals, or mu huang, which contains the sympathomimeticamine, ephedrine. Other causes of secondary hypertension include virtually any form of renal parenchymal disease, renovascular disease(especially due to fibromuscular dysplasia in women under 50 years old), and hypercalcemia from any cause. The clinician should consider rare conditions such as aortic coarctation, primary aldosteronism,Cushingdisease,andpheochromocytoma,becauseofthe possibility of surgical cure. Orthostatic or Post-Prandial Hypotension

Potentialcausesoforthostatic or post-prandialhypotension(fall in systolic pressure more than 20 or in diastolic pressure more than 10 mm Hg) merit careful consideration in evaluation of a patient with suspected autonomic failure. Prolonged bed rest, anemia from blood loss, and any of a large variety of drugs can produceorthostatic hypotension.

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Since drugs used in cardiology (e.g., diuretics, nitrates, vasodilators), psychiatry (e.g., phenothiazines, tricyclic antidepressants, monoamine oxidase inhibitors), and neurology (e.g., L-DOPA, dopamine receptor agonists), can produce orthostatic hypotension, the medical history must include a complete and careful reviewof medications. In patients with sympathetic neurocirculatory failure, orthostatic dizziness and hypotension are worstin the morning, especially after a large breakfast, after showering, or after straining at stool. Blood pressure tends to build up as day progresses. This helps distinguish orthostatic hypotension due to sympathetic neurocirculatory failure from that due to depletion of effective circulating blood volume. Patients can confuse orthostatic intolerance with ataxic dyscoordination, which they label as “imbalance.” Because of severe orthostatic hypotension, pure autonomic failure patients often learn to sit or stand with their legs twisted pretzel-like, since this decreases pooling of blood in the legs. If asked, patients may note that they have adopted this posture. Impotence

In men, impotence often is the earliest symptom of autonomic failure. Smooth muscle relaxation leads to filling of penile sinusoidal spaces, as a result of parasympathetic neural activation and possibly concurrent sympathetic neural inhibition (2). Nitric oxide, which is both co-localized with acetylcholine in parasympathetic nerve terminals and mediates post-synaptic vasorelaxant effects of acetylcholine, is now thought to be a major factor promoting erection in primates (3). Erectiledysfunctionsuggestsparasympatheticfailureand ejaculatory dyshnction sympathetic failure. The clinician should keep in mind the high frequency of impotence as a side effect of anti-hypertensive medications-even thiazides, which one might not predict would interfere with sympathetic or parasympathetic function. Gastrointestinal

Either constipation or loose stools with fecal incontinence can occur patients with autonomic failure. Urinary

Urinary retention and overflow incontinence suggest parasympathetic failure. Nocturia is an early symptom. In severe cases, patients must learn to self-catheterize forrelief.

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Sweating

Abnormalthermoregulatorysweatingcanpresentasheatorcold intolerance.Oneshoulddistinguishabnormalitiesofthermoregulatoryor emotionalfromgustatorysweating,sincethermoregulatoryandemotional sweatingdependimportantlyonsympatheticcholinergicactivation,but gustatory sweating may not (4,5). Central Neurodegeneration

Parkinsoniansymptoms(especiallyslowinitiationofmovement, expressionless face, stooped shuffling gait, complaint of muscle weakness), wide-basedgait,tremor(atrestorintentional),diplopia,slurredspeech, difficulty swallowing, or a history of aspiration suggest central neurodegeneration in patients with autonomic failure. Family History

Hypertension can reflect the occurrence of a pheochromoctyoma, which in a substantial proportion of cases has a familial component. Patients with von Hippel-Lindau disease, multiple endocrine neoplasia type 11, or neurofibromatosis have an increased risk of development of pheochromoctyoma. In evaluating a patient with suspected autonomic failure, one should query the patient about a family history of Parkinson’s disease, amyloidosis, myeloma, fainting, or premature death. Information about ethnic background can be helpful (e.g., Ashkenazic Jewish origin in familial dysautonomia). Treatments and Responses to Treatments

Patients with sympathetic neurocirculatory failure can undergo treatment trialswithfludrocortisone,ahighsaltdiet,midodrine,sympathomimetic amines,&blockers,antidepressants, i.v. fluids,diuretics,non-steroidalantiinflammatory drugs, elevation of the head of the bed, physical therapy, or SinemetTM. Responses to these treatments can help in differential diagnosis. For instance, patients with peripheral autonomic failure associated with Parkinson’s disease usually have overall improvement during treatment with SinemetTM, whereas patients with multiple system atrophy and sympathetic neurocirculatory failure (the Shy-Drager syndrome) usually do not. Patients with POTS often respond dramatically but transiently to i.v. infusion of saline.

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Treatments for symptoms of parasympathetic failure include cathartics, stool softeners and dietary fiber for constipation; cholinergic agonists or selfcatheterization for urination; and yohimbine or ViagraTMfor impotence. PHYSICAL EXAMINATION (Table6-2)

A careful physical examination can yield important information relevant to the diagnosis of neurocardiologic disorders. General Appearance

Patients with orthostatic hypotension may sit or stand with their legs twisted.Thepatient’sgeneralappearancecansuggestsecondarycausesof hypertension or of orthostatic hypotension. Cushing disease classically includes truncal obesity, abdominal striae, moon-shaped face, and a “buffalo hump.”An expressionless face and slow movements suggest a parkinsonian syndrome, such as Parkinson’s disease with peripheral autonomic failure or multiple system atrophy with parkinsonian features. Increased pigmentation can reflect the adrenocortical failure of Addison’s disease. Patients with amyloidosis can have “raccoon’s eyes.” A patient lyingin bed may have orthostatic hypotension from achronicdebilitatingdisease,dehydration, or slowblood loss. Athin, hyperactive patient with sweaty palms noted during the greeting handshake may have thyrotoxicosis or a syndrome associated with paniclanxiety. A “medic alert” bracelet can suggest the presence not only of a serious medical condition but also of concern about that condition. Vital Signs

Not only the mean blood pressure but also the pulse pressure and pulse rateprovidedifferentialdiagnosticinformation in patientswithchronic hypertension. Patients with arteriosclerosis, aortic insufficiency, severe anemia, the hyperdynamic circulation syndrome, anxiety, hypoglycemia, or hyperthyroidism can have isolated systolic hypertension, with an increased pulse pressure.Sinustachycardiaoccurscommonly in fever,severeanemia, hyperthyroidism, postural tachycardia syndrome (orthostatic increase in heart rate exceeding 30 bpm), and hypemoradrenergic hypertension. Decreased systolic pressure in the lower extremities can indicate aortic coarctation. Measurementsofchangesinpulserateandbloodpressureduring orthostasis are crucial for diagnosing orthostatic hypotension resulting from sympathetic neurocirculatory failure. Whereas the increase in pulse rate during orthostasis depends importantly on vagal withdrawal, maintenance of blood

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pressuredependsmainlyonsympathetically-mediatedvasoconstriction. Sympathetic neurocirculatory failure therefore produces orthostatic hypotension. In patients with sympathetic neurocirculatory failure, the blood pressure declines rapidly upon standing. Patients with chronic orthostatic intolerance (alsocalledposturaltachycardiasyndrome, or POTS)canhavedelayed orthostatic hypotension, presumably becauseof extravasation of plasma ( 6 ) but do not typically have orthostatic hypotension. Oneoftencandetectpost-prandialhypotensioninpatientswith sympathetic neurocirculatory failure,if the examiner measures the blood pressure carefully after the patient ingests a meal. Excessive increases in pulse rate during standing can indicate POTS, but blood volume depletion and treatment with vasodilating drugs can produce the same finding. Aging attenuates the extent of increase in pulserateduring standing.

Skin The examiner looks for edema, fingertip sweat (by otoscope), altered skin color or temperature, trophic changes or tobacco staining of the nails, altered hair pattern, and tentingof the skin. Head, Eyes, Ears, Nose, and Throat

Ptosis, miosis, and anhidrosis characterize Homer’s syndrome, reflecting disruption of sympathetic post-ganglionic innervation of the face from the superior cervical ganglion. Classically, in tabes dorsalis, the pupils are small and irregular, and they accommodate but do not react (Argyll-Robertsonpupil). Internalophthalmoplegiafrompalsy of thethirdcranialnerveincludes disruption of parasympathetic innervation of the pupil, resulting in a relatively fixed, dilated pupil that constricts upon local application of the cholinergic agonist pilocarpine. The “tonic pupil” in Adie’s syndrome reacts relatively poorly tolight and contracts more slowly during accommodation to near vision than does the contralateral pupil. The syndrome also includes decreasedor absent deep tendon reflexes, without clear evidence for abnormal locomotion or sensation, and can be associated with sudomotor and neurocirculatory dysautonomia (7). Ross’s syndrome is the combination of a tonic pupil, hyporeflexia, and anhidrosis. The presence of nystagmus can indicate a cerebellar or lower brainstem lesion. Examination of the fundi can detect hypertensiveor diabetic retinopathy. Congenital Homer’s syndrome results in asymmetric iris color. Patients with familial dysautonomia have absent lingual fingiform papillae. Speech quality and the gag reflex can be abnormalin patients with multiple system atrophy.

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Table 6-2 Physical Examination in Neurocardiology Patients

General Appearance Vital Signs

Blood Pressure and Pulse Rate, Supine and Upright Pedal Blood Pressure if Appropriate Body Mass and Height RespiratoryRate Body Temperature Skin

Temperature Color Moisture (Digital, Palmar, Axillary Sweat) Edema Scars, Bruises, Cafe-au-Lait Spot Hair Pattern Cyanosis or Rash NailClubbingor Staining Extremities

Joints Lymph Nodes Head, Eyes, Ears, Nose, and Throat

Eyes: Pupils (Reaction and Accommodation), Visual Fields, Extraocular Movements, Fundi, Sclerae Sense of Smell AuditoryAcuity Palatal Movement, Gag Neck

Mobility JugularVeins Carotid Pulse Thyroid Respiratory

Auscultation

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ForcedExpiration Cardiovascular

Thoracic Palpation (Apica 11 Heartbeat, Lift) Cardiac Auscultation (Murmur, Rub, Gallop) Pulses (Radial, Brachial,Carotid,Femoral, Pedal, Pulse Quality, Respiratory Sinus Arrhythmia) Costophrenic Angle Auscultation Gastrointestinal

Abdominal Palpation (Liver, Spleen, Mass, Tenderness, Fluid) Abdominal Auscultation (Bowel Sounds, Bruit) Neuropsychiatric

Cranial Nerves Short-Term Memory, Reasoning, Primitive Reflexes Speech Motor: Handgrip, Muscle Tone, Muscle Strength, Deep Tendon Reflexes Babinski Sensation (Pain, Temperature, Vibration, Position) Coordination (Finger-Nose, Heel-Shin) Stance and Gait Genitorectal

Breasts Pubic Hair Pattern Penis and Testes, Labia and Clitoris Anal Sphincter Tone, Prostate Stool Guaiac Internal Female Examination if Appropriate

Grave’sdiseaseincludesexophthalmos,withlidlaguponsudden downward gaze.

Neck Thyrotoxicosis, such as from toxic nodular goiter, often produces systolic hypertension, tachycardia, arrhythmias, and altered mental state. The external jugular veins (distended or down) should be observed. The examiner should note the presenceor absence of a carotid bruit.

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Cardiovascular

The cardiovascular examination includes checking the pedal pulses, since decreasedorabsentpedalpulsesoccurinobliterativeatherosclerosisor coarctation of the aorta.In the mid-abdomen or costophrenic angles in the back, a bruit can suggest renal artery stenosis as a cause of hypertension. Examinationofthepulseincludesassessingitsregularityandthe presence and extent of respiratory sinus arrhythmia. A small, weak pulse with slow upstroke (pulsus parvus)in a patient with syncope suggests aortic stenosis. Auscultation is used to detect murmurs or gallops. Both aortic and mitral stenosis can present as syncope. Respiratory

Hyperventilation can suggest paniclanxiety disorder.An ineffective cough or rales can suggest multiple system atrophy and a tendency to aspirate. Gastrointestinal

Abdominal examination includes checking for the presence of bowel sounds, hepatomegaly, and splenomegaly, checking anal sphincter tone, and checking the stool for blood. Reduced anal sphincter tone can indicate multiple system atrophy, and occult gastrointestinal bleeding can produce orthostatic symptoms. Neuropsychiatric

Neuropsychiatricevaluationincludesnotingthepatient’slevelof alertness and orientation, affect, and short-term memory. Tests of cranial nerve function should include evaluation of the sense of smell. In examining the motor system, one looks for rigidity, cogwheeling, and tremor at rest or with intentional movement. Examination of the motor system notes muscle bulk and strength and presence or absence of involuntary movements. The deep tendon reflexes are assessed, as well as the ability to perform finger-nose and heel-shin tests. One looks for Babinski or primitive reflexes (e.g., grasping, rooting). Tests of sensation should include pressure, temperature, position, and vibration. Finally, one notes the patient’s gait, speech, and handwriting. Patients with Parkinson’s disease typically have micrographia, and patients with cerebellar ataxia have sloppy writing.

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PHYSIOLOGICAL TESTS Reflexive Regulation of Blood Pressure

Orthostasis decreases cardiac filling acutely. Because of the dominance of thesympatheticnervoussystem in maintainingbloodpressureduring orthostasis, the evaluation of patients with known or suspected dysautonomia often includes physiological tests based on acute responses of blood pressure to decreased cardiac filling. The most well known manipulation for this testing is the Valsalva maneuver.

The Valsalva maneuver Despite its apparent simplicity, the Valsalva maneuver constitutes one of the most important clinical physiological tests in the diagnostic evaluation of autonomic failure. The Valsalva maneuver consists of blowing against a resistance 10-1 for 5 seconds and then relaxing. The patient can blow into a tube connected to a blood pressure gauge, keeping the gauge's needle at20-30 mm Hg. Theinstantthepatientbeginstoblow,thesuddenincrease inintrathoracic pressure enhances ejection of blood by the heart (Phase I of the maneuver). The blood pressure briefly increases (Figure 6-1). Soon afterwards, however, the amount of blood ejected by the heart with each beat (the stroke volume) plummets, because the straining impedesentry of blood from the veins into the heart. Blood pressure progressively falls (Phase 11). As the blood pressure falls during Phase I1 of the Valsalva maneuver, the baroreceptors in the walls of the carotid artery and in the walls of the cardiac atriadetectlessstretch.Afferentnervetraffictothebrainstemfromthe baroreceptors decreases. Virtually immediately, by way of baroreceptor reflexes, sympathetic neural outflows to blood vessels increase, and parasympathetic vagaloutflowtotheheartdecreases.Thesympatheticstimulationevokes vasoconstriction, and the vagal inhibition increases the heart rate. Thus, if the baroreceptor reflex is intact, as Phase I1 progresses, the heart rate increases, and the average blood pressure begins to increase toward the baseline value. When the patient relaxes at the end of the maneuver, the blood pressure falls briefly (Phase 1II)"a mirror image of the brief increase in Phase I. Blood rushes back into the chest, and within a few heartbeats the heart ejects this blood. The blood pressure increases (Phase IV). Sudden fillingof the reflexively constricted vessels produces an overshoot of blood pressure. In response to this Phase IV overshoot of blood pressure, sympathetic outflow to blood vessels falls and vagal outflow to the heart increases. The latter causes a rapid fall in heart rate from the increased rate during Phase 11.

Chapter 6

346 200 n

0

180

E

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I W

W p:

2 VI W

a

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120

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9 m

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Figure 6-1 Beat-to-beat bloodpressureassociated Normally, blood pressure increases neartheend baseline value in Phase IV.

with the Valsalva maneuver. of Phase I1 and overshootsthe

In a patient with sympathetic neurocirculatory failure, during Phase 11, the blood vessels do not constrict reflexively, and so as the blowing continues, blood pressure usually falls progressively and does not increase toward baseline at the end of Phase I1 (Figure 6-2). During Phase W ,for the same reason, no rapid increase in blood pressure or overshoot of blood pressure occurs. Instead, the blood pressure increases slowly back to the baseline value. All sympathetic neurocirculatory failure syndromes share this finding. As of this writing, no quantitative standardization of beat-to-beat blood pressure responses during Phase I1 or Phase IV has appeared. Because of the lack of the Phase IV overshoot, one would not expect a Phase IV reflexivefallinheartrateinapatientswithsympathetic neurocirculatory failure, and so the absence of such a fall does not of itself indicate parasympathetic failure; however, sympathetic failure should not prevent a reflexive increase in pulse rate during Phase 11, and the absence of such an increase would indicate cardiovagal parasympathetic failure. In order to diagnose sympathetic neurocirculatory failure based on the Valsalva maneuver, one must monitor the beat-to-beat blood pressure changes. Until recently, such monitoring required insertion of a catheter into an artery. Since clinicians rarely feel comfortable doing this, they often settle for recording only the peak and trough pulse rates during and after performance of the maneuver. This may enable a diagnosis of cardiovagal parasympathetic failure but cannot diagnose sympathetic neurocirculatory failure. Oscillometric,photoplethysmographic,ortonometricdevices (e.g., FinapresTM, PortapresTM, ColinTM) provide non-invasive means to follow blood

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I1

!I1 IV

1'

I

I1

[I1 IV

Figure 6-2 Beat-to-beatbloodpressureassociated with theValsalvamaneuver, in a patientwithperipheralautonomicfailure.Toptracing was producedusingthe Finapresmdevice and thebottomfromdirectlyrecordedintra-arterialpressure. By both the invasive and non-invasive measures, the blood pressure decreases progressively during Phase II and does not overshoot in Phase N. m beat-to-beat Theobtained pressllre WBvefOrms can reSemble closely the waveform of the htxa-arterially recorded blood pressure (Figure 6-2) and detect abnormalities in beat-to-beatblood pressure associatedwiththe Valsalva manewer in patients with sympathetic neurocirculatory failure.

p

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Figure 6-3 Beat-to-beatbloodpressureassociatedwith spontaneously occurring premature ventricular contractions. The top tracing shows the response in a normal volunteer. The post-extrasystolic bloodpressure overshoots baseline. The middle tracing shows the response in the same subject during ganglion blockade produced by i.v. infusion of trimethaphan. The blood pressure does not overshoot. The bottom tracing shows the response ina patient with sympathetic neurocirculatory failure. The post-extrasystolic blood pressure does not overshoot.

A new sign of sympathetic neurocirculatory failure Thediagnosisofsympatheticneurocirculatoryfailuredependson detection of impaired reflexive sympathetically-mediated vasoconstriction, such as during performance of the Valsalva maneuver. A new sign of sympathetic neurocirculatoryfailure is based on thebeat-to-beatbloodpressureafter spontaneous premature ventricular contractions (PVCs).

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Afterapost-extrasystolicbeat,thesystolicbloodpressurenormally increases to above baseline and then decreases to baseline over a few beats (Figure 6-3). In patients with sympathetic neurocirculatory failure, after the postextrasystolicbeatthesystolicbloodpressureisbelowbaselineandthen increases to baseline over several beats. The same pattern occurs in control subjects who have PVCs during ganglion blockade. The characteristic pattern of beat-to-beatpost-extrasystolicbloodpressureinpatientswithsympathetic neurocirculatory failure therefore arises from and can indicate deficient reflexive sympathetically-mediatedvasoconstriction, evenif the patients cannot perform a technically adequate Valsalva maneuver. One can detect the presence of the abnormal post-extrasystolic blood pressure using one of the above-described non-invasive devices. Whether the beat-to-beat blood pressure after a premature atrial contraction can be used to indicate sympathetic neurocirculatory failureis unknown; this would probably dependon the extent of prematurity of the beat and duration of delay until the next beat. Tilt table testing Tilting reduces venous return to the heart. This normally elicits reflexive increasesinsympathoneuraloutflowsandinhibitsvagalparasympathetic outflow to the heart. Total peripheral resistance to blood flow increases, and heart rate increases. These compensatory responses tend to counter the fall in stroke volume and help maintain mean arterial pressure. In patients with chronic fatigue syndrome, fibromyalgia, POTS, or a history of repeated episodes of syncope or presyncope, tilt table testingis used, in an attempt to provoke acute vasodepression (8). Thevasodepression is associated with, and probably results from, sudden withdrawal of sympathetic neuronal outflows (9,lO). Concurrently, epinephrine secretion increases(1 1-14), helping to explain the cutaneous pallor and increased total limb blood flow in evoked vasodepressor episodes. Iftiltingalonedoesnotelicitsuchanepisode,theclinicianmay administer isoproterenol, edrophonium, or nitroglycerine (8,15). By stimulating B-adrenoceptorsonvascularsmoothmusclecells,isoproterenoldecreases resistance to blood flow in skeletal muscle, and by stimulating myocardial Badrenoceptors, isoproterenol increases the force and rate of heart contraction. Exactly which of these effects precipitate acute vasodepression is unknown. The cardiac effects are consistent with the “collapse firing” hypothesis, discussed in a separate chapter. Edrophonium increases occupation of cholinergic receptors by inhibiting metabolic breakdown of acetylcholine by cholinesterase and therefore would be expected to augment bradycardic, negative inotropic, and cardiac sympathoinhibitory responses to vagal stimulation. Nitroglycerine decreases venous return to the heart and therefore augments orthostatic stress.

Chapter 6 1 oa

Normal

80

HEART RATE

6o

AutonomicFailure

(bpm) 40

- 5 sec

End

Figure 6-4 Beat-to-beat heart rate near the end of Phase I1 of the Valsalva maneuver. Normally, heart rate increases progressively, due mainly to reflexive inhibition of parasympathetic cardiovagal outflow. Patients with autonomic failure often have a smaller, more delayed increase in heartrate. Reflexive Regulation of Pulse Rate

In patients with failureof the cardio-vagal component of the baroreceptor reflex, respiratory sinus arrhythmia is absent, and orthostatic increases in pulse rate are attenuated. During Phase I1 of the Valsalva maneuver, the heart rate fails to increase normallyin response to the fall in blood pressure (Figure 6-4). Power Spectral Analysis of Heart Rate Variability

Classical cardiologists such as Wenckebach referred to a variable pulse rate as the sign of a healthy heart (1 6). During slow, deep inspiration, the pulse rate normally increases, and’at the beginning of expiration, the pulse rate normally decreases-”respiratory sinus arrhythmia”-a change in the heart rhythm resulting from a change in the firing rate of the sinus node as a function of respiration. Respiratory sinus arrhythmia results mainly if not exclusively from alterations in the rate of cardiac vagal nerve traffic. Thus, abolition of the effects of parasympathetic activation by administration of atropine abolishes respiratory sinus arrhythmia. If one displays on a chart recorder the instantaneous heart rate, calculated from the time between heartbeats, the heart rate often changes cyclically, as the person breathes in and out. The cyclic changes in heart rate give the appearance of a waveform, and one can describe waveforms in terms of frequency and he (amplitude). If one wishes to consider heart changes from zero, regardless of whether the change is an increase or decrease, one can express the changeas a square, since a negative value squared and a positive value squared both lead to

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positive values. This in essence converts the amplitude of a heart rate change (which can be positive or negative) to the “power,” whichis a positive number. Using Fourier analysis, one can then describe any repeating waveform in termsoffrequencyandthepoweratthatfrequency.Acrossarangeof frequencies-across a spectrum of frequencies-the different frequencies will have different powers. At the frequency corresponding to the respiratory rate, a high-power “peak”occurs,correspondingtothecyclicchanges in heartratedueto respiratory sinus arrhythmia. The high-frequency peak therefore can indicate the extent of vagal parasympathetic effects on the sinus node. Atalowerfrequency,anotherpeakoccurs in thepowerspectrum. Investigators have proposed that the height of the low-frequency peak can indicatetheextentofsympatheticoutflowtotheheart (17). Thus, manipulationssuchasexercise (18,19), head-uptilting (20,21), or administration of various drugs produce the predicted changes in low-frequency power. The notion that low-frequency power provides a valid means to indicate cardiac sympathoneural “tone” has proven oversimplistic at best. For one thing, asubstantialproportionofthelow-frequencypowerdependsonvagal parasympathetic outflow, because destruction of parasympathetic fibers in the sinus node not only eliminates the high-frequency wave but also decreases the height of thelow-frequency wave by about half(22). Moreover, several studies have reported findings inconsistent with the validity of low-frequency power, the ratio of 1ow:high frequency (LF:HF) power, or low-frequency power normalized for total power, to indicate cardiac adrenergic “drive.” Differences across studies in the dependent measures-LF power, LF:HF power, LF power normalized for total power-have complicated theissue.Forinstance,althoughduringbicycleexercise,theLF:HFand LF:totalpowerratiosincreaseappropriately,neitherindexresponds appropriately to autonomic blockade with theB-adrenoceptor blocker esmolol or the muscarinic blocker glycopyrrolate (23). Prolonged head-down bed rest, which decreases urinary excretion of catecholamines, indicating sympathoinhibition, does not affect the presumed sympathetic component of heartratevariability (24). LF:HFratiocandetecttheshift in autonomic “balance” during B-adrenoceptor blockade, but not when the subjects are in the supine position (25). Whereas patients with early left ventricular dysfunction have increased cardiac norepinephrine spillover (26), they have decreased lowfrequency and log total power of heart rate variability(27). During performance of the Stroop color-word conflict test, when heart rate, systolic blood pressure, and plasma norepinephrine and epinephrine levels all increase, the ratio of LF:HF power does not increase (28). And whereas total body and cardiac

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norepinephrine spillover increase with normal aging (29), total power and lowfrequency power correlate negatively with age (30,3 1). To date, studies that have attempted to correlate low-frequency power or the LF:HF ratio with cardiac norepinephrine spillover in the same subjects have noted only weakly positive relationships. For instance, patients with a cardiac transplant, and therefore with a denervated heart, have absent low-frequency power and absent cardiac norepinephrine spillover; however, during exercise, increments in low-frequency power correlate poorly with increments in cardiac norepinephrine spillover (32). Reflexive Regulation of Cutaneous Blood Flow

Laser-Doppler flowmetry enables assessments of reflexive changes in cutaneous blood flow velocity in a small (about 1 mm3) volume of skin (33). In humans, whole body heating elicits cutaneous vasodilation. By combininglaser-Dopplerflowmetrywithlocaliontophoretic or intradermal administration of drugs, one can examine specific aspects of local autonomicfunctionrelatedtothermoregulation.Iontophoreticlocal administration of atropine does not prevent cutaneous vasodilation in response to whole body heating, implying that the vasodilation does not depend on occupation of muscarinic cholinergic receptors. Since atropine does abolish the vasodilation resulting from iontophoretic administration of acetylcholine, and sinceintradermalinjectionofbotulinumtoxineliminatesthecutaneous vasodilationattendingwholebodyheating,atransmitterotherthan (4). acetylcholine may produce the vasodilation Sweating

Stimulationofsympatheticnervousoutflow in theskinincreases secretion of sweat, producing the classic sweaty palms associated with distress. In rats, the neurotransmitter phenotype in sudomotor function changes during development from catecholaminergic to cholinergic (34). In humans, both cholinergic and adrenergic agonists elicit sweating, both in vivo (35) and in vitro, in isolated sweat glands (36). Histological studies, however, have shown cholinergic but not catecholaminergic terminals near human axillary sweat glands (37). Systemicinjectionofacholinergicagonist,suchasthe cholinesteraseinhibitor,physostigmine,evokesprofusesweating;and iontophoretically applied atropine blocks local sweating responses to whole body heating (4). Patients with deficiency of dopamine-l3-hydroxylase, and therefore an inability to synthesize either norepinephrine or epinephrine, have normalsweating (38) andnormalsympatheticskinresponses (39). These findings support the view that both thermoregulatory sweating and sweating

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detected by the skin sympathetic response depend importantly on cholinergic muscarinic stimulation. Decreased sweating constitutes a classical sign of anticholinergic toxicity (“Red as a beet, mad as a hatter,dry as a bone.”) Acutedischargeofcatecholaminesintothebloodstreambya pheochromocytoma also elicits sweating; and disruption of sympathetic postganglionic innervation of the head produces Homer’s syndrome, a triad of ptosis,miosis,andanhidrosis.Neitherfindingnecessarilyimpliesthat catecholaminesmediatesweating in thesesettings,becauseintense vasoconstriction in a patientwith pheochromocytoma could decrease evaporation of sweat (40), and sympathetic post-ganglionic terminals in the head could releaseacetylcholine.Ithasbeensuggestedthat“adrenergicsweating” is relatively localized, such as in the palms, whereas “cholinergic sweating” is diffixe (4 1). Thermoregulatory Sweat Test (TST) One straightforward way to assess thermoregulatory sweating involves measuringthechange in colorofindicatorssuchasiodinewithstarch, quinizarin, or alizarin red, in response to raising the body temperature using an external source of heat (42). This is called the Thermoregulatory Sweat Test (TST). One can obtain a quantitative TST (43) by measuring sweat volume or responselatency.Thesilasticimprintmethodinvolvesiontophoresisora cholinergic agonist such as pilocarpine and counting of active sweat glands. Galvanic Skin Response (GSR) Since dry skin offers substantial electrical resistance, whereas the ionsin sweat facilitate electrical conduction, sweating decreases electrical resistance and increases electrical conductance. Increases in electrical conductance of the skin in response to provocative stimuli constitute the “Galvanic Skin Response” (GSR). The GSR figures prominently in non-invasive measures of sympathetic nervous “activity” in polygraphic “lie detection.” Because of the often marked changes in sympathoneural and adrenomedullary outflows during distress, the GSR can reflect acute distress-induced sympathetic effects on sweat glands. Measurementofperipheralautonomicskinpotential(PASP), or sympathetic skin response (SSR), analogously assesses sweating indirectly from changes in cutaneous electrical resistance in response to maneuvers such as cough, inspiratory gasp, or electrical stimulation.

Chapter 6

Sweat (axon rellex)

Sweat (dlrect

stlrnulallon)

Figure 6-5 Principle of the Quantitative Sudomotor Axon Reflex Text (QSART). QSART A pharmacological approach to examine post-ganglionic, sympathetic cholinergic sudomotor function consists of iontophoretic administration of acetylcholine and measurement of the resulting increase in production of sweat (Figure 6-5). Thistest,calledQSART(forQuantitativeSudomotorAxon Reflex Test), can sensitively detect increased or decreased cholinergic sweating. Most reports using this technique have emanated from the Department of Neurology at the Mayo Clinic(44); however, a commercially available QSART device has recently been introduced. In theQSARTprocedure,dehumidifiednitrogenatacontrolled temperature and flow rate passes through a plastic two-chamber capsule placed on the skin. The increment in humidity as sweat droplets evaporate provides a virtuallyinstantaneousmeasure of sweatproduction.Iontophoresis of a cholinergic agonist (e.g., 10% acetylcholine) evokes sweating at the site of

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administration under one capsule but also at an adjacent site under the second capsule, via a sudomotor axon reflex. Patients with pre-ganglionic lesions have normal QSART responses, in contrast with decreased sudomotor responses to increased body temperature. Application of the QSART approach should take into account that men have larger responses than women and that responses decline with age (45,46). Genitourinary Function

Although patients with autonomic failure often have disturbances of genitourinary function, relatively few undergo specialized cystometric testing. Parasympathetic cholinergic activation elicits detrusor muscle contraction; and sympathetic noradrenergic activation contracts the bladder neck (47). During micturition, contraction of the detrusor and distention of the bladder neck occur in concert. Cystometrography relates intra-vesicular pressure to volume in response to instillation of fluid. Classically the cystometrogram contains three phasesaninitialincrease in pressurerelateddirectlytotheincrease in volume, a “tonus” phase, when the bladder expands passively, and a contraction phase, when smooth muscle contraction, in which autonomic reflexes play a role, increases intra-vesicular pressure markedly (48). Thecystometrogram in patientswithmultiplesystematrophycan indicate both decreased detrusor contraction and decreased contraction of the distal urethral sphincter, which consists of striated muscle. These findings seem associated pathologically with neuronal loss in Onuf s nucleus in the spinal cord (49,50). Normal micturition requires a highly coordinated sequence of reflexive smoothandskeletalmusclecontractionsandrelaxations(47).Even in the absence of nervousinput-a condition termed “automatic bladder”-the bladder can accumulate urine and partly excrete it. Patients with parasympathetic failure therefore have some ability to urinate, but with a large post-void residual. Patientswithdiabeticautonomicneuropathyalsooftenhaveanautomatic bladder. Oropharyngeal and Gastrointestinal Function

It has been suggested that degeneration of the nucleus ambiguus in the medulla may explain dysfunction of the cricoarytenoid muscle of the larynx and slurred speech in patients with multiple system atrophy (47); however, necropsy studies have not confirmed loss of motor cellsin the nucleus ambiguus (51). Gastrointestinal functional studies in patients with suspected dysautonomia have focused on smooth muscle motility (e.g., esophageal or

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anorectal manometry, liquid and solid gastric emptying) and on biochemical indices of vagal effects on secretion of gastrointestinal hormones. Patients with pure autonomic failure have deficient increases in plasma levels of pancreatic polypeptide in response to insulin-induced hypoglycemia (52).

Pupillometry Measurements of pupillary responses to locally applied drugs can detect sympathetic or parasympathetic failure. Conjunctival instillation of atropine (1%) produces mydriasis that can last for days. Shorter-acting parasympatholytics, such as tropicamide (1%) and cyclopentolate (1%) are used clinically to dilate the pupil for funduscopic examination. Adrenoceptor agonists also produce mydriasis. The a*-adrenoceptor agonistphenylephrine(2.5%)isoftenusedclinicallyforthispurpose. In contrastwiththedirecteffectofphenylephrine,tyramine(5%)produces mydriasis via release of endogenous norepinephrine. Thus, in a patient with decreased or absent post-ganglionic sympathetic traffic to intact terminals, the pre-constricted pupil would be expected to have a mydriatic response to both phenylephrineandtyramine,whereas in a patient with absent sympathetic terminals, the pupil would be expected to have an augmented dilation response to phenylephrine (due to denervation supersensitivity) and no dilation response to tyramine. Mydriatic responses to cocaine (5-10%) depend on blockadeof reuptake of norepinephrine released from local sympathetic terminals. Thus, the finding of absence of pupillary dilation in a pre-constricted pupil after local instillation of cocaine indicates loss of post-ganglionic sympathetic terminals. Mydriaticresponsestolocallyadministeredanti-cholinergicagents dependonparasympathetictonus,andabsenceofpupillarydilationafter instillationofadministeredanti-cholinergicagentsindicateslossof parasympathetic terminals. Again becauseof denervation sensitivity, augmented constriction of a pre-dilated pupil by pilocarpine (0.1-1%) or the more rapidlyacting arecoline (0.025%) would indicate parasympathetic denervation. Cholinesterase inhibitors, commonly used as insecticides, produce miosis by interfering with inactivation of acetylcholine. These drugs would not be expected to produce miosisin parasympathetic failure. Patients with the “harlequin syndrome” have a loss of thermoregulatory facial flushing and sweating. Since excessive pupillary responsiveness to both phenylephrineandpilocarpineoccur,thesyndromeappearstoinclude denervationsupersensitivity in responsetodecreasedrelease of both acetylcholine and norepinephrine from autonomic nerve terminals (53).

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NEUROPHARMACOLOGICALTESTS Tests of Arterial Baroreflex Function

Two general types of baroreflexes regulate the circulation reflexively: the arterialhigh-pressurebaroreflexandthecardiopulmonarylow-pressure baroreflex. Most researchers have accepted the “goal” of the high-pressure baroreflex to be to regulate mean arterial pressure and of the low-pressure baroreflex to regulate central venous pressure, cardiac filling, cardiac output, extracellular fluid volume,or “effective” blood volume. The arterial baroreceptors restrict the range of arterial pressure, since studies have agreed that disruption of the arterial baroreflex markedly and permanently increases blood pressure variability (54,55). One may question, however, whether the “goal” of the arterial baroreflex is to regulate absolute levels of mean arterial pressure, since not only mean arterial pressure but also pulsepressureandheartrateinfluenceafferentinputfromthearterial baroreceptors to the brain. One may alternatively hypothesize the “goal” of the arterial baroreflex to be the maintenance of delivery of blood to the brain--not necessarily the same as the maintenance of arterial blood pressure. This would explain the positioning of the carotid sinus baroreceptors at the arterial gateway to the brain. The “goal” of the low-pressure baroreflex homeostatic system remains even more obscure. The low-pressure barostat may or may not be the “volustat”; however, for the rest of this chapter, the two terms are used largely interchangeably, referring to the parameter controlled by the homeostat that receives low-pressure baroreceptor information. In the arterial baroreflex, nerves from distortion receptors in the walls of major arteries, including the carotid sinus region, transmit afferent information about at least one monitored variable, arterial blood pressure, to the brain; the medulla oblongata of the brainstem contains the homeostat, which directs the reflexivecompensatoryresponsesofseveraleffectors.Thehypothalamus containsregulatorycentersthatadjustarterialbarostatsettings.The sympathoneural and parasympathetic vagal systems are the two most prominent effectors in this reflex. The arterial baroreceptors sense systemic blood pressure indirectly, by the extent of stretching of receptors in the walls of the aorta and carotid arteries. Injectionofavasoconstrictordrugintoahealthysubjectincreasesblood pressure acutely, and stretching of the arterial walls containing the baroreceptors increases afferent nerve traffic to the nucleusof the solitary tract. This leads to reflexively decreased sympathoneural and increased cardiac parasympathetic outflows, tending to normalize blood pressureby relaxing blood vessels and by decreasing the rateand force of heart contraction.

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The arterial dilation results not only from sympathetic noradrenergic inhibitionbutalso,toanextentthatappearstovaryacrossspecies,from sympathetic cholinergic stimulation. The reflexive sympathetic inhibitory effects of arterial baroreceptor activation are diffuse among several vascular beds; however, cutaneous sympathoneural activity, which seems quite sensitive to psychological stress, seems relatively insensitive to alterations in input from hemodynamic interoceptors. Most relatively simple physiological homeostatic systems such as the arterial baroreflex system function rapidly and silently. When a person stands up, that person normally senses nothing unusual, despite almost immediate reflexiveadjustments in heartrateand in thecaliberofbloodvessels. Nevertheless, orthostasis constitutes a threat to homeostasis, as demonstrated by the consequences ofany of several typesof neurological degeneration that cause failure to release norepinephrine adequately reflexively from sympathetic nerve terminals. Blood then pools in the legs and splanchnic bed during orthostasis, venous return to the heart decreases, and hypotension ensues. Pharmacological approaches to assess baroreflex-cardiac gain (usually termed baroreflex “sensitivity”) rely on measurements of the extent of change in electrocardiographic R-R interval for the change in systolic blood pressure after bolus i.v. injectionofphenylephrine(56)ornitroglycerine(startingdoses usually 50 pg). Phenylephrine, by stimulating al-adrenoceptors, elicits diffuse vasoconstriction, and nitroglycerine, by generating nitric oxide, dilates veins, decreasingvenousreturntotheheart,strokevolume,andsystolicblood pressure. Neither drug exerts important direct effects on heart rate (Figure6-6). One may also examine baroreflex-cardiac sensitivity by measuring beatto-beat blood pressure and heart rate during and after performance of theValsalva maneuver. Decreased venous return to the heart during PhaseI1 decreases stroke volume and systolic pressure, eliciting reflexive tachycardia, and during Phase IV, because the heart ejects blood into the reflexively constricted vasculature, systolic pressure overshoots baseline, eliciting a reflexive fall in heart rate. Resultsofbaroreflex-cardiacsensitivitymeasurementsusingthese pharmacological and physiological approaches generally agree fairly well, but by no means perfectly (57). Both approaches entail several assumptions, the most obvious of which is that alterations in responsiveness of vascular smooth muscle, such as from up-regulation of post-synaptic adrenoceptors or increased wa1l:lumen ratios,wouldbeexpectedtoproducedecreases in estimated baroreflex-cardiac sensitivity as a result of, rather than a cause of, pressor hyperresponsiveness. Approaches for measuring low pressure baroreflex sensitivity often have used pulse-synchronous bursts of peroneal microneurography, as an index of the rate of skeletal sympathetic nerve traffic, during exposureto lower body negative pressure. Other manipulations to decrease cardiac filling and thereby inhibit

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Arterlal Baroreceptors

Phenylephrine

HEART RATE

BLOOD PRESSURE

TIME Figure 6-6 Measurementofarterialbaroreflex“sensitivity” blood pressure responses to bolus injection of phenylephrine.

from heart rate and

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afferent input from low pressure baroreceptors include simple standing, various levels of tilt, or inhsion of vasodilators, and other dependent measures include plasma levels of norepinephrine. These techniques require specialized technical and clinical laboratory procedures, and the extent of agreement among these approaches remains incompletely understood. Patients with essential hypertension have decreased baroreflex-cardiac gain (58,59). Subjects with decreased baroreflex-cardiac sensitivity have increased spontaneous systolic pressures and pressure variability. Because resetting of the cardiaclimbofthearterialbaroreflexaccompaniesvirtuallyallformsof experimentalhypertension,itisunclearwhetheralterations in baroreflex function in essentialhypertensionconstituteaprimaryorsecondary phenomenon. Whether patients with essential hypertension have alterations in arterial baroreflex-vascular or arterial baroreflex-sympathoneural gain has been less clear. Patients with mild or borderline essential hypertension appear to have if anything increased cardiopulmonary baroreceptor reflex gain,in contrast with blunted baroreflex-cardiac gain. Since this augmented gain would tonically restrain sympathetic outflow, increased cardiopulmonary baroreflex gain could offset a central neural abnormality in regulation of sympathetic vascular tone, and orthostasis could expose the abnormality. In established hypertension, or hypertension associated with myocardial hypertrophy and increased stiffness, the restraining influence of the cardiopulmonary baroreceptors could decline. Clonidine Suppression Test

Pheochromocytoma, a rare cause of clinical hypertension, is a tumor of chromaffin cells. Pheochromocytomas occur most commonly in the adrenal gland or along pathways of embryological development from the neural crest, i.e., along the aorta to the organ of Zuckerkandl at the aortic bifurcation. The tumor presents clinically as sustained hypertension or paroxysmal hypertension, pallor, sweating, headache, anxiety, palpitations, orthostatic hypotension, and hyperglycemia. Pheochromocytomas are often benign and surgical removal curative, and catecholamine-induced hypertensive paroxysms, arrhythmias, or cardiomyopathy can be life-threatening, These aspects justify efforts to diagnose pheochromocytoma in patients with suggestive signs or symptoms, despite the rarity of the tumor. The diagnosis of pheochromocytoma depends on detecting release of catecholamines by the tumor. For this, measurements of urinary excretion of “metanephrines”(thesumoffreeandconjugatednormetanephrineand metanephrine)andofvanillylmandelicacid(ahepaticend-productof norepinephrine metabolism) often are used.

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CNS I

Muscle ,S,;

-1,

D J

YOHIMBINE

NE

Bloodstream Figure 6-7 Principles of the clonidine suppression and yohimbine challenge tests. Both drugs traversethe blood-brain barrier toaffectthefunctions of a2adrenoceptors inthebrain,withsubstantial effects on sympathetic nervous system (SNS) outflows. In addition, both drugs affect the functions of a2-adrenoceptors on sympathetic nerve terminals.

Some hypertensive patients can have high rates of excretion of these catecholamine levels without havinga metabolites or highplasma pheochromocytoma, for example as a result of anxiety. Clonidine suppression (60,61). testing decreases the frequency of false positive results In this test (Figure 6-7), blood pressure is measured and antecubital venous blood sampled before and threehours after oral clonidine administration decreases plasma (usually 300 pg).Clonidinenormallysubstantially norepinephrine levels; however, patients with pheochromocytoma who have

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ongoing secretion of norepinephrine by the tumor have a failure of clonidine suppression of plasma norepinephrine. This therefore constitutes a positive test result. Glucagon Stimulation Test

Clonidine suppression testing does not decrease the likelihood of falsenegative results. This problem has led to various pharmacological stimulation tests, with measurements of blood pressure after administration of drugs that stimulatecatecholaminesecretion by thetumor.Massivesecretionof catecholamines can result, with disastrous consequences. Glucagon administration at a low dose (1 mg) given as an i.v. bolus seems relatively safe, andpatientswithpheochromocytomaoftenhavelargeincreases in plasma norepinephrine levels that support the diagnosis (61). Even this test, however, can yield false-negative results, especially in patients with familial pheochromocytoma, such asin von Hippel-Lindau disease ormultipleendocrineneoplasiatype2A.Probablythemostsensitive biochemical test for pheochromocytomais measurement of plasma levels of free metanephrines (62,63); however,few laboratories have the capability to carry out this difficult assay. Yohimbine Challenge Test

Patients with established hypertension often have exaggerated increments in blood pressure or total peripheral resistance after administration of any of a varietyofvasoactivedrugs,includingnorepinephrine.Excessivepressor responsiveness in hypertensives probably results from a complex combination of pre-synapticandpost-synapticfactors.Mechanismsofpre-synaptichyperresponsiveness include increased sympathoneural outflow, abnormal processing of baroreflex afferent information, or overexpression of centrally determined emotionalorbehavioralreactions.Mechanisms of post-synaptichyperresponsiveness include altered vascular geometry, microvascular rarefaction, altered vascular smooth muscle excitation-contraction mechanisms, deranged localgenerationofvascularrelaxantorstimulantfactors,andaltered adrenoceptornumbersorfunction.Moststudieshavenotassessed simultaneously more than one of these processes. One way to do this is by a “yohimbine challenge test.” In this test, the a2-adrenoceptor antagonist yohimbine is given as a bolus (0.125 m g k g over 3 minutes),followed by aconstanti.v.infusion(0.001mg/kg/minfor12 minutes). Yohimbine releases norepinephrine from sympathetic terminals, both via increases in sympathetic neural outflows and by blockade of inhibitory a 2 adrenoceptor on sympathetic nerves (Figure6-7).

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Combinedassessmentsofneurohormonalfactorsandhemodynamic responses to adrenergic drugs can improve the accuracy of identifying patients withanaugmentedsympathoneuralcontributiontobloodpressure.The combination of high baseline levels of norepinephrine and plasma renin activity, alargedepressorresponsetoclonidine,andalargepressorresponseto yohimbine may identify patients with an increased sympathoneural contribution to blood pressurebetter than does any of these measuresin isolation (64,65). Among hypertensives, pressor and plasma catecholamine responses to yohimbine are distinctly bimodal. An identifiable subgroup have both large pressorresponsestoyohimbineandlargeresponsesofarterialplasma norepinephrine levels. Patients in this subgroup typically report yohimbineelicited anxiety, panic, or emotional feelings similar to those experienced at sometime in thepast.Amongyoungpatientswithborderlineormild hypertension, some have normal pressor responses and normal responses of arterial norepinephrine levels during yohimbine infusion; some excessive pressor responses for a normal increment in plasma norepinephrine; and some excessive increments in plasma norepinephrine levels, with pressor responses appropriate for the increases in norepinephrine levels. Thus, the yohimbine challenge test may distinguish patients with pressor hyper-responsiveness due to increased sympathetically-mediated norepinephrine release from patients with pressor hyper-responsiveness due to increased post-synaptic responsiveness for a given amount ofnorepinephrine release. One may also examine vascular responses to endogenously released norepinephrine by measuring blood pressure and plasma norepinephrine during infusion of tyramine. This sympathomimetic amine displaces norepinephrine fromvesicles in sympatheticterminals,andsomeofthedisplaced norepinephrine enters the extracellular fluid and stimulates adrenoceptors on vascular smooth muscle cells, evoking vasoconstriction and increased mean arterial pressure. Patientswithexcessivepressorresponsestotyraminecanhave upregulated adrenoceptors, decreased baroreflex sensitivity, increased arteriolar wall:lumen ratios, or various combinations of these changes. Patients with sympathetic neurocirculatory failure associated with the Shy-Drager have markedincreases in blood pressure during yohimbine infusion, in contrast to patients with peripheral autonomic failure who have decreased or absent sympathetic terminal innervation. Thus, yohimbine challenge testing provides a relatively simple tool to distinguish among types of chronic, primary autonomic failure. In a patient with suspected Shy-Drager syndrome, yohimbine should be given at a low dose and with caution, due to the likely large pressor response.

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Ganglion Blockade

One can induce temporary blockade of sympathetic and parasympathetic ganglionicneurotransmissionpharmacologically,usingtrimethaphanor pentolinium. In healthy adults, these drugs produce orthostatic hypotension, dry mouth,conjunctivalvasodilation,bladderatony,decreasedgastrointestinal motility, increased pulse rate, and decreased pulse pressure. Plasma levels of norepinephrine decrease, and peroneal skeletal sympathetic traffic can disappear entirely. In contrast, plasma epinephrine levels remain about the same. Performance of the Valsalva maneuver during ganglion blockade produces progressive declines in blood pressure during Phase I, with an absence of the usual overshoot in systolic pressure during Phase IV, mimicking the pattern in sympathetic neurocirculatory failure, and with an absence of heart rate changes in both phases, mimicking the pattern in parasympathetic or baroreflex failure (66). Pentoliniumsuppressiontesting in thediagnosticevaluationof pheochromocytoma has the same rationale as clonidine suppression testing. In patients with pheochromocytoma, ganglion blockade with pentolinium fails to suppress plasma norepinephrine levels (67). Isoproterenol

In the evaluation of patientswith chronic fatigue syndrome, fibromyalgia, or predisposition to neurocardiogenic syncope, isoproterenol can be infused during tilt table testing, in order to determine if the patient has a predisposition to neurally mediated syncope. Isoproterenol infusion during tilting, however, also increases the probability of false-positive results. Isoproterenol infusion normally does not increase plasma epinephrine levels-indeed,epinephrinelevelstendtodecrease (68). Inpatientswith functional neurocirculatory syndromes, however, isoproterenol administration can produce excessive increases in pulse rate, associated with high plasma epinephrine levels (69). For instance, in the hyperdynamic circulation syndrome, resting tachycardia, labile, predominantly systolic hypertension, and increased heartrateresponsivenesstoisoproterenolareassociatedwithincreased catecholaminelevelsatrestandduringprovocativemaneuvers(70). RAdrenoceptor blockers or benzodiazepines ameliorate the syndrome. It is unclear whether patients with this syndrome havean increased frequency of subsequent development of established hypertension. Onemayspeculatethatevocationofadrenomedullarystimulation associated with a panidanxiety response, instead of the usual adrenomedullary inhibition, explains the increased sensitivity of isoproterenol infusion as an adjunct to tilt table testing.

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Other

Cardiac autonomic blockade One can determine the “intrinsic rate” of the heart by administration of atropine to block cholinergic muscarinic receptors and propranolol to block Badrenoceptors. In patients with absent cardiac vagal innervation, one would expect a failure of atropine to increase heart rate, and in patients with absent sympathetic innervation (or absent B-adrenoceptors), one would expect a failure of propranolol to decrease heart rate. Tyramine stimulation test Intravenous infusion of the sympathomimetic amine, tyramine, displaces norepinephrinefromvesicularstores in sympatheticnerves.Someofthe norepinephrineexitstheterminalsandbinds to adrenoceptors on vascular smooth muscle cells. This increases total peripheral resistance to blood flow and thereby increases blood pressure. The pressor response to tyramine therefore requires synthesis and vesicular storage of norepinephrine, post-synaptic aadrenoceptors, and intact intracellular mechanisms for excitation-contraction coupling in vascular smooth muscle cells. The arterial baroreflex buffers the pressor response. Patientswithperipheralautonomicfailureduetodiffuselossof sympathetic vascular innervation therefore have a failure to increase blood pressurenormally in responsetotyramine;becauseofdenervation supersensitivity, they have excessive responses to exogenous norepinephrine. Patientswithmultiplesystematrophyandpresumablyintactsympathetic vascularinnervationhaveaugmentedresponsestobothtyramineand norepinephrine, because of deficient baroreflex function (7 1,72).

NEUROPHYSIOLOGICAL TESTS Sympathetic Microneurography

By recording pulse-synchronous bursts of nerve traffic in a peripheral nerve, such as the peroneal nerve, one can obtain neurographic information about post-ganglionic sympathetic activity directly in skin and skeletal muscle in humans. Underrestingconditions,theskinandskeletalmusclecontribute relatively little to overall circulatory regulation; however, cutaneous and skeletal musclesympatheticactivityreflectprocessesthatproducesystemic neurocirculatorychanges(Figure 6-8). Skinsympatheticactivityincreases

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Metabostpt

+

Central Distress Command

+

-'+

7 Thermostat

Barostat

.- - - ..- - - -

Temperatbre

Arterial

\

I I Baroreceptors

A

l

""""r"""/

I I

+

I

Temperature

Peroneh Nerve

Figure 6-8 Determinants of peroneal skin sympathetic activity (SSA) and skeletal muscle sympathetic activity (SMSA). Different homeostats regulate sympathetic outflows to theskinandskeletalmusclevasculature. SSA includesboth sudomotor and vasomotor outflow. SMSA is especially dependenton baroreflex function (bloodpressure, BP, andcardiacfillingrelatedtobloodvolume, BV) and SSA to thermoregulatoryfunctionandemotionaldistress.Theperonealnerveisusedmost often, because of itsposition close to the skin surface, anatomic location atthe fibular head, and distance from major blood vessels.

during emotional provocation and exposure to cold, decreases during exposure to warmth, and remains generally unchanged during exposure to hemodynamic perturbationsthatalterbaroreflexactivity. In contrast,pulse-synchronous skeletal muscle sympathoneural activity (SMSA) increases as part of baroreflexmediated patterns of neural activation, such as during changesin blood pressure, cardiopulmonary filling associated with the Valsalva maneuver, and exercise. Sympathetic post-ganglionic activity, both to blood vessels and sweat glands, occurs in bursts (73). The origin of the bursts remains unclear, but preganglionic cell firing appears to drive them. The regulation of burst amplitude, probablyreflectingthenumberofconcurrentlyfiringfibers,occursbya mechanismindependent of theprobabilityofburstfiring.Baroreflex manipulationsaffectburstprobabilitymorethanaverageburstamplitude. Because of the population nature of the firing, measurements of activity in single fibers may not indicate sympathetic neuroeffector activation.

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Whether SMSA increases during psychological stress has been unclear. Relatively recent positive findings (74,75) contrast with earlier negative findings (76,77). Decreased cardiac baroreceptor afferent activity during application of lower body negative pressure (LBNP) rapidly increases peroneal SMSA (78-81), as does decreased cardiacand arterial baroreceptor afferent activity during infusion of nitroprusside (82). Systemic injection of epinephrine also increases SMSA (83), possibly via baroreflex responses to vasodilation. Under baseline conditions, antecubital venous norepinephrine concentrations correlate strongly positively with peroneal SMSA (84-87). In all situations tested so far where SMSA has been found to change, antecubital venouslevelsofnorepinephrinehavebeenfoundtochange in thesame direction. For instance, dietary salt loading tends to inhibit SMSA (88) and to decrease plasma norepinephrine levels (89). Insulin- or 2-deoxyglucose-induced glucopenia increases SMSA (90,91) and plasma norepinephrine levels (92,93). Both SMSA and plasma norepinephrine levels increase with normal aging, and both decrease-despite orthostatic hypotension-during fainting (1 0,94,95). Duringorthostasis,plasmanorepinephrinelevelsand SMSA bothincrease rapidly about 2-fold (96-98). One explanation for the agreement between norepinephrine levels in antecubitalvenousplasmaandperoneal SMSA isthatbothreflect sympathoneuraloutflowstotheskeletalmuscle,andthatreleaseof norepinephrine in skeletalmusclecontributesimportantlytoentryof norepinephrine into the circulation in the body as a whole. In contrast with the suggestionthat SMSA determines arterial levelsofnorepinephrine(99), however, skeletal muscle norepinephrine spillover constitutes only a minor source of the total spillover of norepinephrine into arterial plasma (100,101). More likely, although sympathoneural responses can be heterogeneous during stress,underrestingconditionssympathoneuraloutflows in severalbody regions are regulated to some extent as a unit-e.g., via baroreflexes and medullary“generators”(102-104).Thiscanexplainwhy SMSA correlates positively not only with antecubital venous norepinephrine levels but also with arterial norepinephrine spillover ( 7 9 , cardiac norepinephrine spillover (105,106), pulse rate, and plasma renin activity (84). Several reports have related directly recorded sympathoneural activity to regional norepinephrine spillover. In laboratory animals, nitroprusside-induced hypotensionandphenylephrine-inducedhypertensionproducecorrelated increases in renal sympathetic nerve activity and renal norepinephrine spillover (107-109). In humans, LBNP increases peroneal SMSA proportionately more thanitdoesforearmnorepinephrinespillover(110).Thebasisforthis discrepancy is unknown.

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Pathological conditions such as autonomic neuropathy can obscure or preventvalidmeasurementsof baroreflex-sympathoneural function by microneurography. For example,patientswiththeShy-Dragersyndrome typically have orthostatic hypotension and decreased or absent orthostatic increases in plasma norepinephrine levels, consistent with a central derangement of baroreflexes. Since measurements of sympathetic nerve traffic by peroneal microneurography depend on identification of sympathetic bursts from effects of manipulationsofcardiacfilling(e.g.,breath-holding),afailuretodetect sympathetic traffic could result from absent baroreflexes or from tonically decreased post-ganglionic sympathetic neural outflows. NEUROCHEMICAL TESTS

Historical Overview Biochemical measurements havebeen a mainstay in clinical research and diagnostic evaluation about sympathetic cardiovascular regulation. Soon after the identificationof epinephrine as the vasoactive principalof theadrenalglandaboutacenturyago,andtheapproximatelyconcurrent descriptionoftheprofoundcardiovasculareffectsofsympatheticnerve stimulation, clinical investigators began to attempt to measure sympathoadrenal “activity.” Observations of the effects of surgical sympathectomy, measurements of physiological parameters such as blood pressure and pulse rate responses to stressors, and administration of various drugs that interfere with sympathetic function have all had their day. All had important theoretical and practical limitations. Sympathectomies could only be done in patients with underlying pathologyjustifyingtheoperations,andvaluesfornocardiovascular physiological parameter were correlated specifically with sympathetic nervous traffic. Moreover, since sympathectomy or administration of drugs blocking catecholamineeffectselicitscompensatorychanges in thenumbersof catecholamine receptors or activates other homeostatic systems, studies using these techniques tended to underestimate the sympathetic contribution to values for cardiovascular parameters-i.e., they did not take into account the principle of compensatory activation. Attentionthereforeturnedearlytochemicalmeansforassessing catecholaminergic fkction. Since epinephrine was known to be secreted by the adrenal medulla, and since epinephrine, or a substance closely related to it (originallycalledsympathinandfinallyidentifiedasnorepinephrine),was thought to be released during sympathetic stimulation, attempts to measure endogenous epinephrine levels beganin the early 20th century.

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Bioassaypreparations,suchasusedbyCannon,exploitedthe extraordinarilypotenteffectsofepinephrineoncirculatoryandother physiological parameters. For instance, Cannon and others used the magnitude of the increase in heart rate in animals with denervated hearts to reflect the circulating level of the cardioactive hormone. Abolition of the increasein heart rate in adrenalectomized animals confirmed the hormone’s adrenal source 1(11). Thepotencyofcatecholaminesexplainstheirverylownormal concentrations in the bloodstream. In antecubital venous plasma of resting humans, epinephrine levels can be less than 5 pg/ml, or less than about 30 pmol/L. Early attempts failed to measure endogenous levels of these compounds chemically. Assays for plasma catecholamine concentrations remain difficult, and epinephrine concentrations in arm venous plasma of subjects at rest still strain the sensitivityof current methods. The first chemical method for detecting catecholamines was colorimetric, based on the unusual susceptibility of catecholamines to oxidize, forming a brownish solution, “adrenochrome.” This is why all ampules of epinephrine used clinically contain much higher concentrations of an antioxidant, such as sodium metabisulfite, thanof epinephrine itself. Sinceabout1980,methodsusingliquidchromatography,usually coupled with electrochemical detection (LCEDor HPLC methods) have rapidly gained popularity. Thebasisforelectrochemicaldetection is the same as for the early colorimetric techniques--the tendency of catecholamines to oxidize at very low oxidizing potentials, generating electric current. The compounds of interest are separated by passagethroughahighpressure(highperformance)liquid chromatographic column (hence the designation, HPLC), and the compounds are identified basedon characteristic retention times of standards on the column. LCEDassaysforplasmacatecholaminesalwaysincludeasample preparationsteptopurifythecatecholaminespartially, in ordertoobtain interpretablechromatographicrecordings.Thisstepusually is analumina extraction.Alumina(aluminumoxide)hasthepropertyofbindingtothe hydroxyl groups of catechols under basic conditions and freeing the catechols under acidic conditions. Alumina extraction has proven to be a remarkably simple, reliable, and effective way to purify catechols. The alumina procedure allows detection not only of the catecholamines but also of the precursor of the catecholamines,L-DOPA,which is acatecholaminoacid;ofthecatechol metabolite of norepinephrine, dihydroxyphenylglycol; and of the catechol metabolite of dopamine, dihydroxyphenylacetic acid. Each of these compounds has its own particular source and meaning in the examination of sympathetic “activity” (Figure 6-9).

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I

TYR

oz

TH Tyrosmase

"*'I

B6 L A A A D

VMA

VMA

t MN-S

Figure 6-9 Relationshipsbetweencatecholsandthe synthesis andmetabolismof catecholamines.Theendogenouscatecholsare in boxes. The maincatechol metabolites are inboldboxes. The minor metabolites, dihydroxyphenylethanol (DHPE) and dihydroxymandelic acid (DHMA) are in fineboxes. 3-MT = 3methoxytyrosine; 3-MT-S = 3-methoxytyrosine sulfate; AD = aldehyde dehydrogenase. AR = aldehyde reductase; BH4 = tetrahydrobiopterin; COMT = catechol-O-methyltransferase; DA-S = dopamine sulfate; DHPG = dihydroxyphenylglycol; DHPG-S = dihydroxyphenylglycolsulfate; DOPAC = dihydroxyphenylacetic acid; EPI = epinephrine; LAAAD = L-aromatic-amino-acid = monoamine oxidase; MHPG = decarboxylase; MAO methoxyhydroxyphenylglycol; MHPG-S = methoxyhydroxyphenylglycol sulfate; MN-S = metanephrine sulfate; MN = metanephrine; mPST = monoamine-preferring phenolsulfotransferase; NAAT = neutral amino acid transporter; NE = norepinephrine; NMN = normetanephrine; NMN-S = normetanephrine sulfate; PNMT = phenylethanolamine-N-methyltransferase; SAM = S-adenosyl methionine; TH = tyrosine hydroxylase; U1 = Uptake-l; U2 = Uptake-2; VMA = vanillylmandelic acid; VMAT = vesicular monoamine transporter.

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Plasma norepinephrine Norepinephrine in the bloodstream emanates mainly from networks of sympatheticnervesthatenmeshbloodvessels-especiallyarteriolesthroughout the body and pervade organs such as the heart and kidneys. Because the average caliber of the arterioles determines total peripheral resistance to blood flow, the sympathetic innervation of the smooth muscle cells in arteriolar walls represents a focal point in neural regulation and dysregulation of the circulation. In the heart, sympathetic nerves run alongside the myocardial cells, forming a lattice-like network in close proximity to the capillaries. From the architecture of the sympathetic nerve supply to the heart and blood vessels, one mightpredictanimportantroleofsympatheticnervesinregulationof cardiovascular performance. Most of norepinephrine released from sympathetic nerves does not reach the bloodstream unchanged. The main route of inactivation of endogenously released norepinephrine is by reuptake into the nerve terminals. Considering the sympathoneural origin of plasma norepinephrine, many researchers have used plasma norepinephrine levels to indicate activity of the sympathetic neuronal component of the “sympathico-adrenal system.” Clinicalandlaboratoryevidencehasconfirmedagenerallyclose relationship between plasma levels of norepinephrine and the rate of sympathetic nerve traffic. For instance, patients who have undergone surgical removal of the sympathetic nervous supply to a limb have decreased entry of norepinephrine intotheveinsdrainingthesympathectomizedlimb (33); norepinephrine concentrations in forearm venous blood correlate positively with the amount of directly recorded sympathetic activity in the peroneal nerve (85,112); and during exposure to lower body negative pressure, increases in plasma norepinephrine levels correlate with increases in sympathetic nerve traffic (87). In animals, stimulation of sympathetic nerves evokes release of norepinephrine into the bloodstream (1 13); physical ablation of sympathetic pathways decreases plasma norepinephrinelevels(114);andreflexivechanges in regionalreleaseof norepinephrine into the renal vein correlate positively with reflexive increasesin directly recorded renal sympathetic nervetraffic (1 07). Several factors affect the relationship between plasma norepinephrine levels and sympathetic nerve traffic (Table 6-3). First, the concentration of norepinephrine in the plasma, as that of any substance released into the bloodstream, is dynamic. Plasma norepinephrine levels depend on the rate of release of norepinephrine into the plasma and the rate of removal of norepinephrine from the plasma. Because of the continuous releaseofnorepinephrineintotheplasmaandtherapidremovalof norepinephrine from plasma, the finding of a high plasma norepinephrine level

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does not necessarily indicate a high rateof sympathetic nerve traffic. Alow rate ofremovalofnorepinephrinefromtheplasmaalsocanincreaseplasma norepinephrine levels, with a normal rate of sympathetic nerve traffic. Second,thesympatheticnervoussystemconsistsofmyriadnerve networks throughout the body, and stress responses often include patterned changes in sympathetic nerve traffic to the different organs. The doctrine of primitivespecificity is consistentwiththispatterning,asdiscussed in the chapter about stress as a scientific idea. For blood sampling, most clinicians use the antecubital vein. Since sympathetic nervous activityin the forearm and hand arm influences levels of norepinephrine in antecubital venous plasma, those levels may not detect changes in sympathetic nervous activity elsewhere in the body, especially during stress. Third,onlyasmallproportionofnorepinephrinereleasedfrom sympathetic nerve endings actually reaches the circulation unchanged. Instead, thevastmajority is takenbackup by thenerveterminals,wherethe norepinephrine can undergo metabolic breakdown or vesicular sequestration. Because of this (there are other explanations as well), plasma concentrations of the metabolitesof norepinephrine far exceed those of norepinephrine itself. Until the 1970s, thelowconcentrationsofnorepinephrine in antecubitalvenous plasma in humans under resting conditions (about 200 pg/ml, or 1 nmol/L), strained the limits of available assay methods. The high rate of neuronal reuptake of norepinephrine also means that inhibition of the reuptake process, suchas by atricyclicantidepressant,increasestherateofdeliveryof norepinephrine to the bloodstream for a given rate of release from the nerve terminals. Fourth, any of several endogenous biochemicals-including norepinephrine itself-have the potential to modulate release of norepinephrine from the nerve terminals. In particular, clinical studies have indicated that a2adrenoceptors inhibit norepinephrine release into the bloodstream in the human heart and forearm(1 15). Disease processes affecting this modulation would alter the plasma norepinephrine level for a given amount of sympathetic nerve traffic. Fifth, although norepinephrine in plasma derives to only a very small extent from the adrenal gland under resting conditions, the adrenal contribution to plasma norepinephrine levels can increase during stress responses. This seems especially the case for plasma norepinephrine responses to glucoprivation. The increases in plasmanorepinephrinelevels in hypoglycemia probably result mainly from marked adrenomedullary stimulation (93). And sixth, some pathological states can release norepinephrine from sympathetic nerve terminals by an aberrant mechanism that differs from the mechanism of release in response to local sympathetic nerve traffic. An example of such a stateis lack of oxygen delivery to a part of the heart muscle as a result of a coronary blockage. Disruption of norepinephrine recycling in this setting

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Table 6-3 Limitations of Plasma Norepinephrine to Indicate Sympathetic Outflows

The concentration of norepinephrine in the plasma depends on clearance as well as spillover. Norepinephrineextractionandspilloverarebloodflow-dependent. Stress responses often include patterned changes in sympathetic nerve traffic. Uptake-l activity affects the proportion of released norepinephrine that reaches the bloodstream. of Receptors on sympathetic nerve terminals modulate the rate of release norepinephrine for a given amount of sympathetic nerve traffic. The adrenal contribution to plasma norepinephrine levels can change during stress responses. Some pathological states and drugs release norepinephrine from sympathetic nerve terminals by a non-exocytotic mechanism.

greatly increases the net rate of leakage of norepinephrine from storage sites in theterminals,andsomeoftheaxoplasmicnorepinephrineentersthe bloodstream. These considerations do not invalidate plasma norepinephrine levels in arm venous blood in diagnosis, treatment, or prognosis in neurocardiology. One must interpret plasma norepinephrine levels carefully, however, keepingin mind the purpose of the test, the characteristics of the patient, the possible interacting effects of medications, and the aforementioned other factors that can influence the obtained results. In virtually all organs, some of the released norepinephrine enters the venousdrainage. In most,therateofnorepinephrinespilloverintothe bloodstream exceeds the rate of removalfrom the bloodstream. This means that the venous concentration exceeds the arterial concentration--i.e., that there is an arteriovenous increment in plasma norepinephrine levels. An exception is in the heart, which removes such a large proportion of norepinephrine in the coronary arterial blood to the myocardium that the arteriovenous increment in plasma norepinephrine levels across the heart can be zero, despite substantial spillover of norepinephrine into the cardiac veins. Some drugs alter the state of activity of effector cells indirectly, by altering the extent of receptor occupation by released norepinephrine. For instance, a study about effects of the classic B-adrenoceptor agonist and vascular relaxant, isoproterenol, found that the drug could cause delayed constriction of

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blood vessels (1 16). This effect probably resulted from isoproterenol-induced occupation of 8-adrenoceptors on sympathetic nerve terminals in the bioassay preparation. Occupation of neuronal 8-adrenoceptors increases norepinephrine release, and released norepinephrine causes vascular constriction by binding to a different class of adrenoceptors, a1-adrenoceptors, on the effector cells in the blood vessel walls. Thus, even though isoproterenol does not stimulate aladrenoceptors at all, in intact organisms isoproterenol can act indirectly as an a1-adrenoceptor agonist, via increased norepinephrine release from sympathetic nerve terminals. Norepinephrinecaninhibititsownrelease,byoccupying a2adrenoceptors on sympathetic nerve endings and in the brain. Stimulation of a2-adrenoceptors by the anti-hypertensive drug clonidine (CatapresTM) produces correlated decreases in blood pressure and in plasma norepinephrine levels. The fall in blood pressure probably depends on both inhibition of sympathetic neural outflows from the brain and on stimulation of a2-adrenoceptors on sympathetic nerve endings. A lack of suppression of plasma norepinephrine levels after clonidine administration constitutes a positive finding in the diagnostic evaluation of pheochromocytoma, a tumor that releases catecholamines and constitutes a rare but curable cause of high blood pressure, as discussed in Chapter 8. Also as discussed in that chapter, the combination of a high plasma norepinephrine level and a large fall in blood pressure in response to clonidine may identify patients with “hypernoradrenergic hypertension” more accurately than either measure alone. Intravenous infusion of the a2-adrenoceptor blocker yohimbine acts in the brain to increase sympathetic neural outflows and in the periphery to block a2-adrenoceptors. Neurocardiologists have used yohimbine challenge testing to determine whether a patient has releasable norepinephrine stores and therefore has intact sympathetic innervation. Yohimbine challenge testing can also reveal excessive norepinephrine release in the hearts of patients with psychosomatic disorders and non-coronary chest pain. Theindirectlyactingsympathomimeticamines,amphetamines(e.g., dextroamphetamine, DexedrineTM) and tyramine, release norepinephrine from sympathetic nerve endings by displacing norepinephrine from storage vesiclesin sympatheticnerveterminals.Thesedrugsthereforeincreaseplasma norepinephrine levels (1 17). Foodstuffs such as hard cheeses contain tyramine. Dietary tyramine normally does not affect norepinephrine release or blood pressure, because of metabolicbreakdownoftyraminebymonoamineoxidase (MAO) inthe gastrointestinaltract. In patientstakingan MAO inhibitor,tyramineand norepinephrine avoid this metabolic breakdown. Paroxysmal hypertension can result-a phenomenontermedthe“cheeseeffect” (1 18).Becauseofthe

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susceptibility to severe hypertension due to the cheese effect, MAO inhibitors have not had wide usage as antidepressants, despite their clinical efficacy. a-MethylDOPA (AldometTM) isaneffectivedrugforhighblood pressure. In sympathetic nerves and in the brain, a-methylDOPA undergoes conversion to a-methylnorepinephrine, and a-methylnorepinephrine produced in the brain inhibits sympathetic neural outflows by stimulating a2-adrenoceptors, thereby decreasing plasma norepinephrine levels. Other drugs alter norepinephrine release by effects on the rate of synthesis of catecholamines or the rate of degradationby enzymes in sympathetic nerve terminals.a-Methyltyrosine (DemserTM) depletesnorepinephrinestores by so blockingtherate-limitingenzyme in catecholaminebiosynthesis,and repeated administration of a-methyltyrosine decreases plasma norepinephrine levels. Reserpine inhibits uptake of catecholamines from the cytoplasm into the storage vesicles in sympathetic nerve terminals. By blocking vesicular uptake of dopamine, reserpine decreases synthesis of norepinephrine from dopamine, and by blocking reuptake of norepinephrine that leaks from the vesicles back into the cytoplasm, reserpine also prevents recycling of vesicular norepinephrine. The combinationofblockadeofnorepinephrinesynthesis,blockadeof norepinephrine reuptake, and the high rate of leakage of norepinephrine from storagevesiclesdepletesnorepinephrinestores,eventuallydecreasing norepinephrinereleaseandplasmanorepinephrinelevels.Depletionof norepinephrinestores in sympatheticnervesexplainstheeffectivenessof reserpine in treating high blood pressure. Clinicians rarely prescribe reserpine anymore, however, because of a common and severe side effect: depression. The phenomenonofreserpine-induceddepressionsupportsthe“catecholamine theory” of depression, which posits that depression results from depletion of monoamines (serotonin, dopamine, or norepinephrine) in the brain. Reserpine does not decrease norepinephrine levels until extensive depletion of the vesicular norepinephrine stores has occurred. Immediately after reserpine administration, plasma norepinephrine levels remain unchanged; however, plasma levels of other catechols change markedly, as discussed below.

Plasma norepinephrine kinetics Theconcentrationofnorepinephrine in plasmareflectstwohighly dynamic processes-release of norepinephrine into the plasma and removal of norepinephrine from the plasma. The kinetic term, “spillover,” refers to the appearance rate of a substance continuously released into the plasma, and “clearance” refers to the volume of plasma emptied of that substance per unit time. The plasma level of norepinephrine does not indicate norepinephrine spillover or clearance, only their net result.

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Kinetically, the concentration of norepinephrine in arterial plasma (NEa, in units such as nmol/L) is determined by the ratio of the spillover rate of norepinephrine into the arterial plasma (in units of nmol/min) and the clearance of norepinephrine from the arterial plasma (in units of L/min): NEa = Spillover / Clearance The rate of norepinephrine spillover into arterial plasma has also been termed “total body spillover” of norepinephrine. One can use a tracer kinetic method to estimate the rate of entry of norepinephrine into the plasma. From the equation, the spillover equals the concentrationtimestheclearance.Onecancalculatetheclearanceof norepinephrine from the plasma by measuring the concentration of a tracer amount of radioactive norepinephrine during infusion of the tracer. If a high plasma norepinephrine level resulted from a high rate of entry of norepinephrine intotheplasma,then ifa tracer amount of tritiated norepinephrine (3Hnorepinephrine) were infused intravenously, the arterial concentration of 3Hnorepinephrine would be lower than if the high plasma norepinephrine level resulted from decreased clearance of norepinephrine from the plasma. At a given infusion rate, the more rapid the clearance, the lower the plateau concentration of 3H-norepinephrine. The clearance of norepinephrine from arterial plasma can therefore be calculated from the infusion rate of 3H-norepinephrine (in counts of radioactivity per minute, or cpm/min) divided by the plateau concentration of 3H-norepinephrine (in counts of radioactivity per milliliter, or cpm/ml) in the plasma. Healthy people release about 0.3-0.5 micrograms per minute (1.7-3.0 nmoledmin) of norepinephrine into arterial plasma. This rate is too low for norepinephrine in the plasma to exert hormonal effects. In earlystudiesoftracernorepinephrinekinetics,therateof norepinephrine spillover into antecubital venous plasma, as opposed to arterial plasma, was used to estimate “total body” norepinephrine spillover; however, during intravenous infusion of 3H-norepinephrine, tissues of the arm remove about 1/2 ofthelabelledcatecholamine in thearterialplasma, so that norepinephrine clearance calculated from the arterial concentration of 3Hnorepinephrine averages about 1/2 that calculated from antecubital venous 3Hnorepinephrine. Thus, norepinephrine clearances based on samples of antecubital venousbloodoverestimatenorepinephrineclearancesfromarterialblood. Because of the usually small arteriovenous increment in plasma norepinephrine concentrations in the forearm, these findings also indicate substantial release of norepinephrineintothecirculationfromsympatheticnerves in thehuman forearm.

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Withoutotherneurochemicalinformation,onecannotdistinguish increased arterial norepinephrine spillover due to increased sympatheticallymediated norepinephrine release from increased spillover due to decreased neuronal reuptake of norepinephrine. During mental challenge (such as playing a video game), total body norepinephrinespilloverincreasessubstantially,andtheincrementrelates directly to the magnitude of the increases in blood pressure and in the cardiac output (1 19). In contrast, antecubital venous norepinephrine levels can fail to increase and therefore can be unrelated to the systemic hemodynamic response. If one ignored the effects of a stressor on norepinephrine clearance, one could reach erroneous conclusions from antecubital venous norepinephrine levels about the contribution of sympathetic activation to the cardiovascular responses. Manystudieshavenotedthatplasmanorepinephrineconcentrations increase with increasing subject age (120). Directly recorded skeletal muscle sympathetic activity also increases with subject age(1 12,121). Because of patterning of sympathetic nervous responses in different organs during exposure to stressors, assessments of arterial norepinephrine spillover can fail to detect changes in sympathetically-mediated norepinephrine release in particular organs such as the heart, kidneys, and gut. This limitation would not be important for stress responses involving diffuse, directionally similar changes in sympathetic nerve traffic in different organs but would be important in stress responses involving differential and heterogeneous changes in nerve traffic, as occurs after eating a meal, during exposure to altered environmental temperature, and possibly during “defense” responses. Measurements of regional norepinephrine spillover avoid the lack of sensitivity and specificity of measurements of arterial or “total body” spillover. Assessment of regional norepinephrine kinetics distinguishes clearance from spilloverasfactorsdeterminingarteriovenousdifferencesinplasma norepinephrine levels in an organ. Themostcommonapproachformeasuringregionalnorepinephrine spillover uses intravenous infusion of 3H-norepinephrine, with measurements of regional blood flow and of arterial and regional venous plasma concentrations of total and tracer-labelled norepinephrine. This approach offers the potential for examining simultaneously norepinephrine spillovers in more than one organ; however, the method entails potentially large errors of measurement. One may view the regional spillover rate of norepinephrine as the sum of twoprocessesthatdeterminethearteriovenousdifference in theplasma norepinephrine concentration. The first is the rate of release of norepinephrine into the circulation within the organ, and the second is the rate of removal of norepinephrine from the circulation within the organ. If these two processes balancedeachotherexactly,thearteriovenousdifference in theplasma

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norepinephrine concentration would be zero. If norepinephrine were released into thecirculationwithintheorgan,butnoneofthenorepinephrineinthe circulationwereremoved,thenthearteriovenousincrementintheplasma norepinephrine concentration (multiplied by the regional plasma flow) would equal the regional spillover rate. If no norepinephrine were released into the circulation within the organ, but the organ removed a proportion of circulating norepinephrine,thentheregionalspilloverratewouldbezero,andthe proportionatearteriovenousdecrement in theplasmanorepinephrine concentration(multipliedbytheregionalplasmaflowandthearterial norepinephrineconcentration)wouldequaltheregionalremovalrateof circulating norepinephrine. Thus, the regional spillover rate of norepinephrine is the sum of the arteriovenous production rate of norepinephrine and the removal rate of norepinephrine. These relationships have several implications: (1) Regional norepinephrine spillover increases when regional plasma flow increases, unless regional extraction of arterial norepinephrine decreases correspondingly; (2) Regional norepinephrine spillover relates only indirectly and complexly to the regionalvenousnorepinephrineconcentration;and (3) In thepresenceof substantial regional removal of circulating norepinephrine, the arteriovenous increment in plasma norepinephrine levels, multiplied by regional plasma flow, underestimates regional norepinephrine spillover. of The tracer kinetic method has been used to identify abnormalities regional norepinephrine spillover in several cardiovascular diseases, including essentialhypertension,congestiveheartfailure,andautonomicfailure,as discussed in later chapters. If some of endogenouslyreleased norepinephrine were removedwithin the organ before the norepinephrine entered the venous drainage, then the regional spillover calculated from the above equations would underestimate the actual rate of entry of the norepinephrine into the bloodstream within the organ. This sort of problem applies not only within an organ, where release sites and removal sites can be viewed as arranged in series, but also among organs in portal systems where the organs are arranged in series, such as in the splanchnic portal vascular bed, where blood from the gut enters the liver via the portal vein before the blood enters the general circulation. Norepinephrine in urine has a complex source. Only 10% or less of circulating norepinephrine appears unchanged in the urine. A portion of urinary norepinephrine therefore probably derives from renal sympathetic nerves; exactly how much in healthy humans remains unknown. The slow turnover of norepinephrine in heart muscle (replacement halftime probably at least several hours in humans) contrasts markedly with the rapid removal of norepinephrine from plasma (half-time about 1.5 minutes).

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This results mainly from the efficient recycling of norepinephrine stored vesicles in sympathetic nerves.

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Plasma epinephrine Since cells of the adrenal medulla secrete their contents directly into the bloodstream, plasma epinephrine levels generally reflect neural outflow to the adrenal medulla. Thus, increments in adrenomedullary secretion of catecholamines resulting from manipulations of circulatory reflexes or from administration of drugs into the brain correlate with increments in directly recorded adrenal nerve activity (122). Plasma levels of epinephrine are very low in antecubital venous plasma of healthy volunteers at rest-as little as 30 pmol/L-lower than plasma levels of norepinephrine, which normally average about 1 nmolL. Sinceadrenomedullarysecretionincreasesmarkedlyandrelatively selectively in response to hypoglycemia, hemorrhage, asphyxiation, circulatory collapse,anddistress,plasmaepinephrineconcentrationsincrease in these situationsto a greaterextentthandonorepinephrineconcentrations. As discussed in thechaptersaboutstressandaboutstressresponsepatterns, circulatory, metabolic, and visceralstress responses serve to maintain delivery of oxygenandglucosetovitalorgans,andthelargeincreasesinplasma epinephrine levels in response to these stressors reflect the prominence of the adrenomedullary effector. Even mild hypoglycemia that patients do not sense elicits larger increases in epinephrine than norepinephrine levels, and in the relatively benign form of circulatory failure represented by fainting, plasma epinephrine concentrations increase without increases in plasma norepinephrine concentrations (123). Plasma dopamine In the brain, dopamine functions as a neurotransmitter, playing a crucial role in the expression of stereotyped motor behavior. The rigidity, “pill-roll” tremor, and slowness of movement that characterize Parkinson’s disease are thought to result from depletion of dopamine in the brain. Untilrecently,dopamineoutsidethebrainwasconsideredonlyasa biochemicalintermediate in theproductionofthebody’sothertwo catecholamines,norepinephrineandepinephrine(adrenaline).Dopamine circulates at plasma concentrations about those of epinephrine, but because of the much lesser potency of dopamine than of epinephrine, circulating dopamine does not act as a hormone; and stressors that elicit release of norepinephrine from sympathetic nerves produce much larger increases in plasma norepinephrine

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than in plasma dopamine levels. Thus, dopamine in the periphery does not appear to function as a neurotransmitter either. Meager understanding about the sources and clinical significance of plasma dopamine therefore contrasts with rather clear understanding about those of plasma epinephrineand norepinephrine.

Plasma dopamine sulfate In humans,atleast 95% ofdopamine in plasmacirculates in sulfoconjugated form (124). Accordingtoonesuggestion,conjugatedcatecholaminesreflectand provide a marker of long-term sympathetic nervous system “tone” (125), with dopamine sulfate functioning physiologically as a precursor of norepinephrine (126). According to another notion, dopamine sulfate has a mainly dietary source,becauseingestionofastandardmealoroffoodstuffswithhigh monoaminecontents(e.g.,bananas)produceslargeincreases in plasma dopamine sulfate levels (127,128). According to a third, plasma dopamine sulfate derives from intravascular sulfoconjugation, because dopamine infusion produces large increases in plasma dopamine sulfate levels (129), and platelets contain abundant phenolsulfotransferase(1 30). We have suggested that, rather than dopamine sulfate levels reflecting “integrated”sympathoadrenalactivity,metabolicbreakdownofdietary dopamine, or intravascular effects of platelet phenolsulfotransferase, dopamine sulfate could reflect metabolism of dopaminein a “third catecholamine system” (13 1). In this system, dopamine, synthesized from decarboxylation of L-DOPA by L-aromatic-amino-acid decarboxylase in non-neuronal cells, would act locally as an autocrine/paracrine effector and undergo inactivation by sulfoconjugation before it could enter the bloodstream. In a group of experiments, we measured plasma dopamine sulfate levels in selected patient groups and in normal volunteers under several experimental conditions (132). If plasma dopamine sulfate resulted from ordinary dietary constituents, then ingestionof a standard meal would increase plasma dopamine sulfate levels, and prolonged fasting would (depending on the half-time of dopamine sulfate in plasma) decrease plasma dopamine sulfate levels to near zero. We therefore studied normal volunteers after they had ingested a standard meal and after they had fasted overnight and for 4 days, the latter corresponding to more than about 20 plasma half-times of dopamine sulfate (133,134). Ingestion of a standard meal increased dopamine sulfate levels more than 50-fold, with proportionately smaller increasesin plasma levels of L-DOPA and dopamine. The marked stimulatory effect of meal ingestion on plasma dopamine sulfate levels confirmed previous reports (127,135).

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BecauseoftherelativelylowconcentrationsofL-DOPA in food (127,135), the increased plasma L-DOPA concentrations after meal ingestion did not result from L-DOPA itself as a dietary constituent and probably reflected increased L-DOPA concentrations in gastrointestinal cells. This could occur by metabolic breakdown of dietary protein to generate tyrosine and actions of tyrosinase, which is abundant in cereal grain (136), or from increased tyrosine hydroxylation in gastrointestinal nerves or non-neuronal cells (137,138). Other literature has disagreed about effects of meal ingestion on plasma L-DOPA levels (127,135). The results also pointed to substantial non-dietary-i.e., endogenoussources of plasma dopamine sulfate. If plasma dopamine sulfate only reflected dietary intake of foodstuffs containing dopamine or dopamine sulfate, then patients with deficiency of L-aromatic amino acid decarboxylase would have approximately normal plasma dopamine sulfate levels. Instead, such patients had low plasma dopamine sulfate levels, and in the more severely affected patient, in whom L-aromatic amino acid decarboxylase activity was virtually absent, the plasma dopamine sulfate level was less than 1% of normal. Since dopamine infusion into L-aromatic amino acid decarboxylasedeficient patients produced marked increasesin plasma dopamine sulfate levels, plasma dopamine sulfate derives at least partly from circulating dopamine (129); however, the relatively small ratio of dopamine su1fate:dopamine (about 4: 1) in the patients, compared with the much higher ratio in healthy humans (more than 50: l), indicated that at least 90% of the sulfoconjugation of dopamine normally takes place before the dopamine enters the bloodstream, and very little of plasma dopamine sulfateis formed from circulating dopamine. During L-DOPA infusion, increased dopamine sulfate formation depends on synthesis of dopamine in cells. If dopamine sulfate derived exclusively from intracellular dopamine, then during L-DOPA infusion into normal volunteers, there would be a linear relationship between plasma dopamine sulfate and plasma dopamine levels, and the ratio of the increment in plasma dopamine sulfate to the increment in plasma dopamine would equal the ratio of dopamine sulfate to dopamine at baseline. This seemed to be the case. Thus, dopamine sulfate formation depends on synthesis of dopamine from L-DOPA in cells. Analogously, to the extent that sources other than circulating L-DOPA generated intracellular dopamine, at baseline the ratio of plasma dopamine sulfate to plasma L-DOPA would exceed the ratio of the increments during L-DOPA infusion. The ratio of plasma dopamine sulfate to plasma L-DOPA at baseline was about twice the ratio of the incrementin dopamine sulfate to the increment in L-DOPA. Thus, about 112 of plasma dopamine sulfate appears to derive from intracellular synthesis of dopamine after uptake of circulating L-DOPA. The remaining 112 probably derives from intracellular synthesis of L-DOPA.

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Plasma dopamine sulfate does not derive to any important extent from dopamine in sympatheticnerves.Thus,patientswithperipheralautonomic failure or the Shy-Drager syndrome have normal plasma levels of dopamine sulfate (1 39). Moreover, infusion of the ganglion blocker trimethaphan at a dose that virtually abolishes directly recorded post-ganglionic sympathetic nerve traffic (140) and elicits substantial decreasesin plasma norepinephrine levels did not affect plasma dopamine sulfate levels. Finally, infusion of nitroprusside at a dosethatreflexivelyincreasessympatheticnervetrafficandplasma norepinephrine levels (82) did not affect plasma dopamine sulfate levels. These findingsagreewithpreviousreportsaboutsmallorabsentresponsesof dopamine sulfate levels during acute exposure to various stressors (141,142). Mostorgansproducelittledopaminesulfate,asjudgedfrom arteriovenous increments in plasma levels of the compound (143). An exception is the mesenteric organs (137). Patients undergoing gastrointestinal surgery (preparationforwhichalwaysentailsproscriptionofalloralintake)had consistent arterial-portal venous increments in dopamine sulfate levels. The estimated rate of mesenteric dopamine sulfate spillover, 1.18 f 0.3 1 nmol/min, was similar to the mean rate of urinary excretion of dopamine sulfate after 4 days of fasting in normal volunteers (0.93 nmol/min) and about 44% of the meanrateafteranovernightfast.Previouslypublishedvaluesforurinary excretion of dopamine sulfate in non-fasting subjects have averaged about 1.9 nmol/min (144). Thus, most of dopamine sulfate production in the body as a whole appears to derive from conjugation of dopamine in the gastrointestinal tract. About half derives from dopamine synthesized and metabolized after cellular uptake of circulating L-DOPA. Theremaininghalf(about 3.6 nmoledmin)wouldreflectL-DOPA synthesized within the gastrointestinal tract. Assayed concentrations of tyrosine hydroxylase activity (under saturating conditions) in humans average about 0.070nmoles/min/g in stomachtissueandabout0.040nmoles/min/g in duodenal tissue (137). Considering that the mass of the mesenteric organs amounts to several kg, the organs do appear to contain sufficient capacity for tyrosine hydroxylation to account for the estimated rate of local L-DOPA synthesis. The absence of an arteriovenous incrementin dopamine sulfate between the portal and hepatic veins implies that the liver is not an important source of plasma dopamine sulfate. Consistent with this view, post-mortem tissue from human liver expressed the enzyme, phenol-sulfating phenolsulfotransferase (PPST), but not monoamine-preferring phenolsulfotransferase (M-PST). These findings have several potential physiological and pharmacological ramifications.M-PST in mesentericorganscouldcontribute(alongwith catechol-0-methyltransferase and monoamine oxidase) to a “gut-blood barrier,” effectivelydetoxifyingingestedcatecholaminesbeforetheycanenterthe

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Nerves & TH-Containing Cells

Meal

Figure 6-10 Sourcesofplasmadopaminesulfate(DA-S04). 3-MT = 3methoxytyrosine; 3-MT-S = 3-methoxytyrosine sulfate;COMT = catechol-0methyltransferase; DA = dopamine; DOPAC = dihydroxyphenylacetic acid; LAADC = L-aromatic-amino-aciddecarboxylase; MAO = monoamine oxidase;PST = phenolsulfotransferase; TH = tyrosine hydroxylase; TYR = tyrosine.

bloodstream. Thus, oral ingestion of bananas produces little if any increases in circulating levels of unconjugated catecholamines but produces large increases in levelsofdopaminesulfate(145,146);andafteroralingestionof a catecholamine, a major proportion is excreted in the urine in sulfate-conjugated form (147).

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People with polymorphisms of the gene encoding M-PST (148-150), resulting in decreased sulfoconjugation of dopamine, might be susceptible to emetic,cardiovascular,orothersideeffectsofL-DOPAordopamine.In particular, one may hypothesize that hypertensive paroxysms associated with high plasma levels of unconjugated and low levels of conjugated catecholamines in patientswith “pseudopheochromocytoma,” (1 5 1)mayreflectlow gastrointestinal M-PST activity, rendering the patients susceptible to toxic effects of foodstuffs that have high monoamine contents (128). Drugs that inhibit sulfoconjugation of dopamine would be expected to augment actions of L-DOPA, since phenolsulfotransferase inhibition would increase thebioavailability of L-DOPA and interfere with sulfoconjugation of LDOPAitself.Theextenttowhichphenolsulfotransferasecontributesto bioavailability of L-DOPA or to the blood-brain barrier for circulating L-DOPA is unknown. Phenolsulfotransferase could also function to delimit actions of dopamine as an autocrine/paracrine factor in the gastrointestinal tract. Mesenteric organs expressdopaminereceptors(152),andadministrationofdrugsthatalter occupation of dopamine receptors affects bicarbonate secretion and Na+-H+ exchange in thegastrointestinaltract(153), ina mannerconsistentwith gastroprotective actions of dopamine (1 54,155). M-PST in gastrointestinal walls would prevent locally generated dopamine from entering the bloodstream and exerting hormonal effects. Patients with autonomic failure in the setting of Parkinson’s disease can have cardiac sympathetic denervation (156), consistent with the view that in at least some patients, the disease results from a diffuse neurodegenerative process (157). One may speculate that if a subgroup of patients with Parkinson’s disease had not merely nigrostriatal but had diffuse deficiency of dopamine synthesis (158,159), then the fasting, untreated patients would have decreased plasma levelsofdopaminesulfate.Deficientfunctioningof anon-neuronal, gastroprotective, dopaminergic “third catecholamine system” could then help to explain the poorly understood high frequency of gastrointestinal ulceration in parkinsonian patients (1 55,160). The diagram in Figure 6-10 summarizes our current view about the sources and physiological significance of plasma dopamine sulfate levels. First, meal ingestion markedly increases plasma dopamine sulfate levels. This could result from actual ingestion of L-DOPA, dopamine, or dopamine sulfate, from conversion of ingested tyramine to dopamine, from actions of tyrosinase to generate L-DOPA in the gastrointestinal lumen, or from increased release and metabolism of endogenous dopamine in gastrointestinal lining cells. None of these explanations apply to plasma dopamine sulfate detected after an overnight fast. Second, tyrosine generated from breakdown of dietary protein can enter sympathetic nerves or other cells containing tyrosine hydroxylase, resulting in

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production of L-DOPA outside the gastrointestinal tract. Some of this L-DOPA enters the bloodstream, and uptake and decarboxylation of circulating L-DOPA provides a means to generate dopamine sulfate continuously from endogenous dopamine. Third, dopamine sulfate derives to a relatively small extent from circulating dopamine. By this reasoning, in fasting subjects, the rate of entry of dopamine sulfate into plasma should indicate the rate of dopamine production in the gastrointestinal tract. The extent to which dopamine formation in mesenteric organs depends on tyrosine hydroxylation in sympathetic nerves or in nonneuronal cells is currently under study.

Urine dopamine Urine contains relatively high concentrations of free and conjugated catecholamines and catecholamine metabolites. Renal mechanisms determining urinary excretion of these compounds include both glomerular filtration and active secretion by the renal tubular epithelium (161). The predominant free (unconjugated) catecholamine in human urine is dopamine (162). Since in humans the excretion rate of dopamine exceedsby far the rate of delivery of free (unconjugated) dopamine to the kidney, a substantial proportion of dopamine excreted by the kidney must be produced locally. Potential sources include renal dopaminergic nerves, dopamine released from noradrenergic nerve terminals in the kidneys, renal uptake and deconjugation of conjugated dopamine, and renal uptake and decarboxylation of circulating LDOPA. Studies of dopamine excretion after injection of dopamine sulfate have excluded renal uptake and deconjugation of dopamine sulfate in the kidney as a source ofurinary dopamine (163). Theexistenceandfunctionofrenaldopaminergicnerveshavebeen controversial. Renal nerve stimulation increases release of both norepinephrine and dopamine into the renal venous drainage (164), and renal denervation decreasesrenalvenousdopamineconcentrations.Thesefindings,while consistentwithrenaldopaminergicinnervation,donotseparatedopamine released from noradrenergic nerves from dopamine released from the putative dopaminergic nerves.After renal denervation, dopamine secretion continues into the renal venous plasma, although at a decreased rate, and rats with bilateral renal denervation excrete normal amounts of dopaminein the urine (165). These findings question the importance of renal dopaminergic nerves as a source of urinarydopamine,buttheydonotruleoutthepossibilitythatreleaseof dopamine from such nerves can play a physiological role in the kidneys. For at least one function of dopamine in the kidneys, however-sodium homeostasis-evidence presented below supports uptake and decarboxylation of

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circulating L-DOPA as the main source of physiologically active dopamine. Stimulation of renal dopamine production during acute volume expansion does not require intact renal nerves (166). Urinary dopamine derives mainly from renal uptake and decarboxylation of circulating L-DOPA (1 67- 169). Histofluorescence studies of dopamine production in ratkidneyslicesincubated in L-DOPA-richmedium(170), biochemical studies of isolated, perfused kidneys (1 71), and kidney slices (1 72), and micropuncture studies of proximal tubules injected with radioactive LDOPA (173) all have indicated production of dopamine from L-DOPA in proximal convoluted tubular cells of the kidney. Renal dopamine is highly localized to the proximal tubular cells, and production of dopamine from LDOPA occurs mainly in those cells. The production of dopamine from L-DOPA in the tubular cells, and urinary dopamine excretion, does not require renal innervation. For instance, patients with quadriplegia from cervical spinal cord injuryhavenormalurinarydopamineexcretion(174).Renalproductionof dopamine does require Na', apparently co-transported with L-DOPA into the cells. If urinary dopamine were formed from uptake and decarboxylation of circulating L-DOPA, then inhibition of the decarboxylation should decrease urinarydopamineexcretion.Severalstudies, in laboratoryanimalsand in humans, have confirmed thisprediction (1 75- 179). Dietary salt loading increases urinary excretion of dopamine (180-183) and L-DOPA (1 68,181- 183), and interference with conversion of L-DOPA to dopamine can inhibit natriuresis acutely (175,176,184,185). These findings indicate that an increase in the filtered load of sodium activates a homeostatic dopaminergic mechanism involving increased L-DOPA uptake by proximal tubular cells of the kidneys, relatively independently of alterations in renal sympathoneuraloutflow.Inrats,increasedspilloverofL-DOPAintothe bloodstream can explain the increased renal uptake of L-DOPA during dietary salt loading (1 65); however, in humans, this explanation does not suffice (1 68). Increased efficiency of L-DOPA uptake from the tubular lumen would be expected to decrease L-DOPA excretion, and L-DOPA excretion consistently increases rather than decreases during salt loading in humans. One may therefore infer that salt loading increases the efficiency of L-DOPA uptake across the basolateral membrane of proximal tubular cells.

Plasma dihydroxyphenyiglycol (DHPG) Dihydroxyphenylglycol forms from enzymatic breakdown of norepinephrine in the cytoplasm of sympathetic nerve terminals. DHPG in cells diffuses rapidly across the cell membrane into the extracellular fluid and from there into the bloodstream. Liquid chromatographic-electrochemical assays for

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plasma levels of catechols simultaneously measure concentrations of both DHPG and norepinephrine. Since plasma DHPG derives from the metabolism of norepinephrine in the cytoplasm of sympathetic nerves, plasma DHPG has two sources. Most norepinephrine in the cytoplasm comes from continuous vesicular leakage, and a small, variable amount comes from cellular uptake of norepinephrine releasedin response to sympathetic nerve traffic. Thus, most plasma DHPG results from thenetleakageofnorepinephrinefromthevesiclesintothecytoplasm (1 86,187). Since net leakage of norepinephrine from vesicles into the cytoplasm constitutes the main determinant of norepinephrine turnover, plasma DHPG provides an index of norepinephrine turnover, a parameter related to but different from norepinephrinerelease. Some clinical researchers have attempted to compare plasma DHPG and plasma norepinephrine as indices of sympathetic “activity.” Such an attempt misunderstands the clinical meanings of plasma DHPG and norepinephrine levels, which differ because of the related but distinct sources of those levels. Plasma norepinephrine levels provide a better (albeit indirect) index of the release of norepinephrine from sympathetic nerve terminals. Plasma DHPG levels provide a better index of the turnover of norepinephrine in the tissue. Combined measurements of plasma levels of norepinephrine and DHPG can yield unique information about sympathetic nervous function that levels of neitheralonecanprovide.Forinstance,whensympathetically-mediated exocytosisincreases,plasmalevelsofbothnorepinephrineandDHPG increase-the former because a small proportion of released norepinephrine spills over into the bloodstream, the latter because of the increased rate of reuptake of the released norepinephrine. In contrast, for a given rate of norepinephrine release from the nerve terminals, blockade of the reuptake process augments plasma norepinephrine levels and decreases plasma DHPG levels. Conversely, a high plasmanorepinephrinelevelcouldresultfromincreasedreleaseof norepinephrinefromthesympatheticterminalsordecreasedreuptakeof norepinephrine after release. If the plasma DHPG level were also high, this would support increased release;if the plasma DHPG level were low, this would support decreased reuptake. Studies have gone further, using regional spillover rates of norepinephrine andDHPGtoestimatetheratesof most oftheintraneuronalprocesses determining norepinephrine release, reuptake, turnover, and synthesis in humans (187). These estimates indicate a tremendously high exchange rate of amines between the axoplasm and the vesicles; efficient reuptake of endogenously released norepinephrine; and prominent net leakage of norepinephrine from vesicles in the determination of tissue norepinephrine turnover (Figure6-1 l ) .

Chapter 6

Plasma L-DOPA L-DOPAistheprecursorofallthebody’scatecholaminesandthe immediate product of the rate-limiting step in catecholamine biosynthesis, conversion of tyrosine to L-DOPA by the enzyme tyrosine hydroxylase. LDOPA therefore occupies a pivotal position in the function of the effector systems that use catecholamines. In humans, plasma levels of L-DOPA exceed those of norepinephrineby about 10-fold. Until recently it was thought that all the L-DOPA synthesized in sympatheticnerveendingsrapidlyundergoesconversiontodopamine. Traditional concepts about catecholamine biosynthesis therefore do not predict release of L-DOPA from sympathetic nerve endings into the bloodstream. Healthy humans virtually always have an arteriovenous increment of plasma L-DOPA levels in the limbs, heart, head, leg, adrenal gland, and gut. Major sources of L-DOPA levels in arterial plasma appear to be the limbs, lungs, and gut (188). Patientswithsympathectomizedlimbshaveno or reducedregional arteriovenousincrements in L-DOPAlevels(189).Patientswithdiseases associated with loss of sympathetic terminals in the heart have an analogous absence of the cardiac arteriovenous incrementin plasma L-DOPA levels (190); and in laboratory animals, chemical destruction of sympathetic nerve terminals eliminates regional arteriovenous increments in plasma L-DOPA levels in the hindlimb, gut, and kidneys (191). All these findings indicate that plasma LDOPA levels depend at least partly on release of L-DOPA from sympathetic nerves. Acute changes in arterial plasma L-DOPA levels probably can reflect acute changes in the overall rate of synthesis of norepinephrine in sympathetic nerves.Thus, in rats,immobilizationincreasesL-DOPAlevels in arterial plasma within a few minutes, and blockade of catecholamine biosynthesis or of sympathetic nerve traffic prevents these increases (1 92). Nevertheless, in rats, chemical sympathectomy does not decrease arterial plasma L-DOPA levels to zero, andin dogs, chemical sympathectomy does not decrease arterial plasma L-DOPA levels at all. In humans, pure autonomic failure is associated with decreased-but by no means absent-plasma L-DOPA levels. These findings suggest an additional non-neuronal source of plasma LDOPA. The Source of this residual L-DOPA is unknown. Although studies of rats, dogs, and humans have not noted acute effects of ingesting a meal on plasma L-DOPA levels, in our study of normal volunteers, meal ingestion did significantly increase plasma L-DOPA levels (132). Chemical sympathectomy with 6-hydroxydopamine spares both the adrenal medulla and sympathetic ganglion cells, and in both cell types 6-hydroxydopamine increases rates of

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7 DHPG

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5?-

4

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l09 NE

+ OHPG-SO4

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i t

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OS

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-b

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-b

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'

Figure 6-11 Overview of release and turnover of norepinephrine (NE) in cardiac sympathetic nerves. Numbers denote rates, in units of pmol/min. One can estimate the NE turnover rate from the sum of NE spillover and release of dihydroxyphenylglycol (DHPG), dihydroxyphenylglycol sulfate(DHPG-S04), normetanephrine (NMN) and methoxyhydroxyphenylglycol (MHPG). NE turnover normally far exceeds NE spillover, due to substantial metabolism of NE that leaks from storage vesicles into the axoplasm. DA = dopamine; MAO = monoamine oxidase; U1 = Uptake-l; U2 = Uptake-2; COMT = catechol-0-methyltransferase. Modified from a diagram kindly provided by G. Eisenhofer.

catecholamine synthesis. Increased L-DOPA release from adrenomedullary or sympathetic ganglionic cells could partly maintain arterial plasma L-DOPA levels. The possibility of L-DOPA synthesis in non-neuronal cells must also be considered. The at least partial originof plasma L-DOPA from sympathetic nerves, and the fact that L-DOPA is the immediate productof the rate-limiting stepin in regional Lcatecholamine synthesis, lead to the hypothesis that changes

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DOPA spillover into the bloodstream provide an in vivo index of changes in regionalnorepinephrinesynthesis in sympathetic nerves. In every situation examined so far where tyrosine hydroxylase activity changes acutely, plasmaLDOPA levels havebeen found to changein the same direction. Whateveritssources,L-DOPAentersthecirculationcontinuously. Circulating L-DOPA also exits the circulation continuously. After uptake into cells, L-DOPA undergoes metabolism via at least two enzymes-L-aromaticamino-acid decarboxylase (LAAAD, also called L-DOPA decarboxylase, or DDC) and catechol-0-methyltransferase (COMT). LAAAD converts L-DOPA to dopamine. COMT converts L-DOPA to 3-methoxytyrosine. Both LAAAD and COMT figure prominently in the clinical use of LDOPAtotreatParkinson’sdisease.Thecatecholdrugscarbidopaand benserazide inhibit LAAAD outside the brain, and so combinations of L-DOPA with carbidopa (SinemetTM) or with benserazide augment the amount of LDOPA reaching the brain and decrease toxicity resulting from conversion of LDOPA to dopamine outside the brain. COMT constitutes an important part of the “blood-brain barrier” for catechols including L-DOPA. COMT inhibitors (e.g., tolcapine, entacapone) are undergoing clinical testing to determine if they supplement SinemetTM effects by increasing the bioavailability of L-DOPA and the efficiency, smoothness, and duration of delivery of L-DOPA to the brain. Assays of plasma L-DOPA levels can aidin the development of drugs to treat Parkinson’s disease. For instance, just as a DDC inhibitor should increase the ratio of L-DOPA to dopamine in the plasma, compared with the ratio during treatment with L-DOPA alone; aCOMT inhibitor should increase the ratio ofLDOPA to methoxytyrosine in the plasma. BecauseplasmaL-DOPAderivesatleastpartlyfromL-DOPA synthesized in catecholamine-synthesizing cells such as in sympathetic nerves, and because L-DOPA is the immediate product of the rate-limiting step in catecholamine synthesis, clinical investigators have used plasma L-DOPA levels to detect derangement of catecholamine synthesis in a variety of disorders, including tumors and inherited neurological diseases. Neuroblastoma constitutes one of the most common solid tumors of children. By the time of diagnosisof this viciously malignant cancer, the fate of thepatientoftenhasbeensealed.Asthenameofthetumorsuggests, neuroblastoma cells derive from the neural crestin embryological development, and they contain tyrosine hydroxylase. Patients harboring a neuroblastoma have high-sometimes spectacularly high-plasma L-DOPA levels (193,194). So do patients with malignant pheochromocytoma, another tumor of catecholamine-synthesizing cells (193). Malignant pheochromocytoma cells appear to be so undifferentiated that although they can hydroxylate tyrosine to form L-DOPA, they do not decarboxylate L-DOPA efficiently to form dopamine orhydroxylatedopaminetoformnorepinephrine.Patientswithmalignant

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pheochromocytomas therefore may not have high blood pressure, and until examining the tissue pathologically, the clinician may not be able to distinguish the particular form of cancer from others that metastasize early in the clinical course of the disease. In contrast with most other forms of cancer, however, malignant pheochromocytoma is associated with high plasma L-DOPA levels, whereas plasma dopamine and norepinephrine levels can be normal. High plasma L-DOPA levels occur in a third type of cancer, malignant melanoma (195,196), not because the cancer cells contain tyrosine hydroxylase but because they contain tyrosinase, which converts tyrosine to L-DOPA as part of a cascade leading to the pigment, melanin. Tyrosine hydroxylase is vital for normal neurological development. For tyrosine hydroxylase to function, other enzymes must work that promote the synthesis of tetrahydrobiopterin (BHq), an absolutely required co-factor for tyrosine hydroxylase to convert tyrosine to L-DOPA. Genetic mutations of the genes encoding these enzymes typically produce neurological deterioration beginning in infancy and death in early childhood. Low plasma levels of LDOPA can provide a clue to the diagnosis. In contrast, diseases associated with deficient activities of enzymes later in the cascade of catecholamine synthesis, such as of dopamine-0-hydroxylase (DBH), produce a biochemical pattern with high plasma L-DOPA levels and loworabsentlevelsofnorepinephrineorthenorepinephrinemetabolite dihydroxyphenylglycol (DHPG). The buildup of plasma L-DOPA probably resultsnotonlyfromthe low enzymaticactivitybutalsofromincreased tyrosinehydroxylation in sympatheticnerves. A highratioofplasma LD0PA:DHPG occurs in DBH deficiency (197), Menkes disease (198), and familial dysautonomia(1 99). One must distinguish tyrosine hydroxylase activity from tissue content of the enzyme. Acute exposure to stressors increases tyrosine hydroxylase activity rapidly, by phosphorylation of the enzyme. During immobilization stress in rats, plasma L-DOPA levels begin to increase within 1 minute, whereas even after 120 minutes of immobilization, the adrenal content of tyrosine hydroxylase remains unchanged. In contrast, after repeated episodes of immobilization, baseline plasma L-DOPA levels are normal, whereas the adrenal content of tyrosine hydroxylase is increased. One must also distinguish plasma L-DOPA asan index of catecholamine synthesis in sympathetic nerves from plasma norepinephrine as an index of release of norepinephrine from sympathetic nerves. Even maximal stimulation of sympathetic nerves releases only a small proportion of the relatively large vesicular stores of norepinephrinein the nerve terminals. Most of the irreversible loss of stored norepinephrine (norepinephrine turnover) results from net leakage of norepinephrine from the vesicles into the cytoplasm of the nerve terminals, with subsequent metabolism of norepinephrine in the cytoplasm, and not from

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release of norepinephrine in response to sympathetic nerve traffic. In order to maintain norepinephrine stores, the rate of synthesis of norepinephrine must balance the rate of turnover. This explains why the regional rate of entry of LDOPA into the circulation correlates betterwith regional spillover of DHPG, an index of norepinephrine turnover, than with an indices of norepinephrine release, as discussed in the preceding section about DHPG. Plasma L-DOPA appears to have both dietary and non-dietary (189) sources. Regional entry of L-DOPA into plasma in organs such as the heart and skeletalmuscledependsontyrosinehydroxylation in localsympathetic terminals (1 13,190- 192,200,201); however, dietary factors also influence plasma L-DOPA levels (127,132). Thus, the notion that plasma L-DOPA levels reflect “total body” tyrosine hydroxylase activity (200) may be valid only in fasting individuals.

Plasma dihydroxyphenylacetic acid (DOPAC) Ofthesixcatecholsdetectedroutinely in humanplasma-the catecholamines dopamine, norepinephrine, and epinephrine, the precursor LDOPA, and the metabolic breakdown products dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), DOPAC probably constitutes the least well understood, despite the facts that plasma DOPAC levels can exceed those of any of the other catechols, that the concentration of DOPACin human plasma averages about 50 times that of dopamine, and that in human urine, excretion of DOPAC exceeds that all of other catechols combined. DOPAC forms from the metabolism of dopamine by monoamine oxidase (MAO), the same enzymeresponsible for converting norepinephrine to DHPG in sympathetic nerves. An acidic metabolite, DOPAC undergoes active secretion by cells into the bloodstream. Several lines of evidence indicate that plasma DOPAC derives at least partly from metabolism of dopamine in the cytoplasm of sympathetic nerves. For instance, MAO exists as two subtypes, MAO-A and MAO-B. Nerve cells contain only MAO-A, whereas non-neuronal cells contain both MAO-A and MAO-B. Administration of a selective blocker of MAO-B does not produce large decreases in plasma DOPAC levels, whereas administration of a selective blocker of MAO-A decreases plasma DOPAC levels substantially. Plasma DOPAC levels probably relate indirectly to the rate of tyrosine hydroxylation in sympathetic nerves. Conversion of tyrosine to L-DOPA by the action of the enzyme tyrosine hydroxylase occurs slowly, whereas conversion of L-DOPA to dopamine, conversion of dopamine to DOPAC, and release of DOPACfromcellsintothebloodstreamoccurrapidly.Blockadeof catecholamine biosynthesis decreases plasma DOPAC levels to very low values (189), and stressors such as immobilization in rats rapidly increases plasma

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DOPAC levels, with blockade of catecholamine biosynthesis preventing the stress-induced increases (192). Nevertheless, plasma DOPAC also derives partly frommetabolismofdopamineinnon-neuronalcells,suchasinthe gastrointestinal tract (137). Dihydropteridinereductase(DHPR)deficiencyresults in impaired regeneration of tetrahydrobiopterin (BHq), an absolutely required co-factor for tyrosinehydroxylationandthereforeforcatecholaminesynthesis.DHPR deficiency therefore is associated with low plasma DOPAC levels (202). In contrast, Menkes disease and dopamine-R-hydroxylase deficiency exemplify diseases associated with decreased ability to synthesize norepinephrine from dopamine in sympathetic nerves. Tyrosine hydroxylation appears to increase compensatorily in these diseases, and the patients have high plasma DOPAC levels and especially high ratios of plasmaD0PAC:DHPG (197,198). Clinicians can prescribe SinemetTM in any of various combinations of LDOPA and carbidopa. In response to oral L-DOPA treatment, plasma L-DOPA levels can reach 1 microgram per milliliter of plasma, about 500 times that of the L-DOPA normally present in human plasma. In the absence of carbidopa, one would expect the plasma DOPAClevel to increase by about the same extent as the plasma L-DOPA level. At a carbidopa:L-DOPA ratio of 25:100, the carbidopa in SinemetTM appears to inhibit dopamine production outside the brain by more than 95%. Nevertheless, since the plasma DOPAC level increases by about 20-fold, patients taking SinemetTM actually have a substantial increase in the production andmetabolism of dopamine outside the brain. As noted above, in humans MAO exists in two forms, MAO-A and MAO-B. The genes encoding these subtypes exist very close to each other on the X-chromosome. Deficiency of MAO-A presents clinically entirely differently fromthatofMAO-B.WhereasMAO-Bdeficiencyproducesfew if any neurobehavioralconsequences,MAO-Adeficiencyproduces an inherited tendency to violent anti-social behavior (188). Since plasma DOPAC derives mainly from the neuronal metabolism of dopamine, and since MAO-B does not exist in nerves, patients with MAO-A deficiency have very low plasma DOPAC levels, whereas patients with MAO-B deficiency have normal plasma DOPAC levels (203). BecauseoftheneuronaloriginofplasmaDOPACenteringthe bloodstream in the heart, an absence of a regional arteriovenous increase in plasma DOPAC levels supports the occurrence of loss of sympathetic nerve terminals in the heart, such as occurs in some autonomic failure syndromes and in heart transplant recipients.

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Plasma metanephrines The term, “metanephrines,” refers to the 0-methylated metabolites of norepinephrine,epinephrine,anddopamine. Catechol-0-methyltransferase (COMT) catalyzes the methoxylation of the 3-hydroxyl group in the catechol nucleus. The methoxy derivative of L-DOPA is methoxytyrosine, of dopamine methoxytyramine, of norepinephrine normetanephrine, and of epinephrine metanephrine. Inmostcells,themethoxylatedcompounds,whichcontainamine groups, can undergo hrther metabolic breakdown by MAO. Deamination of methoxytyramine yields homovanillic acid (HVA) and of normetanephrine and metanephrine vanillylmandelic acid (VMA) the in liver and methoxyhydroxyphenylglycol (MHPG) elsewhere. Finally, at sites that to date remain unidentified, the non-acidic metabolites, methoxytyramine, normetanephrine,metanephrine,andMHPG,undergoextensivesulfateconjugation. Since COMT exists in non-neuronal cells and in adrenomedullary cells, formation of normetanephrine in the body derives from the extraneuronal uptake and metabolism of norepinephrinereleased from sympathetic terminals and from 0-methylation within the adrenal gland. Because of the efficient reuptake of endogenously released norepinephrine, plasma levels of normetanephrine are much smaller than those of DHPG, the neuronal metabolite of norepinephrine. Although low, extra-adrenal production of normetanephrine provide a unique marker ofextraneuronal metabolism of norepinephrine. Patients with pheochromocytomas virtually always have high plasma normetanephrine or metanephrine levels, reflecting extraneuronal metabolism of norepinephrineorepinephrine in thetumor(62,63,204).Plasmalevelsof metanephrines (normetanephrine and metanephrine) constitute the most sensitive means to detect pheochromocytomas devisedso far. The sensitivity exceeds that ofplasmanorepinephrineandepinephrinelevels,becauseasubstantial proportion of thenorepinephrineandepinephrineproduced in thetumor undergoesmetabolismbyCOMTbeforethecatecholaminesreachthe bloodstream. Thecommonpainkiller,acetaminophen(TylenolTM),resembles normetanephrinestructurally,and in theassayformeasuringplasma normetanephrine levels, acetaminophen in the plasma interferes with the assay. Patientsundergoingbloodsamplingforassaysofplasmalevelsof metanephrines should not take any medications containing acetaminophen for at least 3 days before the test.

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End-products In plasma,cerebrospinalfluid,urine,andbrainmicrodialysate, concentrations of metabolites resultingfrom the combined actions of MAO and COMT on catecholamines exceed by far metabolites resulting from the actions of either enzyme alone. Thus,in human plasma, levels of norepinephrine, the0methylatedmetabolite,normetanephrine,andthedeaminatedmetabolite, DHPG, average less than about 5 nmol/L, whereas levels of the 0-methylated, deaminated metabolites, MHPG and vanillylmandelic acid (VMA), exceed 20 nmol/L. Analogously, plasma dopamine levels normally average less than 0.1 nmol/L, DOPAC levels 10-20 nmol/L, and homovanillic acid (HVA) levels more than 50 nmol/L. PlasmalevelsofMHPGhaveamixedsource.Inratsundergoing infusions of 3H-norepinephrine, Uptake-l blockade with desipramine markedly decreases plasma levels of 3H-DHPG, whereas 3H-MHPG levels decline by slightly over 1/2 (186). This suggests that a small proportion of MHPG in plasma derives from deamination and 0-methylation of norepinephrinein nonneuronal cells, whereas most of plasma MHPG derives from intraneuronal deamination of norepinephrine, release of DHPG, and 0-methylation of DHPG in non-neuronal cells. The rate of conversion of DHPG to MHPG appears to vary among vascular beds, and so the validity of plasma MHPG levels to indicate regional norepinephrine turnover depends on the vascular bed under study. In the heart, relativelylittleMHPG is producedfromDHPG,andthelargecardiac arteriovenous increment in plasma DHPG levels exceeds that of plasma MHPG levels. ClinicalMicrodialysis

Microdialysisallowsdirectsampling of substrateconcentrations in interstitial fluid in vivo. Microdialysis has been used extensively in animal research and has been used in clinical research studies since 1987 (205). In human studies, where use has in general been limited to muscle and adipose tissue, over 200 microdialysis publications have already appeared. Microdialysis is conceptually a very simple technique. A tubular dialysis membrane is introduced into the tissue, and a liquid is perfused that equilibrates by diffusion with the fluid outside the tube. While microdialysis has been demonstrated to be a useful technique in determining interstitial concentrations and changes in these levels of glucose (206-208), glycerol (206,209-212), adenosine (2 13), and amino acids (206,2 1 l), its validity in determination of interstitial catecholamine concentrations has only recentlybeentested in humans(2 14). Microdialysatenorepinephrine

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concentrations in skeletal muscle exceed those in subcutaneous adipose tissue. Concentrations in bothtissuesincreaseduringorthostasis(Goldsteinetal, unpublished observations). Cholinergic “Tone”

Because of the extremely evanescent nature of acetylcholine in the extracellularfluid,nosimplebiochemicaltestexistsforassessing parasympathetic outflows. Upon power spectral analysis of heart rate variability, the power of the high frequency component, corresponding to respiratory sinus arrhythmia, probably reflects cardiac parasympathetic neuroeffector “tone”; however, relationships of this index with indices of cholinergic sudomotor, gastrointestinal, or urinary bladder tone remain poorly understood. Pancreatic polypeptide, gastrin, and insulin Vagalcholinergicmechanismscontributetoreleaseofpancreatic polypeptide,gastrin,andinsulin,consistentwithstimulationofreleaseof gastrointestinalhormones in the“cephalicphase”ofdigestion.Pancreatic polypeptide is secreted from F cells in the islets of Langerhans (A cells secrete glucagon, B insulin, and D somatostatin). Glucoprivation stimulates pancreatic polypeptide secretion (2 15-2 19). Atropine markedly attenuates the response of pancreatic polypeptide levels to insulin (219), and both cardiac high-frequency power and circulating pancreatic polypeptide levels increase after ingestion of a meal or glucose (220,221), supporting the use of pancreatic polypeptide levels as an index of vagal parasympathetic outflow. SYMPATHETIC NEUROIMAGING

Several imaging agents can visualize the sympathetic innervation of the heart. These include 1231-labelled meta-iodobenzylguanidine (MIBG), racemic IIC-norepinephrine, 6-[18F]-fluoro-L-norepinephrine,llC-metaraminol,and llC-hydroxyephedrine. 1231-MIBGscintigraphyhasprovenusefulinevaluatingcardiac sympathetic innervation in autonomic failure (222), including that attending Parkinson’s disease (223-225), familial amyloidotic polyneuropathy (226), and diabetes mellitus (227-232), as well as in several cardiologic conditions (233237). 1231-MIBG scintigraphy has limited resolution and requires a relatively long period of scanning. Cardiac nuclear scanning after injectionof radiolabelled sympathomimetic amines provides only limited information about sympathoneural function, because interference with anyof several processes produces identical decreases in

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myocardial radioactivity after injection of these agents. For instance, the finding ofdecreased1231-MIBG-derivedradioactivity ina patientcouldreflect sympathetic denervation, interference with a neuronal membrane transporter, inefficient sympathetic vesicular transport and storage, accelerated metabolic breakdown or plasma clearance of 1231-MIBG, or uptake of the tracer by nonneuronal cells (238). Moreover, since these nuclear imaging agents are retained without undergoing metabolism by MAO or COMT, they provide little or no information about sympathoneural traffic, the key presynaptic determinant of sympathetic neuroeffector function. The physical half-life of IC-norepinephrine may be too short to evaluate turnover of vesicular stores, and 6-[ 8F]-fluoro-L-norepinephrine(239) has proven difficult to synthesize in a manner suitable for administration to humans and cannot be used to examine conversion of dopamine to norepinephrine. 6-[18F]Fluorodopamine PET Scanning

Positronemissiontomographic(PET)scanningaftersystemic administration of 6 4 8F]fluorodopamine rapidly visualizes tissue sympathetic innervation, especially in the heart (240,241), with excellent spatial resolution. 6-[ 18F]Fluorodopamine acts as a substrate for all the known neuronal and extraneuronal processes of catecholamine uptake, vesicular translocation, release, metabolism, and excretion (242,243). This introduces a potentially important advantage of 6-[1sF]fluorodopamine PET scanning-the ability not only to visualize sites of sympathetic innervation but also to assess different aspects of sympathoneural function. Intravenouslyinfused6-[1sF]fluorodopaminerapidlyexitsthe bloodstream, enters myocardial sympathetic nerves via the Uptake-l transporter, and undergoes translocation into terminal vesicles (Figure 6-12). Thereafter, myocardial 6-[l 8F]fluorodopamine-derived radioactivity declines at a rate that depends partly on post-ganglionic autonomic nerve traffic. Thus, administration of neuropharmacological agents with classic effects on neuronal uptake of catecholamines, post-ganglionic autonomic traffic, or turnover of vesicular amines produce distinctive effects on time-activity curves (TACs) relating myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity to time. The findings lead to the hypothesis that analyses of TACs in patients with neurocardiologicaldisordersmightindicatespecificpathophysiological mechanisms. As discussed in more detail later, patients with pure autonomic failure or Parkinson's disease and sympathetic neurocirculatory failure haveno myocardial 6-[ 18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic nerve terminals. In marked contrast, patients with parkinsonism as part of multiple system atrophy with sympathetic

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SYMPATHETIC NERVE ENDING

I

"G4NQKWC NWE rmmc

SMOOTH MUSCLE CELL

Figure 6-12 Fate of injected 6-[18F]fluorodopamine ([I8F]-6F-DA). Vesicles in sympathetic nerve terminals become radiolabeled. 6F-3MT = 6-fluoro-3methoxytyramine; 6F-DOPAC = 6-fluoro-dihydroxyphenylaceticacid; 6F-HVA = 6fluoro-homovanillicacid; COMT = catechol-0-methyltransferase; MAO = monoamine oxidase; Ves. Upt. = vesicular uptake. neurocirculatoryfailure(theShy-Dragersyndrome)haveincreased6[ 8F]fluorodopamine-derived radioactivity. Since the loss of 6[ 18F]fluorodopamine-derived radioactivitydependspartlyonongoing sympathoneural traffic (244), decreased sympathetic outflow to the heart can explain increased myocardial 6-[ 8F]fluorodopamine-derived radioactivity in patientswiththeShy-Dragersyndrome.Dysautonomiapatientswithout sympathetic neurocirculatory failure have normal myocardial 6[ 8F]fluorodopamine-derived radioactivity and normal cardiac norepinephrine spillover. Recentstudieshavedemonstratedthat 6-[ 8F]fluorodopamine PET scanning can also visualize sympathetic innervation of structures in the head and neck and in the limbs. In the head, the nasopharyngeal mucosa, parotid glands, sublingual glands, and thyroid have high concentrations of 6[ *8F]fluorodopamine-derivedradioactivity. Because of the effective blood-brain barrier for catecholamines, 6-[18F]fluorodopamine PET scanning of the head

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PAF

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SDS

Park+

Figure 6-13 Thoracic positron emission tomographic (PET) scans after injection of 13NH3 or 6-[18F]fluorodopamine (FDA). Shown are PET scans for a normal volunteer, a patient with pure autonomic failure (PAF), a patient with the Shy-Drager syndrome (SDS), and a patient with Parkinson's disease and autonomic failure (Park+). Patients with PAF or Park+ have little or no myocardial 6[ 8F]fluorodopamine-derived radioactivity.

indicates the central nervous system by negative contrast. In the limbs, 6[18F]fluorodopamine-derivedradioactivity concentrationsare especially high in regions corresponding to blood vessels. Indeed, it is possible that some of the circulating 6-[18F]fluorodopamine becomes trapped in blood vessel walls and undergoes metabolism before it can enter the tissue interstitial space. Since 6-[' 8F]fluorodopamine delivery to tissues depends on blood perfusion, expression of6-[ 18F]fluorodopamine-derivedradioactivity for a given amount of perfusion,as indicated by 13NH3 perfusion scanning (245,246), can be especially informative (Figure 6-13). SUMMARY AND CONCLUSIONS

In the evaluation of a patient with suspected dysautonomia, the astute clinician can cull key differential diagnostic information from the medical historyandphysicalexamination.Neurologistsandcardiologistsshould recognize the importanceof measurements of pulse rate and blood pressure with the patient supine and also standing, in order to detect orthostatic hypotension

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and diagnose sympathetic neurocirculatory failure. In patients with sympathetic neurocirculatory failure, orthostatic dizziness and hypotension are worst in the morning, especially after a large breakfast, after showering, or after strainingat stool. Many drugs can produce orthostatic hypotension, mandating a complete and careful review of medications. Impotence often is the earliest symptom of autonomic failure. Physiological,neurochemical,andneuroimagingtestsfacilitate differential diagnosis in patients with a variety of neurocardiologic disorders, including conditions that cannot be differentiated efficiently by the medical history and physical examination. Becauseofthedominanceofthesympatheticnervoussystem in maintaining blood pressure during orthostasis, the evaluation of patients with known or suspected dysautonomia often includes physiological tests based on acute responses of blood pressure to decreased cardiac filling. The most well known manipulation for this testing is the Valsalva maneuver. In sympathetic neurocirculatory failure, theblood pressure decreases progressively during Phase I1 and fails to overshoot during Phase IV. Tilt table testing is often used in the evaluation of patients with a history of orthostatic intolerance or syncope. Eccrine sweating reflects sympathetic cholinergic activation and can be assessed by the thermoregulatory sweattest or QSART. Pharmacological approaches to assess baroreflex-cardiac gain rely on measurements of the extent of change in electrocardiographic R-R interval for the change in systolic blood pressure after bolus i.v. injection of phenylephrine or nitroglycerine. The clonidine suppression and glucagon stimulation tests are used in the evaluation of pheochromocytoma, and the yohimbine challenge test can detect pressor hyper-responsiveness. Skeletal muscle microneurography can be used to evaluate baroreflexmediated alterations in sympathoneural outflows. Neurochemical measurements, however, have been a mainstay in clinical research and diagnostic evaluation about sympathetic cardiovascular regulation. Considering the sympathoneural origin of plasma norepinephrine, many researchers have used plasma norepinephrine levels to indicate “activity”of the sympathetic nervous system. Several factors affect the relationship between plasmanorepinephrinelevelsandsympatheticnervetraffic.Forinstance, norepinephrine can inhibit its own release, by occupying a2-adrenoceptors on sympatheticnerveendingsand inthebrain.Measurementsofregional norepinephrinespilloveravoidthelackofsensitivityandspecificityof measurements of arterial or “total body” spillover. Since cells of the adrenal medulla secrete their contents directly into the bloodstream, plasma epinephrine levels generally reflect neural outflow to the adrenal medulla.

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Dopamine circulates at plasma concentrations about those of epinephrine, but because of the much lesser potency of dopamine than of epinephrine, circulating dopamine does not act as a hormone. In humans, at least 95% of dopamine in plasma circulates in sulfoconjugated form. In humans who have fastedovernight,plasmadopaminesulfatelevelsprobablymainlyreflect metabolism of dopamine produced from endogenous L-DOPA, and the rate of entryofdopaminesulfateintoplasmamayindicatetherateofdopamine production in the gastrointestinal tract. The predominant free (unconjugated) catecholamine in human urine is dopamine.Urinarydopaminederivesmainlyfromrenaluptakeand decarboxylation of circulating L-DOPA. Plasma DHPG provides an index of norepinephrine turnover, a parameter related to but different from norepinephrine release, and combined measurements of plasma levels of norepinephrine and DHPG can yield clinical information about sympathetic nervous function that levels of neither alone can provide. The at least partial origin of plasma L-DOPA from sympathetic nerves, and the fact that L-DOPA is the immediate product of the rate-limiting step in catecholamine synthesis, tyrosine hydroxylation, lead to the hypothesis that changes in regional L-DOPA spillover provide an in vivo index of changes in regional norepinephrine synthesis in sympathetic nerves. High plasma L-DOPA levelsoccur in neuroblastoma,malignantmelanoma,andmalignant pheochromoctyoma. The term, “metanephrines,” refers to the 0-methylated metabolites of norepinephrine, epinephrine, and dopamine. Patients with pheochromocytoma virtually always have high plasma normetanephrine or metanephrine levels, reflecting extraneuronal metabolism of norepinephrine and epinephrine in the tumor. Several imaging agents can visualize the sympathetic innervation of the heart. Probably the most frequently used sympathoneural imaging agentis 1231metaiodobenzylguanidine (1231-MIBG). A potentially important advantage 6-of [18F]fluorodopamine PET scanning is the ability not only to visualize sites of sympathetic innervation but also to assess different aspects of sympathoneural function.

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7 Diseases in Which Activation of Catecholamine Systems Worsens an Independent Pathologic State Selye attributed the existence of a wide variety of common disorders to maladaptive (i.e., excessive or inappropriate) stress responses. Among these disordersheincludedhighbloodpressure,othercardiovasculardiseases, eclampsia, rheumatoid arthritis, inflammatory disorders of the skin and eyes, infections, allergic and hypersensitivity diseases, nervous and mental diseases, cancer,anddiseasesofresistance in general (1). Heemphasizedthatthe development of a disease process requires not only an inciting stimulus but also a somehow ineffective or inappropriate bodily response. Continuing the tradition of Selye, a tenet of modem psychosomatic medicine is thatwhereasactivationofhomeostaticsystemscancounter perturbations of the external and internal environments, maladaptive responses contribut: to tissue damage or disease. Thepresentconceptionabouttheroleoftheautonomicsystems in diseases adopts theview expressed by Peters (2): The disorders encounteredin disease may be regarded as normal physiologic responses to unusual conditions produced by pathologic processes ((2), p. 353). This chapter considers several common situations in which activation of catecholamine systems worsens a largely independent pathologic state. Because of the crucial and ubiquitous role of catecholamine systems in maintaining circulatory homeostasis, virtually every cardiovascular disease state and every medicationused in clinicalcardiologyaffectscatecholaminergicfunction indirectly if not directly. Because several homeostats share the sympathoneural and adrenomedullary effectors, these effectors act in concert with many othersin maintainingcardiovascularperformance.Accordingly,theoccurrence of abnormalcatecholaminergicfunctionrelatesonlyindirectlytoabnormal regulation of any single monitored variable. 421

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CARDIOVASCULAR One may ask why modem treatments in clinical cardiology so often offset, rather than assist, activationof effector systems presumably “designed” to foster homeostasis. Harris (3,4) has considered this apparent paradoxin a discussion of cardiac edema and offers an appealingly straightforward answer, based on the likely determinants of the evolution of stress responses: Cardiac failure is, in nature, a rare event and not likely to have had a perceptible influence on the survival of the species. The mechanismswhichareset in motionin cardiacoedemaaremorelikelytohave evolved to deal with circumstances vital to preservation which are far more commonplace. In which case it may be that, rather by accident, disease of the heart calls up these mechanisms by somehow simulating the circumstances for which they had properly been developed .... Whentheoutputofthediseasedheart becomes diminished, the body responds in exactly the way it has been programmed to function in shock or physical stress. But the programming was designed to service the body during a few hours of physical stress or a few days of traumatic shock. Now it is maintained in action over months or years and an over-retention of saline ensues ((4), pp. 328-329). One can offer an identical argument for the occurrence of hypertension or any other chronic disorder in modem cardiology. These conditions have been irrelevantthroughouthumanevolution, in contrastwithlife-preserving neurocirculatory reflexes. Chronic disorders such as hypertension and congestive heart failure may plague the elderly today, but natural selection has favored the evolution of acute mechanisms of self-preservationin the young ( 5 ) . According to Harris’s concept, the occurrence of chronic cardiovascular disorders in modem civilization has resulted partly from powerful but inappropriate activation of neuroendocrine systems, which worsens an independent pathologic state. The above considerations help explain why alterations in sympathetic nervous system or adrenomedullary hormonal system activity accompany so

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many clinical physiological and pathophysiological situations, several of which receive attention in this chapter; why commonly used drugs in cardiovascular pharmacotherapy act in the nervous system to alter catecholamine concentrations or effects at cardiac or vascular sympathetic neuroeffector junctions; and why neuroendocrine activation can worsen rather than ameliorate cardiovascular conditions. Most information about deleterious effects of activation of catecholamine systems refers to acute or subacute situations, although in some disorders, such as congestive heart failure and hypertension, research has pursued effects of longterm catecholaminergic activation on cardiovascular growth and various aspects of sympathetic neuroeffector function.

Myocardial Ischemia and Infarction Changes inmyocardialsympathoneuralfunctionassociatedwith myocardial infarction can be primary, with augmented cardiac or extra-cardiac norepinephrinereleaseincreasingmyocardialoxygenconsumptionand exacerbating ischemia, or can be secondary, with recruitment of cardiac and extra-cardiac sympathetic nervous system outflows that maintains cardiovascular performance. The fate of the patient depends on the balance of these beneficial and harmful effects (Figure 7-1). Because of these possibilities, which are not mutuallyexclusive,separatingpathologicfrombeneficialincreases in sympathetic activity in the management of patients with myocardial infarction requires careful clinical judgment. The frequency of myocardial infarction varies during the day, with the peak incidence early in the morning. Since plasma catecholamine levels also peak at this time,many investigators have speculated that increased sympathetic nervous or adrenomedullary hormonal outflows in the morning contribute to the circadian variation in the frequency of myocardial infarction. Consistent with this hypothesis, patients treated with R-adrenergic blockers do not have an increased morning incidence of myocardial infarction (6). Effects of coronav occlusion on sympathoneural function It is generally accepted that cardiac sympathetic outflow increases in responsetocoronaryocclusionandacutemyocardialinfarction.Coronary occlusionrapidlyandmarkedlyimpedesventricularfunction,andatrial distention due to decreased ventricular compliance would be expected toincrease cardiacefferentsympatheticnervoussystemtrafficandthereforecardiac norepinephrine spillover. In laboratory animals, coronary occlusion increases both afferent and efferent cardiac sympathetic activity (7,8). Whether these

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-\ Arrhythmogenesis

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Infarction

I CoronaryOcclusion I Figure 7-1 Beneficial andadverseeffectsofsympatheticnervoussystem activation in acute myocardialinfarction.Sympatheticactivationincreases perfusion of vital organs, via increased cardiac rate and contractility and increased peripheralvascularresistancein the skin, skeletalmuscle,kidneys, and splanchnic beds; however, sympathetic activation also increases myocardial oxygen consumption (MV02) and decreases thresholds for arrhythmias. Either of the latter processes can precipitate a lethal positive feedback loop.

increases reflect compensatory activation to maintain cardiac performance or responses to coronary occlusion or myocardial anoxia is unknown. Acutemyocardialinfarctioncanalsoelicitvagaldepressorand sympathetic excitatory reflexes, by stimulation of vagal and sympathetic afferent fibers (7,9). A sympatheticexcitatorycardio-cardiacreflex (10,ll) would increase the likelihood of a neurocardiac positive feedback loop (12), which could easily play a role in the mechanism of sudden death during myocardial ischemia.

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pa," Homeostats Anxletv I Cardrac NocIceprors

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Figure 7-2 Mechanisms of sympathetic nervous system activation in coronary ischemia.

Perhapssurprisingly,duringmyocardialischemia,cardiacreleaseof norepinephrine does not necessarily increase(1 3,14). Silent myocardial ischemia is associated with increased cardiac norepinephrine spillover, but this may reflect decreased neuronal reuptake of norepinephrine (1 5 ) . Patients with unstable angina have increased cardiac norepinephrine spillover at rest (16), and the occurrence of angina selectively augments the exercise-induced increase in cardiac norepinephrine spillover (17). These findings suggest that increases in cardiac sympathetic outflow during myocardial ischemia require left ventricular dysfunction, arrhythmias, pain, or anxiety (Figure 7-2). Myocardialanoxicischemiaincreasesnon-exocytoticreleaseof norepinephrine in laboratory animals, possibly via reverse transport through the Uptake-l carrier (18). The increased release by this process results from increased net leakage of norepinephrine from storage vesicles into the axonal cytoplasm. Norepinephrine washout increases markedly after release of coronary occlusion (19), suggesting that decreased coronary blood flow augments accumulation of norepinephrine in the heart. Nerve fibers have lower oxygen requirements than myocardial cells, and whereas the local blood supply provides the sole source of fuel and waste removal for myocardialcells, local blood supply and perfusion of the cell bodies in sympathetic ganglia contribute to these processes for sympathetic nerve terminals.Theoretically,myocardialsympatheticnervesshouldbeless susceptibletoimmediatedamageresultingfromcoronaryocclusionthan myocardial smooth muscle cells. Transmural myocardial infarction of the anterior left ventricle interferes with sympathetic and parasympathetic neurotransmission in the infarcted region

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as well as apical to the infarct. Myocardial concentrations of norepinephrine and norepinephrinehistofluorescencedecrease in thenon-infarctedareas,with physiological evidence of denervation. Subendocardial infarction appears to spare sympathetic transmission apical to the infarct, since the sympathetic fibers travel in thesubepicardium (20). Scintigraphicassessmentofsympathetic cardiac innervation using MIBG and thallium imaging in dogs has revealed that after transmural infarction, the zone of reduced MIBG-derived radioactivity exceeds in size the zone of reduced thallium uptake, indicating viable but dysfunctional or denervated myocardium distal to the infarct (21). After nontransmuralinfarction,regionalsympatheticdenervationoccurs,butwith apparent sparing of subendocardial nerve trunks, since innervation distal to the infarct persists. Reperfusion after 30 minutes of occlusion of the left anterior descendingartery in dogsisassociatedwithdecreasedregional [ l 8F]fluorometaraminol-derived myocardialradioactivityandnorepinephrine concentrations,indicatingresidualfailuretoretainamines in sympathetic terminals (22). After myocardial infarction, humans also have decreased MIBGderived radioactivity in perfused regions, consistent with local sympathoneural denervation or dysfunction (23). The clinical significance of denervation after myocardialinfarction,andwhethermyocardiumdenervatedasaresultof myocardial infarction can undergo reinnervation, remain unknown.

Arrhythmias Myocardialinfarctiondecreasesthresholdsforlethalventricular arrhythmias. About half of patients with fatal myocardial infarction die from this complication. Proposed mechanisms of ventricular arrhythmias in this settingincludelocalizedconductiondefectsduetonecrosisandfibrosis, electrolyte abnormalities such as hypokalemia, side effects of drugs, myocyte damage, sympathoneural activation,and norepinephrine accumulation at sites of denervation supersensitivity. Myocardialinfarctionalonemaynotexplainsuddencardiacdeath. Superimposed increased local effects of catecholamines seem required. Many studies of laboratory animals have shown that sympathetic nervous system or adrenomedullary hormonal system activation contributes to arrhythmogenesis in the setting of acute myocardialinfarction. This activation exaggerates the spatial dispersionofactionpotentialdurations in infarctedhearts,increasingthe probability of developing reentry-type ventricular arrhythmias, and enlarges delayed afterdepolarizations, increasing the probability of developing ectopic arrhythmias. In addition, epinephrine produces hypokalemia (24), which may add to hypokalemic effects of diuretics and increase the probability of digitalis toxicity.Sinceventricularextrasystoles, by momentarilydecreasingstroke volume, almost immediately evoke reflexive increases in cardiac preganglionic

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sympathetic activity (25), and since cardiac norepinephrine release increases ventricular automaticity, incitement of a neurocardiologic positive feedback loop may lead to rapid degeneration of cardiac rhythm in patients with myocardial infarction. These mechanisms may explain why signs of sympathetic activation often precede ventricular fibrillationin myocardial infarction patients(26). In 193 1, Leriche and co-workers reported that excision of the upper thoracic sympathetic ganglia decreased the frequency of occurrence of ventricular fibrillationassociatedwithsuddencoronaryocclusion (27), a finding later confirmed and extended by others. Sympathetic blockade increases the threshold for ventricular arrhythmias in dogs with acute coronary ligation, and bilateral stellateganglionectomyoftenattenuatestheincreasedsusceptibilityto ventricular fibrillation in this preparation (8,25,28-30). Chronic, bilateral stellate ganglionectomy, administration of the noradrenergic neurotoxin, 6-OHDA, or total cardiac denervation also decreases the likelihood of ventricular fibrillation induced by acutecoronaryocclusion.Thesefindingsindicatethatthe arrhythmogeniceffect of cardiacsympatheticactivationduringcoronary occlusion depends on releaseof norepinephrine from sympathetic nerves. Abundant evidence indicates that emotional distress in the setting of myocardial infarction increases the likelihoodof ventricular arrhythmias and that sympatholytic procedures or adrenoceptor blockade prevent this tendency. In conscious animals, coronary ligation does not produce ventricular fibrillation, if psychological stress is minimized by behavioral adaptation. In dogs with acute coronary ischemia, exposure to a classically conditioned aversive stimulus does not precipitate ventricular arrhythmias (31). In the setting of acute anterior myocardialinfarction,however,coronaryischemiacaninteractwiththe classically conditioned stimulus to precipitate ventricular arrhythmias. During subsequent exercise or coronary occlusion, only a proportion of “susceptible” animals develop worsening of ventricular arrhythmias when exposed to the conditioned stimulus, suggesting that classically conditioned aversive stimuli do not consistently increase susceptibility to ventricular arrhythmias during coronaryischemia,even in thesettingofapreviousanteriormyocardial infarction. A dog will become obviously enraged when another dog challenges its access to food. In dogs with circumflex coronary stenosis produced using an adjustable occluder, exposure to this situation increases coronary flow, but within 2 to 4 minutes after the episode, coronary flow proximal to the occluder decreases, and coronary vascular resistance increases markedly (32), accompanied by electrocardiographic evidence of ischemia. The coronary vasoconstriction is neurogenic, since stellate ganglion ablation prevents the post-anger ischemic changes.Duringagonisticbehavior,sympathetically-mediatedincreases in systemic blood pressure may increase the distending force in coronary vessels; after the behavior ends, blood pressure may fall abruptly, leaving the artery

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susceptible to local sympathetic vasoconstriction. The canine data lead to the suggestion that patients with moderately severe coronary disease who are prone to coronary vasoconstriction during anger reactions may be predisposed to develop acute coronary ischemic events. Vagal stimulation during acute myocardial ischemia generally increases rather than decreases electrical stability,and increased parasympathetic nervous systemoutflowprobablydecreasessusceptibilitytoventricularfibrillation during myocardial ischemia. Thus, intravenous injection of atropine can evoke ventricular fibrillationin bradycardic subjects (33). Cellularelectrophysiologiceffectsofcatecholaminesresultingin arrhythmogenesis have been ascribed to B- and al-adrenoceptors. By several mechanisms, stimulation of myocardial R-adrenoceptors during myocardial ischemiaincreasessusceptibilitytoventricularfibrillation.B-Adrenoceptor stimulation during coronary ischemia exaggerates the temporal dispersion of refractory periods. Tachycardia produces a functional conduction delay in the ischemic region. Increasesin the size of delayed after-depolarizations increase the likelihood of triggered rhythms. B-Adrenoceptor stimulation also increases the already accelerated rate of depolarization of ischemic tissue. Superimposed on all thesechanges,B-adrenoceptorstimulationincreasesmyocardialoxygen consumption, worsening the ischemic state. AdministrationofR-adrenoceptorantagonistssuchaspropranolol thereforedecreasestheacuteoccurrenceofventriculararrhythmiasduring myocardialischemia.Long-termtreatmentwiththeseagentsreducesthe incidence of sudden deathin survivors of myocardial infarction. Ofall therapies currently available to prevent sudden cardiac death in patients with coronary artery disease,B-adrenoceptor blockade exceeds all others in established efficacy (34). Theroleofa-adrenoceptors in thesusceptibilitytoventricular arrhythmias during myocardial ischemia is less clear. Norepinephrine prolongs effective refractory periods, apparently via stimulation of a-adrenoceptors. Although the number of B-adrenoceptors on myocyte cell membranes remains unchanged in thesettingofmyocardialischemia,thenumberof a 1adrenoceptors increases rapidlyin the ischemic region (35). Thus, whereas under normal conditions stimulation of B-adrenoceptors mediates the cardiac effects of catecholamines, during myocardial ischemia a 1 -adrenoceptors may play an increased role. Although it is commonlythoughtthatleftventricularinferiorwall myocardial infarction results in vagal hyperactivity and anterolateral infarction results in sympathetic hyperactivity, clinical evidence for this distinction has been indirect, based mainly on electrocardiographic and hemodynamic findings. Increased discharge of both parasympathetic and sympathetic nerves can occur simultaneously in patients with myocardial infarction-e.g., in inferior wall

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myocardial infarction with reflexive sympathetic stimulation in response to hypotension. In this setting, vagal effects may predominate at the sinus node or atrioventricular node and noradrenergic effects in the ventricles. As noted above, coronary occlusion produces sympathetic denervation in the infarcted area as well as apically. In a patient with a non-infarcted region apicaltoamyocardialinfarction,thedenervatedregioncouldbecome supersensitive to circulating catecholamines, leading to a predisposition to the development of ventricular arrhythmias. Dogs with chronic coronary occlusion or myocardial denervation have supersensitivity, as indicated by exaggerated norepinephrine-induced shortening of electrocardiographic refractory periods (36,37). Theheartseemsparticularlyvulnerabletothedevelopmentof ventricular fibrillation when apical sympathetic denervation supersensitivity accompanies non-transmural myocardial infarction. Prognosis High plasma levels of norepinephrine and epinephrine indicate a poor18month prognosis in patients with myocardial infarction(38). Whether the worse prognosisresultsfromdecreasedthresholdsforventriculararrhythmias, sympathetic stimulation superimposed on denervation supersensitivity, or more compensatory sympathoneural activation due to more extensive infarction, is unknown. In dogs, disruption of vagal reflexive bradycardia, as indicated by low baroreflex-cardiac gain, is a major risk factor for the development of ischemiarelated ventricular fibrillation after anterior myocardial infarction. Patientswhohavesurvivedmyocardialinfarctionhavedecreased respiratory sinus arrhythmia. Myocardial infarction causes a steeper slope and decreased height of the power law regression relation between log(power) and log(frequency) of interbeat interval fluctuations. The power law regression parameters predict death better than do power spectral bands (39). Angina pectoris In patients with coronary heart disease, emotional distress can provoke attacks of angina pectoris. One of the earliest, best-documented, and most ironic illustrations of this phenomenonwas the case of Dr. John Hunter(40).Hunter, a renowned lSth century surgeon, was by all accounts an extraordinarily hard worker, customarily arising before dawn. He was also notoriously prone to defensiveargument,irrationaloutbursts,obstinateness,andimpatienceepitomizing a hostile “Type A” individual. In 1785, he began to experience anginapectoris,asyndromethathisfriend,WilliamHeberden,hadonly recently described. Despite having conducted the dissection of one of Heberden’s

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cases, Hunter either never recognized or never admitted his own condition for whatitwasandthoughtthatrheumatismordyspepsiacausedit.Hedid recognize,however,therelationshipbetweenemotionalupsetandhis symptoms, and because argumentation frequently brought it on, he claimed, “My life is at the mercy of any rogue who chooses to provoke me” (41). This proved to be one of the most ironic statements in the history of medicine. On October 16, 1793 Hunter became incensed at critical, insolent remarks against him at a meeting of the board of governors of St. George’s Hospital. He left the room, collapsed, and dropped dead. His brother-in-law and colleague,EverardHome,publishedHunter’s A Treatise on the Blood, Inflammation, and Gun-Shot Wounds. As a preface, Home described Hunter’s condition and death. This description is a classic of cardiology:

...the first attack of these complaints was produced by an affection of the mind, and every future return of any consequence arose from the same cause; and although bodily exercise,ordistentionofthestomach, broughtonslighteraffections, it still required the mind to be affected to render them severe; and as his mind was irritated by trifles, these produced the most violent effects on the disease. His coachman being beyond his times, or a servant not attending tohisdirections,broughtonthespasms, while a real misfortune produced no effect.... OnOctober16,1793,when in his usualstateofhealth,hewenttoSt. George’s Hospital, and meeting with some thingswhichirritatedhismind,andnot being perfectly master of the circumstances, he withheld his sentiments, in which state of restraint he went into the next room, and turning around to Dr. Robertson, one of the physicians of the hospital, he gave a deep groan and dropt down dead. During emotionally arousing self-descriptions, coronary patients often have left ventricular wall motion abnormalities and decreased ejection fraction, as indicated by radionuclide ventriculography, even without anginal pain (42). Electrocardiographic indices usually do not detect the silent ischemia attending

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mental stress in patients with coronary disease (43). Mental challenge can reveal ischemic segments that are not evident during exercise (44). Patients undergoing cardiac catheterization for stable angina pectoris have approximately normal arterial plasma levels of norepinephrine and normal norepinephrine spillover into arterial plasma, in contrastwithpatientswith unstable angina, recent acute myocardial infarction, or heart failure, who have increased values for these variables (16,45). In patients with ischemic heart disease, emotional status, recorded in diary entries, relates to the likelihood of ischemia detected by electrocardiographic monitoring during the subsequent hour (46). Negative emotions, such as frustration and sadness, have the closest association with subsequent ischemic changes.

Coronary spasm Typical angina pectoris results from an excess of myocardial oxygen consumption compared to the supply provided by the coronary arteries, which have limited flow reserve due to atherosclerosis. Coronary artery spasm, which occurs usually in areas of underlying coronary atherosclerosis, can evoke angina pectoris even in the absence of increased myocardial oxygen consumption. Over a century ago, Huchard (47) wrote that angina pectoris can result when emotions produce coronary spasm and thereby myocardial ischemia. In 1932, Leriche continued this idea(47): Fromtonustovasoconstriction,that is to p h y s i o l o ghiyc pa el r t ofnr oi am, vasoconstrictiontospasm,thereisno borderline. One passes from one state to the other without transition, and it is the effects rather than the thing itself which makes for differentiations.Betweenphysiologyand pathology there is no threshold. Even with perfect conservation of the arterial structure the spasm, at a distance, has grave pathological effects. It causes pain, produces fragmented or diffuse necroses; last but not least it gives rise to capillary and arterial obliteration at the periphery of the system. Osler also recognized that coronary arteries can go into spasm, evoking anginapectorisandmyocardialinfarction. In 1959,Prinzmetaldescribed patients with an atypical form of angina, characterized by chest pain at rest or

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Figure 7-3Neuroendocrinepattern in congestive heartfailure. AHS = adrenomedullary hormonal system; ANP = atrial natriuretic peptide; AVP = arginine vasopressin; BP = blood pressure; CO = cardiac output; HR = heart rate; RAS = reninangiotensin-aldosterone system; SNS = sympathetic nervous system; SV = stroke volume; TPR = total peripheral resistance; X = vagus nerve.

with mild exertion and by transiently elevated electrocardiographic ST segments (48). It was thought that this syndrome was rare, until studies of patients during coronary angiography revealed the common occurrence of spasm in coronary arteries already narrowedby atherosclerosis. This has led to a revival of interest in coronary spasm as a cause or contributor to ischemic heart disease. Of the many postulated mechanisms of coronary spasm, several impute abnormalities at the level of the coronary sympathetic neuroeffector junction. Coronary vascular smooth muscle cells possess a- and B-adrenoceptors, and since R-blockade unmasks coronary vasoconstrictor responsesto norepinephrine, desensitization of B-adrenoceptor-mediated processes due to chronic increases in localconcentrationsofendogenousnorepinephrineorepinephrinecould intensify a-adrenoceptor-mediated coronary vasoconstriction. Some patients without fixed coronary narrowing or coronary arterial spasm have pacing-induced angina and limited coronary vasodilator reserve (49). There is no consensus yet as to whether “microvascular angina” constitutes a distinctclinicalpathophysiologicalentityandif so whethercoronary sympathoneural or adrenoceptor function play a pathophysiological role.

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Heart Failure

Generalized and cardiac sympathoneural activation Several pathophysiologic mechanisms explain generalized and cardiac sympathoneuralactivationandincreaseddeliveryofnorepinephrineto adrenoceptors in heart failure. In terms of homeostat operation, heart failure alters inputs to several homeostats that share the sympathoneural effector (Figure 7-3). Activation of the sympathetic nervous system plays an important role in maintaining cardiovascular performance in “compensated” heart failure. Thus, administration of reserpine (50) or guanethidine (51) causes marked clinical deterioration in patientswithheartfailure.Consistentwiththeviewthat recruited sympathoneural outflow maintains cardiovascular performance in clinical heart failure, beneficial treatments such as diuretics and vasodilators decrease or do not change plasma norepinephrine levels, whereas the same drugs increase plasma norepinephrine levels in healthy subjects. Patients with heart failure usually have high norepinephrine concentrations in systemic venous plasma. The norepinephrine concentrations increase progressively as functional status declines (52). In patients with left ventricular dysfunction but without clinically overt heart failure, plasma levels of norepinephrine, atrial natriuretic peptide, and vasopressin are increased (53). The neuroendocrine values increase further, accompanied by high levels of plasma renin activity, as overt heart failure develops. Sympathoneural activity thereforedoesnotnormalize,despitehypervolemia, in patientswithheart failure. One explanation for this phenomenon is the U-shaped curve relating cardiac sympathetic outflow to cardiac filling (54). Even before total body norepinephrine spillover increases, cardiac norepinephrine spillover increases (55). Patients with compensated heart failure do not have elevated epinephrine levels. The basis for elevated cardiac norepinephrine spillover in this setting has been somewhat controversial. As discussed in the chapter about assessment of catecholaminergicfunction,measurementsofmyocardialnorepinephrine spillover using steady-state systemic intravenous infusions of 3H-norepinephrine cannot distinguish increased cardiac sympathetically-mediated norepinephrine release from decreased neuronal reuptake. Rose et al. (56) interpreted tracer norepinephrine kinetic evidence using a bolus-injection technique as indicating reduced cardiac norepinephrine release as well as reduced uptakein heart failure patients.Incontrast,recentfindings by Eslerandco-workers,basedon simultaneous measurements of spillovers of norepinephrine and dihydroxyphenylglycol, have indicated markedly increased cardiac norepinephrine spillover-about 10-fold-in heart failure patients, which the

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Figure 7-4 Alterations in different aspects of cardiac sympathoneural function in congestive heart failure. Numbers indicate estimated rates (in pmol/min) of the various processes. Cardiac norepinephrine spillover increases by more than 3-fold. COMT = catechol-0-methyltransferase; DHPG = dihydroxyphenylglycol; DHPG-SO4 = dopamine sulfate; DOPA = L-dihydroxyphenylalanine; DOPAC = dihydroxyphenylacetic acid; MAO = monoamine oxidase; MHPG = methoxyhydroxyphenylglycol;NE = norepinephrine; NMN = normetanephrine; U1 = Uptake-l; U2 = Uptake-2. Modified from a diagram kindly provided byG. Eisenhofer. relatively small concurrent estimated decreases in cardiac Uptake-l activity cannot explain(5537). Myocardial norepinephrine depletion

In animal models of congestive heart failure,as well as in humans with heart failure, myocardial norepinephrine stores decrease. The norepinephrine depletion may be clinically significant, because reduced availability of releasable norepinephrine stores may impair homeostatic increases of cardiac rate or output

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during stresses such as exercise. Thus, patients with a cardiac transplant have limited increments in values for these variables during exercise (58). Patchy depletion of myocardial norepinephrine stores in heart failure might predispose to the development mechanical or electrical cardiac dysfunction. Severalexplanationshavebeenproposedforthedepletionof norepinephrine stores in congestive heart failure. The most obvious is that the increased rate of synthesis of norepinephrine does not keep pace with the markedlyincreasednorepinephrineturnover.Otherpossibilitiesinclude Rdeficiency not of tyrosine hydroxylation but of the vesicular uptake or hydroxylationofdopamine.Accordingtoanotherhypothesis, in sodiumretaining states such as heart failure, elaboration of a circulating inhibitor of Na+/Kf ATPase decreases the extracellular-intracellulargradient of Na+, partly inhibiting Uptake-l. Cardiac norepinephrine stores would then decline due to inadequate recycling of the release norepinephrine. Another hypothesis proposes attenuation of metabolic processes that normally maintain the steep gradient of amine concentrations between the interior of vesicles and the axoplasm. These processes depend on ATP, which may be depletedin heart failure. A comprehensive study of norepinephrine synthesis, release, reuptake, andturnoverhasresolvedthisissue (57). Increasedneuronalreleaseof norepinephrineanddecreasedefficiencyofnorepinephrinereuptakeboth contribute to increased cardiac adrenergic drive in congestive heart failure. Decreasedvesicularleakageofnorepinephrine,secondarytodecreased myocardialstoresofnorepinephrine,limitstheincreaseincardiac norepinephrine turnover. Decreased norepinephrine store size in the failing heart appearstoresultnotfrominsufficienttyrosinehydroxylationbutfrom chronicallyincreasednorepinephrineturnoverandreducedefficiencyof norepinephrine reuptake and storage (Figure7-4).

Prognosis Patientswithheartfailurewhohavehighplasmanorepinephrine concentrations have poor long-term survival (59). Heart failure patients with poorprognosesnotonlyhavehighplasmacatecholaminelevelsbutalso increased levels of angiotensin 11, aldosterone, and atrial natiuretic peptide, indicating concurrent compensatory activation of other circulatory homeostatic systems. These findings have led to re-consideration of whether sympathetic activation in heartfailureisbeneficialordeleterious.Chroniccardiac sympathetic nervous system activation may accelerate cardiac decompensation, byaugmentingcardiachypertrophy (60), therebydecreasingmyocardial compliance and diminishing cardiac baroreceptor restraint of sympathetic nervoussystemoutflows.Concurrently,norepinephrinemightstimulate

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Figure 7-5 Possible mechanisms of deleterious effects ofchronic sympathetic nervous activation inheartfailure. Chronic sympathetic activation in this setting can generate inherently unstable positive feedback loops. M V 0 2 = myocardial oxygen consumption; SNS = sympathetic nervous system.

apoptosis of myocardial cells (61). The combined operation of these factors therefore would increase the likelihood of one or more positive feedback loops (Figure 7-5). Cautious &blockade seems beneficialin patients with heart failure related to dilated cardiomyopathy, and large-scale clinical trialsin other forms of heart failure are underway. Attempts to improve clinical status or survival in heart failure patients by blocking catecholamine synthesis using a-methyl-tyrosine (62), sympatheticoutflowusingclonidine (63), or a]-adrenoceptors using prazosin (64) have been disappointing (59). The novel new drug, carvedilol, which features B-adrenoceptor blockade, al-adrenoceptor blockade, and antioxidant properties, seems especially promisingin the treatment of chronic heart failure (65,66). Arrhythmias and Sudden Death

Literature since antiquity has noted an association between acute distress and sudden cardiovascular collapse. In the New Testament, in the Acts of the Apostles, Ananias and his wife Sapphira “fell down and gave up the ghost” after being chastised by Peter. Josephus wrote about the circumstances of the death of the murderous king Aristobulus: ButAristobulusinstantlyrepentedthe slaughter of his brother. Guilt aggravated a disease and so disturbed his mind that his entrails were wracked by intolerable pain and

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he vomited blood. Once, a servant carrying away this blood slipped and shed some of it-by divineprovidence, as I cannot but think-at theveryspotwherestainsof Antigonus’ blood still remained ...he shed many tears and gave a deep groan: “I am not, I see, to escape God’s detection of the impiousandhideouscrimes I havebeen guilty of. Unforeseen punishment threatens me for shedding the blood of my kin. And now,mostimpudentbodyofmine,how long will you retain a soul that, to appease the ghosts of my brother and my mother, oughttodie?” ...Withthesewordshe died ...((67), pp. 58-59). Modem medical reports generally have confirmed an association between acute emotional distress and sudden cardiac death. In a classic study, Engel (68) reviewed 170 cases of sudden death during psychological stress, noting that “people are described as dying suddenly while in the throes of fear, rage, grief, humiliation, joy ...as far back as written records exist ...intense emotional distress may induce sudden death.” Supplementing a body of largely anecdotal literature, a study of 45,000 workers for the Eastman Kodak Company found that 22 patients died suddenly in “asettingofacutearousalengenderedbyincreasedworkactivity or circumstances precipitating reactions of anxiety or anger” (69). Compared with an unselected population studied over a similar time frame, people undergoing unusually emotionally disturbing events have an increased frequency of sudden cardiac death (70). Other epidemiological evidence has confirmed the view that presumed psychosocial stressors, such as the recent death ofa spouse, increase the likelihood of subsequent sudden death. Vasovagal circulatory collapse represents a situation where markedly increased parasympathetic nervous system outflow occurs concurrently with withdrawal of sympathetic nervous system vasoconstrictor tone. Tilt-table testing in the diagnostic evaluation of unexplained syncope detects “malignant vasovagal syncope” (abrupt onset of hypotension and bradycardia and loss of consciousness) in about 20% of patients (71). In the presence of normal coronary arteries, emotional distress rarely induceslife-threateningarrhythmias, in animals or in humans. In contrast, substantialclinicalandlaboratoryanimalevidencesupportstheviewthat distress can evoke lethal ventricular arrhythmias in the setting of coronary occlusion, as discussed in thesectionaboutacutemyocardialinfarction. In

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laboratory animals, electrical stimulation of the frontal cortex, hypothalamus, and brainstem reticular formation can produce ventricular arrhythmias, even in the absence of coronary ischemia. Patients with sustained ventricular arrhythmias have increased cardiac norepinephrine spillover (72) Although this is consistent with a pathophysiologicroleforincreasedcardiacsympathoneuralreleaseof norepinephrine, patients with reducedleft ventricular ejection fractions have high cardiac norepinephrine spillover, and so myocardial dysfunction could elicit compensatory increases in cardiac sympathetic nervous system outflow in the patients. PatientswiththeidiopathiclongQTsyndromehaveincreased susceptibility to develop life-threatening ventricular arrhythmias during exposure to physical or emotional stressors, including fear, exercise during emotional distress, swimming, and being awakened by a loud noise. In some patients with prolongedelectrocardiographic Q T intervals,leftstellateganglionitisor inflammationofgangliawithinthesino-atrialnodehasbeenidentified pathologically (73). &Adrenergic blockade is the treatment of choice, and left cardiac sympathetic denervation can be effective(47). Schwartz and co-workers have suggested that increased cardiac sympathetic activity derived from theleft stellate ganglion results in an increased risk of ventricular arrhythmias (47,74). This is the basis of the “sympathetic imbalance” hypothesis. The occurrence of afferent and efferent cardiac nerves in the same trunks complicates inferences fromtheeffectsofelectricalstimulationorsurgicalsectioning.Another complicating feature is that stimulation of efferent sympathetic neurons from a varietyofintrathoracicsitescanproducesubstantiallocalizedchanges in repolarization that are not detectedby total electrocardiographic Q T intervals. In patients with hypertrophic obstructive cardiomyopathy, catecholamineinduced increases in the force and rate of cardiac contraction worsen the outflow obstruction and decrease the threshold for ventricular arrhythmiasin response to several types of stressors.

PSYCHIATRIC Depression Several recent reports have noted an association between depression and increased cardiovascular risk (75-80). The basis for this increased risk remains unknown. Patients with typical melancholic depression have increased plasma norepinephrine levels, due to increased norepinephrine spillover. Despite these findings, blood pressure is not elevated. Apparently, for hypertension to be expressed, other compensatory systems must also fail.

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A recent study found increased cerebrospinal fluid norepinephrine levels at all time points in a 36-hour period of repeated sampling in patients with melancholic depression (Gold et al., unpublished observations). This finding notonlysuggestsincreasedcentralnoradrenergicactivity in melancholic depression but also that the increased noradrenergic activity does not depend in any simple way on consciously experienced distress, since cerebrospinal fluid norepinephrine levels were increased even when the patientswere asleep.

PaniclAnxiety Anxiety or panic can be associated with chest pain that mimics angina pectoris due to coronary heart disease, Attacks often include physiological changesthatsuggestactivationofcatecholaminesystems,withsystolic hypertension, tachycardia, palpitations, and patterned changes in cutaneous blood flow. Psychophysiological research in this area has been criticized severely, with the accusation that mostof the studies “merely selectan ‘off-the-rack’ selfreport measure of trait anxiety, choose an equally ‘off the rack’ physiological index,andsubjecttheexperimentalpopulationtoan‘off-the-rack’and ecologically meaningless laboratory test” ((8l), p. 468). In general, patients with anxiety disorder have normal plasma levels of catecholamines and metabolites under resting conditions (82-84). Moreover, increased circulating catecholamine levels do not result in anxiety in normal volunteers(83,85)or in patientswithhighcatecholaminelevelsfrom pheochromocytoma (86). During threatening situations, however, patients with anxiety disorder have symptoms and signs of physiological activation (84). In a double-blind study, patients with panic disorder were more likely to experience panic during infusion of epinephrine at a physiologically active dose than during infusion of placebo, regardless of whether the patients receive or do notreceiveextensiveinformationaboutthebodilyeffectsofepinephrine (87,88). During laboratory challenges, patients with panic disorder have been reported to have larger plasma norepinephrine responses than control subjects (89). Even during panic attacks, activation of catecholamine systems may not occur. A study of neuroendocrine and cardiovascular changes during 36-hour periods of bed rest in patients with panic attacks found that panic attacks were not associated with increased plasma levels of norepinephrine, epinephrine, or methoxyhydroxyphenylglycol (MHPG),suggestingadissociationbetween neuroendocrine responses and experiential reportsin panic patients (82). Intravenous administration of yohimbine can evoke attacks in patients withpanidanxietydisorder.Treatmentwithalprazolamortricyclic antidepressants attenuates MHPG responses to yohimbine (90), suggesting that

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Figure 7-6 The hypothalamo-pituitary-thyroid axis and sympatheticnervous system in homeostatic regulation of metabolism. From thestructure of the homeostatic system, hypothyroidism should compensatorily activate the sympathetic nervous system.According to this model,thethyroid axis is regulated by a “thermostat,” which senses blood temperature, a “metabostat,” which senses input from metaboreceptors, and an “orexistat,” which determines the sense of satiety. B = B-adrenoceptors; CAMP = cyclic adenosine monophosphate; SNS = sympathetic nervous system. a2-adrenoceptors on noradrenergic terminals in the brain restrain sympathetic nervous system outflows, and in patients with panidanxiety, interference with thisrestraininginfluencereleasesthesympatheticnervoussystemfrom inhibition,concurrentlyprecipitatingthepsychopathologicemotional experience. There is no convincing evidence from prospective studies that anxiety or panic disorder increases the risk for developing coronary heart disease. For instance,Armyveteranswithdisabilityseparationsforpsychoneurosishad normal 25-year mortality rates from arteriosclerotic cardiovascular disease, degenerative cardiac disease, diseases of arteries or veins, and hypertension(91).

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ENDOCRlNElMETABOLlC

Hypothyroidism The hypothalamo-pituitary-thyroid axis and sympathetic nervous systems interact in regulation of body metabolism (Figure 7-6), which is intimately linked to regulation of body temperature and weight. Many studies ofbrown adipose fat in rats have focused on this interaction and have emphasized the importance of sympathetically-mediated release of norepinephrine in calorigenesis in thistissue.Thus,atroomtemperature, calorigenesis in brown adipose tissue can occur in the absence of thyroid hormones, but not in the absence of catecholamines; and during exposure to cold, lack of norepinephrine is more effective than lack of thyroid hormones in preventing increases in calorigenesis (92). Both brown and white adipose tissue possess high concentrations of 4 adrenoceptors, which probably contribute to catecholamine-induced lipolysisespecially in white adipose tissue (93). It has been proposed that in humans, polymorphism of this receptor subtype may play a role in obesity or diabetes; however,thisissueremainsunsettled(94,95).Inrats,thyroidhormone differentially affects expression of 03-adrenoceptors in brown and white adipose tissue. Hypothyroid rats have increased R3-adrenoceptors in brown and decreased receptors in white adipose tissue, and treatment with thyroid hormone reverses these changes (93). Despite the increased expression of B3-adrenoceptors in brown fat of hypothyroid rats, the tissue has decreased generation of CAMP in response to norepinephrine, probably because of decreased expressionof otherBadrenoceptor subtypes (96). Hypothyroidhumanshaveincreasedplasmanorepinephrinelevels (97,98). Concurrent decreases in activity of the hypothalamo-pituitary-thyroid axisandincreases in outflowsofthesympatheticnervoussystemsuggest compensatory activation, where both systems function as effectors for the same homeostat(Figure7-7).Thus,thyroidectomizedanimalshavemarkedly augmented plasma norepinephrine and epinephrine responses to cold exposure (99). Analogously, although hyperthyroidism includes features of catecholamine excess, such as tachycardia, arrhythmias, systolic hypertension, and anxiety, plasma norepinephrine and epinephrine levels usually are decreased (100,101). Whether patients with sympathetic neurocirculatory failure have compensatory activation of the hypothalamo-pituitary-thyroid axis during cold exposure is unknown. Since hyperthyroid rats have increased synthesis and expression of Badrenoceptors (1 02), it has been suggested that hyperthyroid humans may have exaggerated cardiovascular effects of catecholamines for a given amount of release; however, cardiovascular B-adrenoceptor alterations may be species-

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Figure 7-7 Somehomeostaticresponses to mealingestion.From the structure of the homeostatic systems, insulin resistance increases sympathetic nervous system outflows, and sympathetic activation increases insulin resistance. EPI = epinephrine; SNS = sympathetic nervous system.

specific (103). Excised adipose tissue from hyperthyroid patients does exhibit augmentednorepinephrine-inducedandR-adrenoceptor-mediatedlipolytic responses (104); andmonocytemembranesofhyperthyroidpatientshave increased numbers of R-adrenoceptors (101). Patients with multiple endocrine neoplasia have an increased risk of developing medullary carcinoma of the thyroid and pheochromocytoma of the adrenal. The basis for these predispositions is unknown. Obesity, Diabetes, and “Metabolic Syndrome”

Many studies have supported the concept of a “metabolic syndrome,” also sometimes called “Syndrome X,” that includes hypertension, insulin resistance (defined by decreased ability of insulin to stimulate uptake and disposal of glucose by skeletal muscle), and dyslipidemia (defined by an increased serum concentration of triglyceride and decreased concentration of high density lipoprotein (HDL) cholesterol). Obesity is associated epidemiologically with all three components of the metabolic syndrome; however, the syndrome occurs in both obese and non-obese people.

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Abnormal regulation of the sympathetic nervous system may play a role in metabolic syndrome, by one or more of several mechanisms. The following discussion considers only a few. Obese laboratory animals have decreased lipolytic effects of catecholamines in adipose tissue, related to abnormalities of R-adrenoceptors (105,106). Whether obese humans have a polymorphism for the R3-adrenoceptor remains unsettled (94,95). Ingestion of carbohydrate in a meal stimulates insulin secretion. People resistant to effects of insulin on glucose uptake by skeletal muscle might not be resistanttoeffectsofinsulinonglucoseuptakebythebrain.If so, then increasedglucoseuptake in oneormorebraincentersmightdisinhibit sympatheticneuronaloutflows(107).Theincreasedsympatheticneuronal outflows,whileproducingdietarythermogenesisandtherebyhelpingto promote energy balance and maintenance of body weight, could contribute to a tendency towards high blood pressure (Figure 7-7). Insulin acts as a vasodilator, possibly via generation of nitric oxide (lOS), although increased production of adenosine as a tissue metabolite or stimulation of ATP-sensitive potassium channels may also contribute to insulin-induced vasodilation (109). Patients with insulin resistance in the setting of Type 11 diabetes mellitus have decreased nitric oxide-mediated vasodilation, as assessed both by responses to locally administered sodium nitroprusside, which generates nitric oxide directly, and to locally administered acetylcholine or methacholine, which increase nitric oxide generation by stimulation of muscarinic cholinergic receptors(108,110).Analogously,patientswithhypertensionalsohave decreasedinsulin-induced(111)orarginine-induced (1 12) vasodilation. Decreased insulin-induced generation or effects of nitric oxide might therefore contribute to vasoconstriction or hypertensionin the metabolic syndrome. Studiesoflaboratoryanimalshavesuggestedthatinsulininhibits norepinephrine-induced vasoconstriction (1 13), via generation of nitric oxide. Moreover, obese Zuckerrats have impairment of this putative modulatory effect ofinsulin(114).Whetherinsulininhibitsvasoconstrictorresponsesto sympathetically-mediated norepinephrine release and whether insulin inhibits norepinephrine-induced vasoconstriction in humans are unknown. In humans, sympathetic activation increases insulin resistance in the forearm (1 15). As indicated in Figure 7-7, a neuroendocrine positive feedback loop, where insulin increases sympathetic outflows and sympathetic activation increases insulin levels, might produce the metabolic syndrome as a reflection of new, pathologic, apparent steady-states. Leptin is a peptide hormone produced by adipose tissue that acts in the brain to decrease appetite, increase energy expenditure, and increase sympathetic outflows (1 16,117). Catecholamines, via occupation of R-adrenoceptors, inhibit whereas insulin stimulates secretion of leptin by adipose tissue (1 18-120). In

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Figure 7-8 Possible interactionsbetweenleptin andthe sympatheticnervous and adrenomedullaryhormonal systems in regulation of adiposity. EPI = epinephrine; SNS = sympathetic nervous system.

humans,bothleptinlevelsandskeletalmusclesympatheticnervetraffic correlate positively with adiposity and with each other (121). These findingsfit with a negative feedback loop (Figure 7-S), where the extent of adiposity determines the amount of leptin secretion, which in turn stimulates sympathetic neuronalandadrenomedullaryhormonaloutflows,whichbypromoting lipolysis increases energy expenditure and decreases the extent of adiposity. Consistent with this view, in Caucasians, skeletal muscle sympathetic nerve trafficcorrelatespositivelynotonlywithadipositybutalsowithvarious measures of energy expenditure (122). Pima Indians have a high frequency of obesity. Lean Pima Indians have a low rate of peroneal sympathetic nerve traffic, consistent with the notion that reduced sympathetic nervous activityin Pima Indians predisposes individuals to a gain in body weight (122). SUMMARY AND CONCLUSIONS

In severalcommonconditions,activationofcatecholaminesystems worsens a largely independent pathologic state. Changes inmyocardialsympathoneuralfunctionassociatedwith myocardial infarction can be primary, with sympathetically-mediated increases in myocardial oxygen consumption exacerbating ischemia,or can be secondary, withrecruitmentofcardiacandextra-cardiacsympatheticnervoussystem outflowstomaintaincardiovascularperformance.Transmuralmyocardial infarction of theanteriorleftventricleinterfereswithsympatheticand parasympathetic neurotransmission in the infarcted region as well as apical to the infarct. Myocardial infarction decreases thresholds for lethal ventricular arrhythmias;formyocardialinfarctiontoevokesuddencardiacdeath,

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superimposedincreasedlocaleffectsofcatecholaminesmayberequired. Emotionaldistressinthesettingofmyocardialinfarctionincreasesthe likelihood of ventricular arrhythmias. In thepresenceofnormalcoronary arteries, however, emotional distress rarely induces life-threatening arrhythmias. Cellular electrophysiologic effects of catecholamines resulting in arrhythmogenesis have been ascribed toR- and ai-adrenoceptors. In myocardial infarction, plasma catecholamine levels increase with the severity of cardiac damage, and high levels indicate a poor long-term prognosis. Activation of the sympathetic nervous system plays an important role in maintaining cardiovascular performance in “compensated” heart failure. As cardiac sympathetic activation occurs, norepinephrine release increases, and myocardial norepinephrine stores decrease, probably due to increased neuronal release of norepinephrine and decreased efficiency of norepinephrine reuptake. Patients with high plasma norepinephrine concentrations have poor long-term survival. Chronic cardiac sympathetic nervous system activation may accelerate cardiacdecompensation,andlongitudinalclinicaltrialsofR-adrenoceptor antagonists are underway. The hypothalamo-pituitary-thyroidaxis and sympathetic nervous systems interact in regulation of body metabolism. Relatively few studies have focused on this interaction. A“metabolicsyndrome,”alsocalled“Syndrome X,” includes hypertension,insulinresistance(defined by decreasedabilityofinsulinto stimulate uptake and disposal of glucose by skeletal muscle), and dyslipidemia (defined by an increased serum concentration of triglyceride and decreased concentration of highdensitylipoprotein (HDL) cholesterol).Abnormal regulation of the sympathetic nervous system mayplay a role in this syndrome, by one or more of several mechanisms. Insulin acts as a vasodilator, possibly viagenerationofnitricoxide,andinhibitsnorepinephrine-induced vasoconstriction.Conversely,sympatheticactivationincreasesinsulin resistance. In humans, both leptin levels and skeletal muscle sympathetic nerve traffic correlate positively with adiposity and with each other, consistent with a negative feedback loop, where the extent of adiposity determines the amount of leptinsecretion,whichinturnstimulatessympatheticneuronaland adrenomedullary hormonal outflows, which by promoting lipolysis increases energy expenditure and decreases the extent of adiposity.

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87. VeltmanDJ,vanZijderveld CA, vanDyckR. Epinephrine infusions inpanic disorder: a double-blind placebo-controlled study. J Affect Disord 1996; 39~133-140. 88. Veltman DJ, van Zijderveld CA, vanDyckR, Bakker A. Predictability, controllability, and fear of symptomsof anxiety in epinephrine-induced panic.BiolPsychiatry1998;44:1017-1026. 89. Hoehn T, Braune S, Scheibe G, Albus M. Physiological, biochemical and subjective parameters inanxiety patients withpanic disorder during stress exposureas compared with healthy controls. Eur Arch Psychiatry Clin Neurosci 1997;247:264-274. 90. EdlundMJ,SwannAC, Davis CM.PlasmaMHPGinuntreatedpanicdisorder. BiolPsychiatry1987;22:1488-1491. 91. Keehn RJ, Goldberg ID, Beebe GW. Twenty-four year mortality follow-up of army veterans withdisability separations for psychoneurosis in1944.Psychosom Med 1974;36:27-46. 92. Cageao LF, Noli MI, Mignone IR, Farber M, Ricci CR, Hagmuller K, Zaninovich AA. Relativerolesofthe thyroid hormonesandnoradrenalineonthe thermogenic activity of brown adipose tissue in therat.J Endocrinol 1995; 145:579-584. 93. Rubio A, Raasmaja A, Silva JE. Thyroid hormone and norepinephrine signaling in brown adipose tissue. 11: Differential effects of thyroid hormone on beta 3adrenergic receptors inbrownandwhiteadiposetissue.Endocrinology1995; 13613277-3284. 94. Strosberg D. Association of beta 3-adrenoceptor polymorphism with obesity and diabetes:currentstatus. Trends PharmacolSci1997;18:449-454. 95. Buettner R, SchaMer A, Amdt H, Rogler G, Nusser J, Zietz B, EngerI, Hug1 S, Cuk A, Scholmerich J, Palitzsch KD. The Trp64Arg polymorphism of the beta 3adrenergic receptor gene is notassociatedwith obesity or type 2 diabetes mellitus ina large population-based Caucasian cohort. J Clin Endocrinol Metab 1998; 83:2892-2897. 96. Rubio A, Raasmaja A, Maia AL, Kim KR, Silva JE. Effects of thyroid hormone on norepinephrine signaling inbrown adipose tissue. I. Beta 1- and beta2adrenergic receptors and cyclic adenosine 3’,5’-monophosphate generation. Endocrinology 1995; 136:3267-3276. 97. MomoseM, Inaba S, Emori T, Imamura K, KawanoK,Ueda T, Kobayashi H, Hosoda S. Increased cardiac sympathetic activity in patients with hypothyroidism as determined by iodine-l23 metaiodobenzylguanidine scintigraphy. Eur J Nucl Med 1997; 24:1132-1137. 98. Velardo A, Del Rio G, Zizzo G, Venneri MG, Della Casa L, Marrama P. Plasma catecholamines after thyrotropin-releasing hormone administration in hypothyroid patients before and during therapy. Eur J Endocrinol 1994; 1301220-223.

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99. Fukuhara K, Kvetnansky R, Cizza G, Pacak K, Ohara H, Goldstein DS, Kopin IJ. Interrelations between sympathoadrenal system and hypothalamo-pituitaryadrenocorticalhhyroid systems in rats exposed cold to stress. J Neuroendocrinol 1996;8:533-541. 100. MoghettiP,CastelloR,TosiF,ZentiMG,MagnaniC,Bolner A, Perobelli L, MuggeoM. Glucose counterregulatory response to acute hypoglycemia in hyperthyroidhumansubjects.JClinEndocrinolMetab1994;78:169-173. 101. Ratge D, Hansel-Bessey S, Wisser H. Altered plasma catecholamines and numbers of alpha- and beta-adrenergic receptors in platelets and leucocytes in hyperthyroid patients normalized under antithyroid treatment. Acta Endocrinol 1985; 110:75-82. 102. Williams LT, Lefkowitz RJ, Watanabe AM, Hathaway DR, Besch HR. Thyroid hormoneregulationofbetaadrenergicreceptornumber.JBiolChem1977; 571149-155. 103.CrozatierB,SuJB,CorsinA,Bouanani N. Species differences inmyocardial beta-adrenergicreceptorregulation inresponse to hyperthyroidism. Circ Res 1991; 69:1234-1243. 104.HellstromL,WahrenbergH,Reynisdottir S , Arner P. Catecholamine-induced adipocyte lipolysis inhuman hyperthyroidism. J Clin Endocrinol Metab 1997; 82:159-166. 105.GiacobinoJP.Roleof the beta3-adrenoceptor in thecontrolof leptin expression. HormMetabRes1996;28:633-637. 106. Deng C, Moinat M, Curtis L, Nadakal A, Preitner F, Boss 0, AssimacopoulosJeannet F, Seydoux J, Giacobino JP. Effects of beta-adrenoceptor subtype stimulation on obese gene messenger ribonucleic acid and on leptin secretion inmousebrown adipocytes differentiated in culture. Endocrinology 1997; 138:548-552. 107.ReavenGM,LithellH, Landsberg L.Hypertension and associated metabolic abnormalities-the role of insulin resistanceandthesympathoadrenal system. N Engl J Med 1996; 334:374-381. 108. Schemer U, Owlya R, Lepori M, Williams SB, Cusco JA, Roddy MA, Johnstone MT,CreagerMA.Bodyfatand sympathetic nerve activity. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J AmCol1 Cardiol1996;27:567-574. 109.McKayMK,HesterRL. Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation. Hypertension 1996; 281202-208. 1 IO. Watts GF, O’Brien SF, Silvester W, Millar JA. Impaired endothelium-dependent and independent dilatation of forearm resistance arteries inmenwith diettreated non-insulin-dependent diabetes: role ofdyslipidaemia. Clin Sci 1996; 91:567-573.

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control of forearm vascular resistance in normotensive and hypertensive subjects. Hypertens Res1996; 19 Suppl 1:S47-S50. 112. Higashi Y, Oshima T, Sasaki N, Ishioka N, Nakano Y, Ozono R, Yoshimura M, Ishibashi K, Matsuura H, Kajiyama G. Relationship between insulin resistance and endothelium-dependent vascular relaxation in patients with essential hypertension. Hypertension 1997; 29:280-285. G. Insulin-induced attenuation of 113.WalkerAB, Savage MW,DoresJ,Williams noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent. Clin Sci 1997; 92:147-152. 114.WalkerAB, Dores J, BuckinghamRE, Savage MW, Williams G. Impaired insulin-induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistantobese Zucker rats.ClinSci1997;93:235-241. 115. Lernbo G, RendinaV,Iaccarino G, LarnenzaF,VolpeM, Trimarco B. Insulin reduces reflex forearm sympathetic vasoconstriction in healthy humans. Hypertension 1993; 21:1015-1019. 116.Haynes WG, Sivitz WI,MorganDA,Walsh SA, MarkAL. Sympathetic and cardiorenal actions of leptin. Hypertension1997;30:619-623. 117. Dunbar JC, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats. Diabetes 1997; 4612040-2043. 118.DonahooWT,JensenDR,Yost TJ, EckelRH.Isoproterenol and somatostatin decrease plasma leptin in humans: a novel mechanism regulating leptin secretion.JClinEndocrinolMetab1997;82:4139-4143. 119. Fritsche A, Wahl HG, Metzinger E, Renn W, Kellerer M, Haring H, Stumvoll M. Evidence for inhibitionofleptin secretion by catecholamines in man. Exp ClinEndocrinol Diabetes 1998;106:415-418. 120. Pinkney JH, CoppackSW,Mohamed-AliV.Effectofisoprenalineon plasma leptinandlipolysis inhumans. Clin Endocrinol1998;48:407-411. 121. Snitker S, PratleyRE,Nicolson M, Tataranni PA, Ravussin E. Relationship betweenmuscle sympathetic nerveactivityandplasmaleptin concentration. ObesRes1997;5:338-340. 122. Spraul M, Ravussin E, FontvieilleAM,Rising R, Larson DE,AndersonEA. Reduced sympathetic nervous activity. A potentialmechanism predisposing to body weight gain. J Clin Invest 1993; 92:1730-1735.

Disorders in Which Abnormal Catecholaminergic Function Is Etiologic SYMPATHETIC NEUROCIRCULATORY FAILURE

The evolution of the ability of humans to adjust rapidly to assumption of the upright posture and to tolerate orthostasis for relatively long periods freed the hands to signal others and to fashion and use tools. This ability probably evolved concomitantly with-and fostered the evolution of-anatomic and behavioralcharacteristicsthatdefinehumanity. It alsoprobablyevolved relatively recently, so that the dependence on only one effector system-the sympathetic nervous system-for the ability to tolerate orthostasis might reflect insufficient time for other effectors to have evolved. Regardless of these speculations, a basic fact of neurocardiology is that for humans to maintain adequate blood perfusion of the brain during orthostasis absolutely requires intact sympathetic neurocirculatory function. A key clinical consequence of this dependence is that syndromes that include sympathetic neurocirculatory failure always entail inability of the patient to tolerate orthostasis. The patient feels dizzy or weak while in the upright posture, as a result of failure of some aspect of sympathetic neuroeffector function. This chapter considers several of these syndromes. Refined differential diagnosis,clinicalclassification,assignmentofprognosis,andrational treatment of the several syndromes that feature sympathethic neurocirculatory failure depend on sometimes sophisticated physiological, neurochemical, and neuroimaging tests introduced within the past few decades. Many factors can cause a decrease in blood pressure when a person stands-orthostatic hypotension. Prolonged bed rest for virtually any reason can do this, and so elderly, bedridden patients often have orthostatic hypotension. Orthostatic hypotension can also result from any condition that causes depletion of blood volume, such as gastrointestinal hemorrhage, or from any drug that elicits vasodilation, such as sublingual nitroglycerine in a patient with angina pectoris. 455

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Decreasedcardiacfilling,whichoccursclinically in hemorrhageor dehydration,wouldbeexpectedtoenhanceorthostaticresponsesof sympathoneuraltrafficandplasmanorepinephrinelevels,sinceorthostatic hypotension in thissettingoccursdespitecompensatoryincreasesin sympathetic nervous system outflows. In contrast, other conditions, such as diabetes, alcoholism, and amyloidosis, and any of several drugs, are associated with impaired transmission of sympathetic nerve impulses. Commonly used drugs also can interfere with release of norepinephrine from sympathetic nerve terminals or with adrenoceptor-mediated alterations in cardiovascular tone. Finally, several disorders discussed in the following sections feature orthostatic hypotension due to sympathetic neurocirculatory failure that occurs as a primary pathophysiologic entity. In theconductofthemedicalhistoryandphysicalexaminationof patients with known or suspected dysautonomias, the clinician must search carefullyforsymptomsandsignsofsympatheticneurocirculatoryfailure. Patientswithsympatheticneurocirculatoryfailuremaynotcomplainof consistent dizziness, weakness, or faintness during standing but may note such symptoms in the morning, after a meal, after exercise, or after a hot shower or bath,withalleviationofthesesymptomsbylyingdown.Patientswith sympathetic neurocirculatory failure may not complain of orthostatic symptoms at all, even when blood pressure readings demonstrate orthostatic hypotension. Thus, the absence of orthostatic symptoms should not lull the clinician into inferring that the patient cannot have sympathetic neurocirculatory failure. Thefinding of orthostaticsymptomsandhypotensiondoesnot necessarily imply the existence of sympathetic neurocirculatory failure. The resultsofmeasurements of beat-to-beatbloodpressureduringandafter performance of the Valsalva maneuver can confirm this, and with the availability ofmeanstomeasurebeat-to-beatbloodpressurenon-invasively,using a FinapresTM, PortapresTM, or ColinTM tonometric device, measurement of blood pressureresponsestotheValsalvamaneuvercanbepartofascreening evaluation. Patientswithsympatheticneurocirculatoryfailure,regardlessofthe specific syndrome, have characteristic abnormalities of beat-to-beat blood pressure during and after performance of the Valsalva maneuver. As indicated in Figure 8-1, patientswithpureautonomicfailure,multiplesystematrophy (MSA) with sympathetic neurocirculatory failure (the Shy-Drager syndrome), autonomic failure in the setting ofParkinson’s disease, or autonomic failureas a consequence of amyloidotic or diabetic neuropathy or of chemotherapy all have identical abnormalities of beat-to-beat blood pressure responses to the Valsalva maneuver. Briefly, whereas normally mean arterial pressure increases from its nadir by the end of PhaseI1 of the Valsalva maneuver, and during PhaseIV after releaseofthemaneuverthebloodpressure“overshoots,”insympathetic

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I

I

20 - 1

"

I

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PV c

PV c

Figure 8-1 Beat-to-beat blood pressure associated with the Valsalva maneuver (black horizontal bars) in sympathetic neurocirculatory failure syndromes. The same abnormalities occur in patients with pure autonomic failure (PAF), the Shy-Drager syndrome (SDS), and Parkinson's disease with autonomic failure (Park+). The patient with Park+ also had abnormal beat-to-beat blood pressure after spontaneouslyoccurring premature ventricular contractions (PVC). neurocirculatory failure the blood pressure falls progressively during Phase I1 and does not overshoot in Phase IV (Figure 8-1) Chapter 6 , about clinical assessment, explains why and how these abnormalities reflect failure of reflexive syrnpathetically-mediatedvasoconstriction.

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As noted below, decreasesin plasma levels of norepinephrine may or may not attend the various syndromes that feature sympathetic neurocirculatory failure.Anabsenceofthenormalapproximatedoublingofplasma norepinephrine levels during orthostasis indicates the occurrence of sympathetic neurocirculatory failure (1); however, one can obtain a false negative result-an orthostatic increase in the plasma norepinephrine level despite the presence of sympathetic neurocirculatory failure-due to an orthostatic decrease in the clearance of norepinephrine from the plasma (2). The application of several neurochemical and neuroimaging tests now enablescleardistinctionsamongsympatheticneurocirculatoryfailure syndromes. This chapter highlights some of these applications. AUTONOMIC FAILURE WITHOUT CENTRAL NEURODEGENERATION Pure Autonomic Failure

Pureautonomicfailure(alsocalledperipheralautonomicfailure, idiopathic orthostatic hypotension, or Bradbury-Eggleston syndrome) consists of persistent neurogenic orthostatic hypotension in the absence of signs of central nervous system disease and in the absence of other known causes of orthostatic hypotension. Bradbury and Eggleston published the first case report of pure autonomic failurein 1927 (3). The disease is not inherited, and no known environmental toxin causes it, although in laboratory animals, administration of the sympathetic neurotoxin, 6hydroxydopamine, produces a pattern of neurochemical and neuroimaging abnormalities that resembles the pattern in patients with pure autonomic failure (4). The disease typically has an insidious onset in middle age. In men, impotence is an early sign. Abnormalities of sweating, urination, and defecation occur variably. In contrast, the patients have prominent orthostatic dizziness or weakness-especially upon arising in the morning, after a warm shower or bath, after isotonic exercise, or after a large meal. While debilitating, pure autonomic failure is not thought to be lethal. The patient remains lucid without signs of central neurodegeneration. Pathologically,celllossoccursinsympatheticganglia (3), with phagocytosis of neurons, proliferation of satellite cells, perivascular lymphocytic infiltration, and markedly decreased dopamine-D-hydroxylase enzyme activity ( 5 ) . In contrast, tyrosine hydroxylase in sympathetic ganglia can be normal, and the intermediolateral columns of the spinal cord can be unaffected. A case reportedbyvanIngelghemetal. (6), however,hadcell loss inthe intermediolateral columns and Lewy bodies in sympathetic ganglia and nerves,

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without pathologic changes more rostrally in the central nervous system; and a patient reported by Hague et al. (7) had typical and atypical Lewy bodies in the substantianigra,sympatheticganglia,thelocusceruleus,andperipheral innervation sites in epicardial fat, peri-adrenal adipose tissue, and the urinary bladder wall. The findings in the latter case indicate that Lewy bodies typical of Parkinson’s disease can occur in pure autonomic failure at sites distant from the post-ganglionic cell bodies. During Phase I1 of the Valsalva maneuver, patients with pure autonomic failureconsistentlyhaveamarkeddecrease in bloodpressure.Indeed,the patients can become symptomatic after carrying out the maneuver for more than about 10 seconds. The cardiotachometer tracing may demonstrate a reduced or absent increase in heart rate during Phase 11. Since atropinization of normal volunteers abolishes this response (S), the finding of a decreased tachycardic responseduringPhase I1 probablyreflectsconcurrentcardiovagalfailure; however, the heart rate can increase during Phase 11, albeit less than one might expect from reflexive responses to the profoundfall in blood pressure. Sympatheticneurocirculatoryfailure in thisconditionatleastpartly reflects diffuse loss of sympathetic nerve terminals. Thus, plasma norepinephrine levels typically aredecreased-even with the patient supine(9)and the levels fail to increase when the patient stands(1). After cessation of an i.v. infusion of 3H-norepinephrine, the curve relating the plasma concentration of 3H-norepinephrine with time mimics that in control subjects treated with desipramine, consistent with decreased neuronal uptake of 3H-norepinephrine due to decreased Uptake-l sites (10). Finally, the estimated rate of entry of norepinephrine into plasma (total body norepinephrine spillover) is decreased (10). Patients with pure autonomic failure not only have decreased total body spilloverofnorepinephrinebutalsodecreasedplasmaconcentrationsof dihydroxyphenylglycol (DHPG), the main neuronal metabolite of norepinephrine,anddecreasedplasmaconcentrationsofendogenous Ldihydroxyphenylalanine (L-DOPA), the immediate product of the rate-limiting step in catecholaminebiosynthesis (9). Thesefindingsindicatedecreased turnover and synthesis of catecholamines in sympathetic nerves (1 1). Results of sympathetic neuroimaging using 6-[18F]fluorodopamine positron emission tomographic (PET) scanning of the chest have confirmed virtual absence of functional sympathetic nerve terminals in the myocardium of patients with pure autonomic failure(12). The decreased 6-[18F]fluorodopaminederived radioactivity does not result from diffuse coronary arterial narrowing, since the patients generally have normal myocardial perfusion as indicated by I3NH3 PET scanning. In pureautonomicfailure,thelossofsympatheticterminalsseems especially prominent in the heart. Whereas forearm and total body spillovers of

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norepinephrine are decreased but still present, cardiac spillover of norepinephrine is virtually absent. The patients have an absence of the normal arteriovenous increment in plasmaL-DOPAlevels in theheart,consistentwithcardiac sympathetic denervation (1 3). Pharmacological tests can distinguish pure autonomic failure from the Shy-Drager syndrome (14-20). Because of theloss of sympathetic nerve endings in the former condition, administration of drugs such as tyramine, yohimbine, d-amphetamine, and ephedrine, which release norepinephrine from sympathetic nerves, produces relatively small increases in plasma norepinephrine levels and ablood pressure. In contrast, administration of drugs that directly stimulate adrenoceptors, such as midodrine (Pro-AmatineTM) and phenylephrine (NeoSynephrineTM), produce vasoconstriction and increase blood pressure in patients with pure autonomic failure.Indeed, because of the phenomenon of “denervation supersensitivity,” where receptors for norepinephrine increase and other adaptive processes occur that exaggerate constriction of blood vessels, patients with pure autonomic failure can have surprisingly large increases in blood pressure in response to these drugs. Forthesamereason,thepatientswithpureautonomicfailurehave increased tachycardic responses to the R-adrenoceptor agonist, isoproterenol (2 1). Since the clearance of catecholamines from the bloodstream depends partly on Radrenoceptor-mediatedprocesses (22), isoproterenoladministrationmay accelerate its own clearance, and the relationship between the increase in pulse rate for a given infision rate of the drug might not reveal up-regulation of Radrenoceptors as well as would the relationship between the increase in pulse rateandtheplasmaisoproterenolconcentration (23,24). Studiesusing measurements of attained levels of isoproterenol have not been donein patients with pure autonomic failure. Most research about the pathophysiology of pure autonomic failure has not addressed whether loss occurs not only of peripheral but also of central noradrenergiccells.Post-mortemstudieshaveindicatedcell loss in central noradrenergic regions such as the locus ceruleus(25) and in spinal preganglionic neurons (26). Two types of neurochemical approaches, however, have indicated mainly if not exclusively peripheral noradrenergic deficiency. Esler and COworkers (27,28) have used 3H-norepinephrine infusion and arterial and internal jugular venous blood sampling to estimate the rate of entry of norepinephrine intotheinternaljugularvenousdrainage(cerebrovascularnorepinephrine spillover). Patients with pure autonomic failure had normal cerebrovascular norepinephrine spillover but decreased total body norepinephrine spillover (29), consistent with normal norepinephrine release in the central nervous system and decreased release in the periphery. Patients with peripheral autonomic failurepureautonomicfailureorautonomicfailure in thesettingofParkinson’s disease-usually have elevated ratios of cerebrospinal fluid:plasma

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concentrationsofbothnorepinephrineandDHPG,consistentwithmainly peripheral noradrenergic deficiency. Absolute concentrations of norepinephrine and DHPG, however, also tend to be low, and the sources of levels of these catechols in cerebrospinal fluid remain incompletely understood. Treatment of pure autonomic failure-and all other forms of chronic, primary autonomic failure-is directed mainly at the orthostatic hypotension, which is virtually always severe and disabling. Fludrocortisone, a high salt diet, and potassium supplementation (if needed) constitute the mainstay of treatment. Clinicians usually recommend elevation of the head of the bed on blocks, both to decrease hypertension during overnight recumbency and decrease overnight diuresis. Body stockings usually do not help. The patient should not consume large meals-especially for breakfast-because pooling of blood in the gut can decreasebloodpressuremarkedly.Drugssuchasibuprofen,octreotide, midodrine, L-dihydroxyphenylserine,orcombinationsofthesedrugsmay ameliorate orthostatic or post-prandial hypotension(30-32). As noted above, drugs that release norepinephrine from sympathetic nerves (e.g., sympathomimetic amines, yohimbine) might be expected to be ineffective in patients with pure autonomic failure, because of the lack of nerve terminals, whereas drugs that stimulate a-adrenoceptors (e.g., midodrine) would be effective (1 9). A recent study failedto discern differences in responses to the sympathomimetic amine, phenylpropanolamine, and yohimbine, and neither results of autonomic function tests nor plasma catecholamine levels predicted the responses (33). Current studies are assessing the possible therapeutic benefit of Ldihydroxyphenylserine(L-DOPS),acatecholaminoacidthatundergoes conversion to norepinephrine via L-aromatic-amino-acid decarboxylase(34,35). Erythropoeitin increases not only red cell mass but also blood pressure andhasbeenusedsuccessfullytotreatorthostatichypotension in anemic patients with autonomic neuropathy due to diabetes or pure autonomic failure (36). Autonomic Failure with Peripheral Neuropathy

Autonomic failure occurs commonly in conditions producing peripheral neuropathy. Probably the most common situations in which autonomic failure attendsperipheralneuropathyare in patientswithdiabetesmellitusor amyloidosis.Indiabetes,autonomicfailurecanbediffuse or localized,as discussed later.

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Amyloidpolyneuropathy Amyloidosis, whether familial or acquired, often features symmetric distalperipheralneuropathyandautonomicneuropathy,manifestedby orthostatic hypotension and derangements of gastrointestinal motility. Pure autonomic failure does not include sensorimotor neuropathy. Hereditary amyloid polyneuropathy

Most patients with type I familial amyloidotic polyneuropathy have an ability to increase their plasma norepinephrine levels during head-up tilt (37). Cardiac sympathetic nerves, however, seem substantially depleted, as indicated by markedly decreased myocardial concentrations of 1231-metaiodobenzylguanidine-derivedradioactivity (38). Treatment with L-DOPS can produce remarkable improvement (39), as one might expect from the development of denervation supersensitivity.

Diabetic Neuropathy About one-third of patients with diabetes mellitus have a peripheral neuropathy (40). The most common form is sensory; however, asymptomatic autonomic deficiencies occur not uncommonly and surely are under-diagnosed. In general, the more overt the sensory deficits (pain and numbness), the more likely the autonomic deficits(4 1). Diabetic autonomic neuropathy The occurrence of diabetic autonomic neuropathyis an adverse prognostic factor in patients with diabetes mellitus (42,43). Whether the increased risk reflects effects of cardiovascular autonomic pathology itself or an association withotherpathologicchanges(e.g.,nephropathy)orriskfactors(e.g., hypertension,decreasedbaroreflex-cardiacsensitivity)remainsunclear (42,44,45). Diabetic autonomic neuropathy takes several forms.In the cardiovascular system, these include decreased sympathetic neurocirculatory responsiveness, manifested by orthostaticorpost-prandialhypotension,aprogressiveor excessive fall in blood pressure during Phase I1 of the Valsalva maneuver, and a decrease in the Phase IV overshoot of bloodpressureafterreleaseofthe maneuver; decreased parasympathetic cardiovagal responsiveness, manifested by decreasedvariabilityofheartrate;anddecreasedsympatheticcholinergic responsiveness, manifested by a reduced quantitative sudomotor axon reflex test (QSART) response.

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Non-cardiovascular smooth muscle of the vas deferens, stomach, iris, and bronchial wall is also affected, producing ejaculatory failure, gastroparesis, iritis, decreasedbronchialreactivity,andevenrespiratoryarrest(46).Erectile impotence is more common in men with diabetes than in the general population ofmen,occursatayoungerage,andisoftenassociatedwithabnormal ejaculation (47). Patients with evidence of cardiovascular autonomic neuropathy often have concurrent gastroparesis, detected by delayed gastric emptying of radio-opaque markers (48) or by the 13C-octanoic acid breath test (49). The gastroparesiscanimprovewithpancreatictransplantation(50).Whereas cardiovascular autonomic dysfunction does not correlate with the duration of disease, pupillary autonomic dysfunction, sensorimotor neuropathy, retinopathy, and proteinuria do correlate with disease duration (51). Themechanismsunderlyingdiabeticautonomicneuropathyremain unknown. An obvious possibility is neurotoxic effects related to prolonged hyperglycemia (43). Although reversal of chronic hyperglycemia by pancreatic transplantation improves other forms of diabetic neuropathy, studies so far have disagreed about whether indices specifically of autonomic neuropathy improve (50,52). Recent research has considered an autoimmune mechanism (53-56). Small minorities of patients have anti-vagus, anti-cervical ganglia, or anti-adrenal medulla autoantibodies. Although patients with autonomic neuropathy are more likely to have serological evidence for autoimmunity (57,58), no study has demonstrated that autoantibodies actually contribute to autonomic neuropathy. Patients with diabetes and orthostatic hypotension have decreased total body production of norepinephrine, as measured by the sum of its metabolites (59),comparedwithpatientswhodonothaveorthostatichypotension, consistent with the orthostatic hypotension resulting from a generalized decrease in sympathetic terminal innervation. Many studies have used nuclear scanning techniques-especially 1231meta-iodobenzylguanidine ( 1231-MIBG)-to evaluate cardiac sympathetic innervation in patients with diabetic autonomic neuropathy. Although patients with diabetes and autonomic neuropathy are more likely to have abnormal myocardial 1231-MIBG-derived radioactivity than are patients with diabetes but withoutautonomicneuropathy,evenpatients in thelattergroupcanhave abnormal 1231-MIBG-derived radioactivity (60). This suggests that diabetic autonomic neuropathy is more prevalent than previously suspected from results of other commonly used clinical tests, such as power spectral analysis of heart rate variability (61). Overt myocardial denervation does not appear to occur in most patients, although the patients often have quantitative decreases in 1231MIBG-derived radioactivity in the inferior wall of the left ventricle (62-64). This finding seems more common in insulin-independent than in insulin-dependent diabetes (63). In a study that used llC-hydroxyephedrine and positron emission

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tomographic scanning (65), patients with diabetic autonomic neuropathy had sympathetic proximal left ventricular wall innervation, but with a suggestion of decreased coronary vasodilator reserve. These nuclear imaging techniques provide only limited information about the function of cardiac sympathetic nerves. To date, no study has evaluated the rate of spillover of norepinephrine or local production of other catecholsin the hearts of patients with diabetic autonomic neuropathy. Because of the high probability of associated coronary artery disease, patients with diabetes and intact sympathetic terminal innervation may have spotty decreases in delivery of sympathetic neuroimaging agents. Evaluation of possible cardiac sympathetic denervation should express the concentration of radioactivityderivedfromtheneuroimagingagentasafunctionofthe concentration of radioactivity derived from a perfusion imaging agent in the regions of interest. Patients with type 1 diabetes who have autonomic neuropathy have a high risk for developing severe insulin-induced hypoglycemia (66). Regardless of the presence or absence of symptomsof autonomic failure, the patients have impaired responses of glucagon, epinephrine, norepinephrine, growth hormone, and cortisol to hypoglycemia, compared with healthy subjects. Patients with autonomicsymptomshavebothmoreimpairmentofcounterregulatory responses and less awareness of hypoglycemia than do those without autonomic neuropathy (66). Autonomic failure increases the sensitivity to the vasodilator and hypotensive effects of insulin (67). Even without evidence of generalized autonomic failure, some patients withlong-standingdiabeteslosetheirabilitytomountepinephrineand glucagonresponsestoinsulin-inducedhypoglycemiaandcanremain dangerouslyunaware of the hypoglycemia (68). The finding that impaired glucose counterregulation can occur independently of autonomic neuropathy is consistent with separate regulation of the sympathoneural and adrenomedullary effectors. Painful diabetic neuropathy Peripheral symmetric somatosensory polyneuropathy, the most common form of diabetic neuropathy, is a classical long-term complication of both Type 1 andType 2 diabetesmellitus.Prevalenceincreaseswiththedurationof diabetes and the level of glycemia. Symptoms vary widely and can include pain ranging from mild to intractable. Findings at physical examination are decreased or absent ankle tendon reflexes and decreased sensation to touch, vibration and temperature.Thesesignsarefarmorepronounced in the feet. The pain in diabetic neuropathy is often described as shooting, burning, stabbing, or aching

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bilaterally in the feet. Sometimes pain in responsetononpainfulstimuliis reported (allodynia). Although some distinguish pain related to small fiber neuropathy from thatrelatedtolargefiberdysfunction,mostpatientswithpainfuldiabetic neuropathy have a mixture of small and large fiber damage. The mechanisms causing the pain are not well understood. Overexcitability or aberrant firing of neuronal sprouts in regenerating neurons may play a role in some cases. Since plasma norepinephrine levels are higherin painful than in painless diabetic neuropathy ( 5 ) and drugs such as amitryptiline, desipramine, and clonidine canbe beneficial, the hypothesis has been raised that the pain may in some patients be related to abnormal activity of the sympathetic nervous system. In order to examine the possible involvement of local abnormalities of sympatheticinnervationandfunction in painfuldiabeticneuropathy,we measuredregionalnorepinephrinespillovers,conducted 13NH3 and 6[ 18F]fluorodopamine positron emission tomographic (PET) scanning, and evaluated effects of the ganglion blocker trimethaphan in patients with painful diabeticneuropathyofthefeetwhodidnothaveevidencefordiffuse sympathetic neurocirculatory failure. The arteriovenous differences in plasma norepinephrine and DHPG levels and calculated norepinephrine spillover in the unaffectedupperextremitiesofdiabeticpatientsdidnotdifferfrom corresponding values in normal volunteers or in patients with complex regional pain syndrome. In contrast, values for all these variables were significantly lower in the affected lower extremities of the diabetic patients. The fractional extraction of 3H-norepinephrine was also lower in the feet of the patients with painful diabetic neuropathy thanin either comparison group. Ganglion blockade decreased norepinephrine spillover much less in the affected than unaffected limbs the in diabetic patients. Finally, perfusion-corrected 6[ 18F]fluorodopamine-derivedradioactivity was decreased in the affected feet, approaching values observedin normal volunteers whohad been pre-treated with desipramine.Theseresults,unpublishedasofthiswriting,provide neurochemical and neuroimaging evidence for selective regional sympathetic denervation in the feet of patients with painful diabetic neuropathy. Since trimethaphan infusion did not affect the pain, the pain does not appear to be sympathetically-mediated. Dopamine-&-Hydroxylase Deficiency

Deficiency of dopamine-bhydroxylase (DBH deficiency) is a very rare cause of orthostatic hypotension. Because the disease can be treated remarkably effectively, however, the diagnosis merits consideration in patients undergoing evaluation for autonomicfailure.

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DBH catalyzes the conversion of dopamine to norepinephrine in the vesicles in sympathetic nerves, the adrenal medulla, and the brain. In DBH deficiency, binding of norepinephrine to a-adrenoceptors in blood vessel walls does not occur, even with sympathetic nerve traffic and release of the contents of the vesicles. In fact, release of dopamine instead of norepinephrine can actually dilate blood vessels in situations where norepinephrine-induced vasoconstriction normally occurs. Patients with DBH deficiency therefore have severe, persistent orthostatic hypotension. Lack of DBH enzyme activity causes the DBH deficiency. The disease results not from dysregulation but from actual absence of the enzyme. The patients have a normal DBH gene, and the basis for the apparent defect in transcription or translation remains unknown. Cases of DBH deficiency appear to have arisen sporadically, and the mode of inheritance, if any, is unknown. As notedfordeficiency of L-aromatic-amino-aciddecarboxylase,nospecific mutations have been reported to date for patients with absence of DBH. The absence of immunoreactive DBH in plasma or cerebrospinal fluid (69) suggests that the underlying molecular defect may involve abnormal expression of the DBH gene. DBH deficiency produces a striking and unique neurochemical pattern, withextremelyloworabsentconcentrationsofnorepinephrine,DHPG, vanillylmandelic acid, and methoxyhydroxyphenylglycol (MHPG) and increased concentrations of dopamine, dihydroxyphenylacetic acid, homovanillic acid, and L-DOPA (9). The increase in plasma L-DOPA levels suggests compensatorily increased tyrosine hydroxylation in sympathetic nerves (70). Patients with DBH deficiency have essentially no norepinephrine or norepinephrine metabolites in their plasma, cerebrospinal fluid, or urine (9,71). Because of the inability to release norepinephrine, patients with DBH deficiencyhavechangesintheValsalvamaneuverindicatingsympathetic neurcirculatory failure, Since the parasympathetic nervous system is intact, and since the chemical messenger of the parasympathetic system is acetylcholine, not norepinephrine, patients with DBH deficiency would be expected to have normalheartratechangesduringandafterperformanceoftheValsalva maneuver.Onewouldalsoexpectnormaleccrinesweating,sincethe neurotransmitter released from sympathetic nerve terminals in sweat glands is acetylcholine, not norepinephrine. MicelackingtheDBHgeneusuallydie in utero. Norepinephrine therefore seems absolutely required for normal uterine development and survival to birth. Although mutant mice lacking DBH die during fetal development (72), humans with absent DBH activity have surprisingly few neurological signs. The survival of patients with DBH deficiency to adulthood therefore constitutes a paradox of clinical neurogenetics.

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TreatmentwithL-dihydroxyphenylserine(L-DOPS),anaminoacid converted to norepinephrine by decarboxylation, bypasses the enzymatic defect and produces remarkable clinical improvement in patients with DBH deficiency (73,74).L-DOPSresemblesL-DOPA,butwithahydroxylgroupatthe B position of the hydrocarbon chain. Just as L-aromatic-amino-acid decarboxylase catalyzestheconversionofL-DOPAtodopamine,L-aromatic-amino-acid decarboxylase catalyzes the conversion of L-DOPS to norepinephrine. Treatment with L-DOPS therefore enables norepinephrine synthesis by bypassing the deficiency of DBH. In sympathetic nerve terminals of DBH deficient patients, the vesicles store the norepinephrine synthesized by this bypass route. When the treated patients stand, they release norepinephrine from the terminals, blood vessels constrict, and the blood pressure is maintained. Treatment with L-DOPS also rescues DBH-deficient mice (72). Familial Dysautonomia

Of several forms of rare hereditary sensory and autonomic neuropathies (HSAN), familial dysautonomia (originally called the Riley-Day syndrome) is HSANtype 111. HSANsyndromesgenerallyresultfromderangements in maturation or migration of neural crest-derived progenitor cells in the formation of sensory and autonomic populations. The pathogenetic basis specifically of familial dysautonomia remains unknown. Patients with familial dysautonomia share an Ashkenazic Jewish ethnic derivation, suggesting that one or a few mutations account for the majority of cases. The carrier rate among people with this background is about 1 in 30. The disease is transmitted as an autosomal recessive trait. The locus of the genetic mutation causing familial dysautonomia, on chromosome 9q, was described a few years ago(75). The exact mutation is unknown. Familial dysautonomia produces a constellation of clinical findings that suggest deficient activities of multiple peripheral neurotransmitter systems including catecholamine systems. Affected patients have neurogenic orthostatic hypotension, absent lingual fungiform papillae, no histamine-induced flare or overflow tears, and episodic paroxysmal hypertension, nausea, and vomiting. Familial dysautonomia often presents in neonates as poor feeding, with poorsucking,coughing,aspiration,excessivedrooling,aerophagia,and vomiting or regurgitation. Lack of overflow tearing constitutes a distinctive sign. Other signs include episodic blotchy flushing associated with emotional excitement and increased sweating. The infant fails to meet height, weight, and behavioraldevelopmentalmilestones.Expressivelanguageisdelayedbut receptive language is not. Toilet training is difficult, because of constipation and enuresis.

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Children with familial dysautonomia have a tendency to retch and vomit during emotional distress, with episodes of “dysautonomic vomiting crisis” that include tachycardia, hypertension, red blotching, and diaphoresis. They also have a tendency to breath-holding, cyanosis, and fainting. In school years, kyphoscoliosis develops in most patients, and this progresses into adulthood, often necessitating corrective orthopedic surgery. Autonomic and sensory defects become overt, with episodes of orthostatic weakness, hypotension,and fainting, and decreased senses of taste, pain, and temperature, whereas touch and pressure sensations remain intact. Two virtually pathognomonic diagnostic clues are wheal without flare reaction after intradermal injection of histamine and absent fungiform lingual papillae. Despite clinical symptoms and signs of sympathetic neurocirculatory failure,patientswithfamilialdysautonomiahavenormalplasmalevelsof norepinephrine during supine rest, but with absence of the increase in plasma norepinephrine levels during orthostasis (76). The finding of an increased ratio of homovanillic acid and vanillylmandelic acid in urine (77) led to an early suggestion of DBH deficiency. Allpatientswithfamilialdysautonomiaseemtosharethesame abnormality of plasma levels of catechols (78). Plasma levels of L-DOPA are increased and of DHPG decreased, so that the plasma L-D0PA:DHPG ratio is elevated in all patients. As noted in the chapter about clinical assessment, in healthy humans plasma L-DOPAand DHPG levels correlate strongly positively, presumablyreflectingabalancebetweensynthesisandturnoverof norepinephrine in sympathetic nerves. The elevated plasma L-D0PA:DHPG ratio in patientswithfamilialdysautonomicthereforeprobablyreflectsa decreased ability to synthesize norepinephrine and compensatorily increased tyrosine hydroxylation, consistent with arrested development of sympathetic terminalinnervation,whichwouldresultinanabilitytosynthesize catecholamines in post-ganglionic cells bodies but with decreased vesicular norepinephrine storesin the nerve terminals. Such a pattern could reflect decreased effects of nerve growth factor or another neurotrophic factor in embryological and post-natal development of unmyelinated autonomic and sensory nerves. Nerve growth factor has merited particular attention because of its role in the development of both sympathetic and dorsal root ganglion cells. Studies to date have not revealed an abnormality either in the gene for nerve growth factor or its receptor (79-81); however, patients with the related disease HSAN-IV (congenital insensitivity to pain with anhidrosis) have mutations of the gene encoding the Trk A receptor for nerve growth factor (82). The plasma neurochemical pattern in familial dysautonomia does not appeartofitanysingleabnormalityofcatecholaminesynthesis,storage, reuptake, or metabolism. Instead, the findings suggest more global arrested

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differentiationofperipheralcatecholaminesystemsduringembryological development. The phenotypic pattern nevertheless points to deficient innervation of the adrenal medulla and other organs. Mechanisms by which the bound nerve growth factor receptor signals the cell bodies remain poorly understood; from the neurochemical phenotype, one may speculate that the genetic abnormality involves a protein participating in these mechanisms. AUTONOMIC FAILURE WITH CENTRAL NEURODEGENERATION Multiple System Atrophy (MSA)

MSA with Sympathetic Neurocirculatory Failure (the Shy-Drager Syndrome) In 1960, Shy and Drager reported cases of degeneration of the brain associatedwithconsistent,persistentorthostatichypotension (83). The syndrome they described came to be called the Shy-Drager syndrome. Shy-Dragersyndrome is aform of multiplesystematrophy (84). Multiple system atrophy (MSA) consists of signs and symptoms of progressive degeneration of more than one central neural system, including regions involved with outflows to the autonomic nervous system. This differs from multiple sclerosis,characterizedclinically by remissionsandexacerbationsand by relativelyfewautonomicchanges.MSA,withorwithoutsympathetic neurocirculatory failure, is progressive and eventually lethal. Median survival is about 6 years from the time of diagnosis, with death resulting from progressive neurodegeneration. MSA occurs as a sporadic disease of middle-aged or elderly people of either gender. Symptoms and signs of progressive cerebellar, nigrostriatal, or (less commonly) corticospinal, supranuclear, or anterior horn degeneration develop approximately concurrently with symptoms and signs of autonomic failure.Symptomsandsignsofparasympatheticdegenerationinclude constipation, decreased thermoregulatory sweating, and decreased bladder tone, resulting in urinary incontinence, frequency, urgency, and the need for selfcatheterization. Other symptoms and signs of brainstem degeneration include abnormal eye movements, slurred speech, dyscoordinated swallowing, abnormal breathing,andrecurrentaspiration.Thesecanoccurinpatientswithout orthostatic hypotension or other evidence of sympathetic neurocirculatory failure. Upon postmortem examination, patients with the Shy-Drager syndrome havedepletionoftyrosinehydroxylaseimmunoreactivityintherostral ventrolateralmedulla,caudalventrolateralmedulla,andintermediolateral columns of the spinal cord ( 8 5 ) , consistent with diffuse loss of catecholaminergic cellsin this major medullary source of descending projections

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PAF

MSAp MSA, MSA,

Park+AF

Autonomic Parkinsonian Cerebellar, pyramidal, or both Figure 8-2 Classification of chronic, primary autonomic failure. Notesimilar clinical findings in the parkinsonian form of multiple system atrophy (MSAp) and in Parkinson’s disease with autonomic failure (Park+AF). MSAc = MSA with signs and symptoms predominantly of cerebellar degeneration; MSAM = MSA with mixed parkinsonsian and cerebellar signs.

to sympathetic pre-ganglionic neurons. The patients also have loss of dopamineB-hydroxylase and tyrosine hydroxylase enzyme activity in the locus ceruleus, themainsourceofnorepinephrineinthebrain(25).Theoccurrenceof “automatic bladder’’ seems associated pathologically with neuronal loss in Onuf’s nucleus in the spinal cord(86,87). Degeneration of the nucleus ambiguus in the medulla may explain dysfunction of the cricoarytenoid muscle of the larynx and slurred speech (88), although necropsy studies have not confirmed loss of motor cellsin the nucleus ambiguus(89). Recent attention has focused on argyrophilic glial cytoplasmic inclusions as a common pathogenetic feature of striatonigral degeneration (SinemePunresponsive parkinsonism), sporadic olivopontocerebellar atrophy, and the Shy-Drager syndrome. The inclusions, in oligodendrocytes, consist of tubular or anti-betastructures (90) stained by anti-ubiquitin but not by anti-alphatubulin or anti-tau antibodies (91). The inclusions also contain alpha-synuclein, a structural component of the filaments in Lewy bodies of Parkinson’s disease and some forms of dementia. The inclusions seem associated with cell death by apoptosis (92). These findings suggest progressive defects in facilitation of neurotransmission by oligodendrocytes, rather than neuronal cell death, as an etiologic basis of MSA. This might fit with the finding of decreased postganglionic sympathetic nerve traffic but preservation of sympathetic terminal innervation in the periphery in patients with the Shy-Drager syndrome. Some

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have questioned the specificity of glial cytoplasmic inclusions in MSA (93), and a pathogenetic role of the inclusions remains unproven. Currently accepted classification schemes lump all autonomic failure together(Figure 8-2), includingsympatheticcholinergicabnormalitiesof sweating;parasympatheticcholinergicabnormalities of penileerection, urination,anddefecation;andsympatheticnoradrenergicabnormalitiesof neurocirculatory regulation. As discussed in the following, however, clinicaland laboratorytestingcandistinguish MSA withsympatheticneurocirculatory failure(theShy-Dragersyndrome)from MSA without sympathetic neurocirculatory failure, and a pathophysiology-based classification scheme has been published (( 12,94), Figure 8-3). Diagnostic confusion often delays identifying the Shy-Drager syndrome. Part of the confusion results from relative unfamiliarity among neurologists about mechanisms of blood pressure regulation by the autonomic nervous system and from failure to measure routinely the blood pressure and pulse rate responses to standing for five minutes in patients with signs and symptoms of central nervous system degeneration. The diagnosis of the Shy-Drager syndrome depends importantly on the medical history. In men, impotence (inability to experience or maintain erection of the penis, or ejaculatory failure), constitutes an early symptom. Clumsiness ofgait,dizzinessafterstandinguporafteralargemeal,slurredspeech, dyscoordination, and slow initiation of movements develop and progressively worsen over months. Decreased sweating can lead to intolerance of changes in environmentaltemperature,decreasedresponsivenessofgutmotionto constipation, and decreased bladder tone to urinary retention, urinary frequency and urgency. Bladder problems often lead to the eventual requirement to selfcatheterize in order to urinate. Decreased protection of the airway increases susceptibilitytoaspirationoffoodand so tochokingortoaspiration pneumonia. Because of dizziness standing, slow initiation of movement, and clumsiness, the patient becomes more and more debilitated, progressing from cane to walker to wheelchair to a bedridden existence, with increasing risks of deathfrompneumonia,urinarytractinfections,pulmonaryembolism, aspiration, stridor, or sudden death. Themultiplebutnon-specificsignsintheShy-DragerSyndrome probablyrelatetodegenerationofmultipleneurotransmittersystems. Parkinsonian signs include “cogwheel” rigidity in passive movements of the arm, facial stare, “pill-roll” tremor, and slow but accurate movements. Signs of dementia include decreased short-term memory, decreased orientation as to person, place, and time, decreased ability to calculate or to answer questions logically, and infantile reflexes such as grasp or rooting reflexes. Cerebellar signs include a wide-based ataxic gait, intention tremor, and poor performance of rapid alternating movements. Brainstem signs include decreased gag reflex,

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Figure 8-3 Pathophysiology-basedclassificationofchronic,primary autonomic failure.

abnormalities of conjugate gaze, slurred speech and dyscoordinated swallowing, deranged circulatory reflexes, and orthostatic hypotension. Consistentwithabnormalcentralpathwaysmediatingbaroreflexes, patients with MSA and sympathetic neurocirculatory failure often have a failure to increase plasma AVP levels during upright tilt(95). The patients also havean absence of clonidine-induced increases in growth hormone levels, unlike PAF patients or patients with Parkinson's disease (96). The etiology of MSA may be autoimmune, since CSF of MSA patients often contains an antibody that reacts with rat LC tissue in vitro (97). Distinctions among MSA without sympathetic neurocirculatory failure, Parkinson's disease with autonomic failure, and the Shy-Drager syndrome have posed a persistent challenge. Some investigators have equated MSA with the Shy-Drager syndrome. Others consider MSA as an umbrella diagnosis that includestheShy-Dragersyndromewhenorthostatichypotensionfigures prominently in the clinical presentation but also includes forms where signs of cerebellar atrophy or of Parkinson's disease stand out. The relationship of all three to Parkinson's disease with autonomic failure can be unclear clinically. Recent proposals have suggested discarding Shy-Drager syndrome as a diagnosis

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(98). The following discussion uses the Shy-Drager syndrome interchangeably with MSA with sympathetic neurocirculatory failure. Patients with the Shy-Drager syndrome often have a failure to increase the pulse rate normally during standing or manipulations of breathing. Since these responses depend mainly on changes in vagal parasympathetic outflow to the heart, not changes in sympathetic neural outflow to the heart, this finding does not of itself provide convincing evidence for failure of the sympathetic nervous system. Changes in beat-to-beatbloodpressure,however,associatedwith performance of the Valsalva maneuver, can indicate sympathetic neurocirculatory failure and support a diagnosis of the Shy-Drager syndrome in a patient with symptoms and signs of central neural degeneration. As in other conditions associatedwithsympatheticneurocirculatoryfailure, in theShy-Drager syndrome the blood pressure decreases progressively during Phase I1 of the Valsalva maneuver and fails to overshoot the baseline blood pressure in Phase IV after release of the maneuver. Although one can diagnose the Shy-Drager syndrome from the clinical findings and beat-to-beat blood pressure responses to the Valsalva maneuver, other diseases featuring central neurodegeneration and sympathetic neurocirculatory failure exist-in particular, autonomic failure in the setting of Parkinson’sdisease.Patientswithautonomicfailureinthesettingof Parkinson’sdiseasetypicallyrespondtoL-DOPA/carbidopa(SinemetTM), whereas patients with the Shy-Drager syndrome typically do not. Clinicians may not initiate treatment, out of fear of worsening the patient’s orthostatic symptoms.Moreover,somepatientswiththeShy-Dragersyndromereport improvement with Sinemet.TM Although patients with pure autonomic failure or with the Shy-Drager syndrome have decreased or absent increases in plasma norepinephrine levels during orthostasis (l), during supine rest patients with pure autonomic failure usuallyhavedecreasedplasmalevelsofnorepinephrine,L-DOPA,and dihydroxyphenylglycol, whereas patients with the Shy-Drager syndrome have normal plasma levels of all three catechols (9). Patients with the Shy-Drager syndrome also have normal total body and cardiac spillover of norepinephrine (10,12). These neurochemical findings are consistent with functionally intact sympathetic nerve terminals in the Shy-Drager syndrome. Because of sympathetic autonomic failure, patients with the Shy-Drager syndrome pool blood in the legs when they stand. This may impede delivery of plasmanorepinephrinetoremovalsitessuchasthekidney,andsince sympatheticnerveterminalsreleasenorepinephrinecontinuouslyintothe bloodstream, the prolongation of removal from the bloodstream can increase the plasma norepinephrine concentration, even in the absence of an increase in sympathetic nerve traffic during standing (2). Thus, the finding of an orthostatic

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increase in theplasmanorepinephrineconcentrationdoesnotexcludethe diagnosis of the Shy-Drager syndrome. Resultsof6-[18F]fluorodopaminePETscanning(12)andother neuroimaging procedures have indicated the presence of sympathetic terminal innervation in the left ventricular myocardium of patients with the Shy-Drager syndrome.Indeed,the6-[18F]fluorodoparninePETscanningresultshave demonstrated significantly increased myocardial 6-[8F]fluorodopamine-derived radioactivity,comparedwithvalues in normalvolunteers.Sinceganglion blockade with trimethaphan also increases myocardial 6-[18F]fluorodopaminederived radioactivity (99), the increased radioactivity could reflect decreased cardiac post-ganglionic sympathetic nerve traffic to intact terminals. Analogousneuroimagingstudieshavehaveenabledthefirstclear distinctionbetweentheShy-Dragersyndromeandautonomicfailure in Parkinson’sdisease(Figure6-13).WhereaspatientswiththeShy-Drager syndrome have normal uptake and retention of sympathoneural imaging agents, patientswithautonomicfailureinthesetting of Parkinson’s disease have markedly decreased or absentuptakeandretentionofthoseagents(100). Analogously,whereaspatientswiththeShy-Dragersyndromehave approximately normal cardiac norepinephrine spillover, patients with autonomic failure in the setting of Parkinson’s disease have markedly decreased cardiac norepinephrine spillover. SuchstudiesalsocandistinguishtheShy-DragersyndromeMSA without sympathetic neurocirculatory failure. As noted above, these conditions appear to differ clinically in that orthostatic hypotension occurs only in the former.WhereaspatientswiththeShy-Dragersyndromehaveincreased myocardial concentrations of 6-[ 18F]fluorodopamine-derived radioactivity, patients with MSA without sympathetic neurocirculatory failure have normal6[ 8F]fluorodopamine-derived radioactivity. Patients with the Shy-Drager syndrome do appear to have residual postganglionicsympatheticnervetraffictotheheartandvasculature,because ganglion blockade with trimethaphan evokes large decreasesin blood pressure (Figure 8-4) and in cardiac norepinephrine spillover. Thus, in the Shy-Drager syndrome, it appears that the post-ganglionic neurons become “disconnected” fromthecentralnervoussystem.Forthisexplanationtomakesense, considering that cardiac norepinephrine spillover is normal in the Shy-Drager syndrome(12),onemustalsohypothesizethatpre-synapticadjustments augmenting amount of norepinephrine that reaches the bloodstream compensate for the decreased rate of post-ganglionic nerve trafflc. What these adjustments might be remains a mystery.

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180 160

140 120 100

80 ' I-"

70 Minutes

- 1

Figure 8 4 Blood pressure during trimethaphan infusion in a patient with the Shy-Drager syndrome. Trimethaphan infused at a dose (0.25 mg/min) that normally does not affect blood pressure decreases blood pressure substantially in the Shy-Drager syndrome.

Efforts to treat patients with the Shy-Drager syndrome have focused almost exclusively on the orthostatic hypotension. Several forms of treatment can be effective, including fludrocortisone, a high salt diet, and potassium supplementation (if needed); elevation of the head of the bed on blocks; frequent small meals; and drugs such as ibuprofen, octreotide, or L-DOPS to ameliorate post-prandial hypotension. Drugs that release norepinephrine from sympathetic nerves (e.g., sympathomimetic amines, yohimbine) may also be effective, since the patients possess functionally intact sympathetic terminal innervation; drugs that stimulate a-adrenoceptors (e.g., midodrine) can also help (19,20). The reportedly greater beneficial effect of L-DOPS in the Shy-Drager syndrome than in pure autonomic failure (35) has led to speculation that the pressor response to L-DOPS depends on an action in the central nervous system and requires intact peripheral sympathetic innervation (Figure8-5). Thus, in a patient with the ShyDrager syndrome who had recordable skeletal muscle sympathetic activity, administration of L-DOPS increased the rate of sympathetic nerve (34). traffic No drug has been developed or is being studied to treat the central neurodegeneration to which patients with the Shy-Drager syndrome eventually succumb. The mechanism of the central neurodegeneration remains obscure. As noted above, the finding of an immunoglobulin in the cerebrospinal fluid of patients with the Shy-Drager syndrome that binds to rat locus ceruleus suggests an autoimmune process (97); however, no study to date has replicated this finding or extended it to other central noradrenergic areas. Other potential mechanismsincludeneurotoxicityresultingfromongoingoxidative

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CNS

SNS1 X S M O O M MUSCLE

"@q ~~y Bloodstream Figure 8-5 Putative mechanisms of action of L-threo-dihydroxyphenylserine (L-DOPS) compared with those of tyramine (Tyr), amphetamine (Amphet), yohimbine (YOH), and midodrinein the treatment of the Shy-Drager syndrome. Concurrenttreatmentwithcarbidopawouldaugmentproductionof norepinephrine (NE) inthecentralnervoussystem(CNS).LAAAD = Laromatic-atnineacid decarboxylase.

deamination of monoamines, an environmental neurotoxin, an infectious agent thatcausesdamage by molecularmimicry,acceleratedaging-associated apoptosis, decreased production of neurotrophic factors, or various combinations of these mechanisms. Anecdotal evidence has suggested that in patients with the Shy-Drager syndrome, i.v. administration of yohimbine rapidly but transiently improves

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speechandswallowing,leadingtospeculationthatadrugthatincreases occupation of post-synaptic adrenoceptors or increases central norepinephrine synthesis might ameliorate the patient’s clinical status, in a manner analogous to the benefits provided by dopamine receptor agonists and L-DOPA in the treatment of Parkinson’s disease. Clinical trials of L-DOPS are under way. Because patients with the Shy-Drager syndrome have intact sympathetic nerve terminals and have deficient baroreflexes, the patients have marked increases in bloodpressureafteradministrationofadrugthatreleases norepinephrine from sympathetic terminals. Chinese herbal remedies include ma huang, for, among other maladies, asthma. Ma huang taken as a tea has been called “herbal ecstasy,” presumably because of its euphoric effects. Ma huang’s main active ingredient, ephedrine, acts as a sympathomimetic amine, producing its effects by binding to aadrenoceptors and releasing norepinephrine from sympathetic nerves. In a patient with absent baroreflexes, taking ma huang can evoke paroxysmally increased blood pressure. Treatments for the constipation, urinary incontinence or retention, and parkinsonianfeatures in patientswiththeShy-Dragersyndromeare symptomatic. Unfortunately, many patients with the Shy-Drager syndrome and signs of Parkinson’s disease do not respond well to SinemetTM. Indeed, this is one of the few clinical features distinguishing the Shy-Drager syndrome from Parkinson’s disease. Progressive dyscoordination of swallowing and episodes of aspiration can lead to the requirement of placing a tracheostomy. Our recent, anecdotal experience has indicated that at least in some patients with the ShyDrager syndrome, oral yohimbine treatment can improve the patient’s speech and swallowing. The durationof these benefits is currently unknown. MSA with isolated parasympathetic failure The most direct clinical means to distinguish the Shy-Drager syndrome

from MSA without sympathetic neurocirculatory failureis to measure the blood pressure with the patient supine and with the patient upright for a few minutes. One should not assume that an absence of complaints referable to orthostatic hypotension excludes the existence of orthostatic hypotension. Orthostatic hypotension is especially prominent in the morning, after a meal, andin a warm environment. Patients with MSA who do not have sympathetic neurocirculatory failure have normal plasma norepinephrine levels when the patient is supine and an increaseinthoselevelswhenthepatientstands.Cardiacnorepinephrine spillover is normal, as are myocardial concentrations of 6-[18F]fluorodopaminederived radioactivity (12). In response to the Valsalva maneuver, heart rate typicallydoesnotincrease,indicatinglackofmodulationofbaroreflex-

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cardiovagal function; however, blood pressure during Phase IV overshoots baseline,indicatingthepresenceofatleastsomereflexivemodulationof sympathetically-mediated vasoconstriction. The patients usually have other symptoms and signs of parasympathetic failure, such as urinary retention (often eventually requiring self-catheterization), constipation, and oropharyngeal dyscoordination. The prognosis appears the same as thatin patients with the Shy-Drager syndrome. Treatment of the several facetsofMSAissymptomaticanddoesnotamelioratetheprogressive deterioration.Patientsdieofaspiration,aspirationpneumonia,sepsisfrom urinary tract infections, or cardiopulmonary arrest. Autonomic Failure in Parkinson’s Disease

Cliniciansoftenattributeorthostatichypotensioninpatientswith Parkinson’s disease to SinemeFM(1 0 1). Acute administration of a combination of L-DOPA with an inhibitor of L-aromatic-amino-acid decarboxylase, however, does not elicit orthostatic hypotension (102). Recent findings have suggested insteadthatorthostatichypotensioninParkinson’sdiseasecanreflect sympathetic neurocirculatory failure. The prevalence of sympathetic neurocirculatory failure in Parkinson’s disease is unknown-partly because neurologists rarely measure supine and uprightvitalsigns.Orthostatichypotensionappearstooccursurprisingly commonly. In a series of 91 consecutive patients with Parkinson’s disease, an orthostatic fall in systolic blood pressure greater than 20 mm Hg occurred in 58% ofthepatients (103), and ina substantialminoritytheorthostatic hypotension was asymptomatic. Symptomatic orthostatic hypotension is more likely in patients with Parkinson’s disease of long duration and in patients undergoing treatment with relatively high doses of L-DOPA or dopamine receptor agonists. The frequency of autonomic failurein Parkinson’s disease depends on the means used to detect autonomic failure. As indicated above, only a minority of patients with orthostatic hypotension have orthostatic symptoms. In one small series (104), autonomic dysfunction, defined by two or more abnormal scores for heart rate and blood pressure responses to standing, the Valsalva maneuver, or sustained handgrip, occurred in about 1/4 of patients. In our ongoing series, we have noted sympathetic neurocirculatory failure (detectedby absence of the Phase IV overshoot of systolic blood pressure after release of the Valsalva maneuver) or cardiac sympathetic denervation (detected by 6[ 18F]fluorodopamine PET scanning), in most patients with Parkinson’s disease, even without signs or symptoms of autonomic failure. In the diagnostic classification of chronic, primary autonomic failure syndromes, peripheral autonomic failure associated with Parkinson’s disease is

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considered separately from MSA (84,105). Until relatively recently, the only means to distinguish Parkinson’s disease with autonomic failure from MSA with parkinsonian features was responsiveness to SinemetTM, since patients with Parkinson’s disease usually improve with SinemetTM treatment, whereas patients with MSA usually do not. In practice, this distinction often does not help in the differential diagnosis, because, as noted above, clinicians often feel reluctant to treatparkinsoniansymptomsusingSinemetTM,outoffearofWorsening orthostatichypotension;patientswithparkinsonismmaynotrespondto SinemetTM (leading to a diagnosis of “nigrostriatal degeneration”); and because Some patients with MSA and parkinsonian features do benefit clinically from SinemetTM. Patients with Parkinson’s disease and sympathetic neurocirculatory failure havehigherplasmanorepinephrinelevelsthanthosewithoutsympathetic neurocirculatoryfailureand inpatientswithMSAwithsympathetic neurocirculatory failure (17), supporting the existence of Parkinson’s disease withautonomicfailureasadistinctentity,characterizedbydecreased sympathetic terminal innervation. Administrationofthe1x2-adrenoceptoragonist,clonidine,elicits increases in plasma levels of growth hormone in healthy subjects, patients with pure autonomic failure, and patients with autonomic failure in the setting of Parkinson’sdisease,whereaspatientswiththeShy-Dragersyndromehave attenuated or absent growth hormone responsesto clonidine (106). Results of evaluations of 1231-metaiodobenzylguanidinescintigraphy and 6-[18F]fluorodopamine PET scanning have provided clear distinctions between sympathetic neurocirculatory failure associated with Parkinson’s disease from that associated with the Shy-Drager syndrome (12,86,87,89,100). Indeed, the results appear to enable diagnostic distinctions in individual patients. We have found so far that all patients with sympathetic neurocirculatory failure associated withParkinson’sdiseasehavemarkedlydecreasedcardiacnorepinephrine spillover, decreased or absent cardiac arteriovenous increments in plasma levels ofdihydroxyphenylglycol,L-DOPA,anddihydroxyphenylaceticacid,and markedly decreased or absent myocardial 6-[18F]fluorodopamine-derived radioactivity. This pattern indicates decreased or absent synthesis, neuronal uptake, and turnover of catecholamines. Patients with Parkinson’s disease and autonomic failure have relatively smallincreases in plasmanorepinephrinelevelsduringi.v.infusionof yohimbine and relatively small decreases in plasma norepinephrine levels during i.v. infusion of the ganglion blocker, trimethaphan, compared to the levels in patients with the Shy-Drager syndrome and in normal control subjects. These findingsarealsoconsistentwithlossofsympatheticnerveterminals in Parkinson’s disease and autonomic failure.

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These results indicate that Parkinson’s disease can reflect not only central butalsoperipheralcatecholaminergicneurodegeneration.Whetherthe neurodegenerationreflectsaneurotoxic,autoimmune,viral,orprimary neurodegenerative condition is unknown. Patients with autonomic failure in the setting of Parkinson’s disease can have a circulating antibody that recognizes a protein triplet in extracts of rat sympathetic neurons( 5 8 ) ; however, the antibody production could result secondarilyfrom neuronal damage rather than causing it. BothL-DOPAandpharmacologicalmanipulationsthatincreaselevelsof aldehyde intermediates after oxidative deamination of catecholamines produce neurotoxic effects in rat pheochromocytoma (PC12) cells (107). The aldehyde intermediate produced by oxidative deamination dopamine, of dihydroxyphenylacetaldehyde (DOPAL or DOPALD), hasbeen detected in brain tissue of patients with Parkinson’s disease (108) and Alzheimer’s disease (109). No literature has described the occurrence of the aldehyde intermediate produced by oxidative deamination of norepinephrine,dihydroxyphenylglycoaldehyde. Anecdotally, the prognosis for patients with peripheral autonomic failure associated with Parkinson’s disease seems better than that in patients with any form of MSA and depends mainly on the durationof SinemePM responsiveness.

HYPERTENSION Although increased sympathetic nervous system activity or reactivity probably occurs early in the development of hypertension, the determination of both blood pressure and sympathetic nervous outflows by multiple homeostats impliesacomplexandindirectrelationshipbetweensympatheticnervous system outflows, however measured,and blood pressure (Figure 8-6). In some individuals, hypertension might result from interference with inhibitory feedback. Given the effects of homeostat disruption, interference with inhibitoryfeedbackshouldmainlyincreasethelabilityofbloodpressure. Disinhibition of sympathetically-mediated norepinephrine release could reflect interruption of reflex arcs at any of several levels. Thus, patients with baroreflex failure typically have labile hypertension (1 10). Alternatively,abnormalneurocirculatoryregulationcouldreflect inappropriate elicitation of neuroendocrine stress response patterns that include resetting of barostats. The inability to separate cause from effect here has frustrated efforts to elucidate the relationship between baroreflex function and sympathoneural outflow in patients with hypertension. Many neuronal, endocrine, paracrine, autocrine,and intracellular systems, affecting hemodynamic conditions in severalvascularbeds,regulateblood pressure (Figure 8-6). The activities of virtuallyall these systems, including the sympathetic nervous system, adrenomedullary hormonal system, parasympathetic nervous system, hypothalamo-pituitary-adrenocortical axis,

Etiologic Abnormalities

Figure 8-6 Complex regulation of blood pressure systems.

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by homeostatic effector

vasopressinsystem,andrenin-angiotensin-aldosteronesystem,varyduring exposure to different stressors. Because of long-standing controversy about the status and role of the sympathetic nervous system in clinical essential hypertension, discussion of this topic appears in the following chapter about mysterious or controversial entities. The chapters about stress and stress response patterns emphasized the preservation of the internal environment at rest and during stress as putative "goals" of alterations in activities of the effectors; and that as homeostatic systemsevolved, so didcontrolsoverthem,resulting in thepotentialfor homeostat resetting in rapidresponsetoor in anticipation of exposure to distressingstimuli.Ifoneacceptsthesepoints,thenhypertensionmight represent not so much the consequence of abnormal function of a single effector system as the consequence of a failure of coordination of mutually-compensating effector systems. The real issuein assessing the role of the sympathetic nervous system system in essential hypertension may not be whether the activity of a particular effector system is excessive but why the brain does not regulate activities of all effectors appropriate to maintain "normal" blood pressure-why the brain seems to "seek" a higher operating pressure (1 1 1).

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In terms of Dawkins’s “selfish gene” theory, discussed Chapter 5, the questionbecomes:Whyandhowdothegenesofhypertensivesdirect algorithms for cardiovascular performance that include high blood pressure? As Folkow has stated: The more is it realized that unitary explanations do not suffice and therefore a multifactorial background must be considered, the more urgent it becomes to formulate some type of principal interaction scheme for participating mechanisms. Such a scheme would not only aid the search for individualpredisposingelementsbutalso provide a more realistic evaluation of how they may exert their triggering influences” (1 12). Spontaneously Hypertensive Rats

Many investigators have viewed spontaneously hypertensive rats of the Okamoto strain (SHRs) as a model of clinical primary hypertension. SHRs have abnormalities of catecholaminergic function at all levels of thesympatheticneuraxis,includingthebrain,spinalcord,post-ganglionic nerves, and nerve terminals (Table 8-1). Documentation of such abnormalities continues to accumulate in research literature.All tend to increase occupation of cardiovascular adrenoceptors by catecholamines or enhance vascular smooth muscle responses to adrenoceptor occupation. This multiplicity of abnormalities leads to the suggestion that SHRs possess an abnormal genetic “algorithm” that directs abnormal development of sympatheticneuroeffectormechanisms.Whatthe“algorithm”consistsof remains a mystery. One possibility is that SHRs have augmented growth of catecholamine-synthesizing neurons in the periphery and in the central nervous system. The mesenteric arteries, aortas, and spleen of juvenile but not adult SHRs have higher concentrations of nerve growth factor (NGF) than do agematched WKY control rats (1 13-1 16). SHRs (especially juvenile SHRs) also have enhanced tissue expression of mRNA for NGF (1 17- 1 19). The abnormality is associatedwiththegenelocusforNGF(1 16) andparallelsthat of sympathetic innervation (120). Angiotensin I1 seems to modulate NGF gene expression,sincetreatmentwithangiotensin I1 augmentsNGFmRNA expression in thekidneys,andtreatmentwith an inhibitorofangiotensinconvertingenzymeinhibitsNGFmRNAexpressionandelicitspersistent decreases in blood pressure in juvenile SHRs.

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Table 8-1 Multiple Loci of Catecholaminergic or Sympathoneural Abnormalities in Spontaneously Hypertensive Rats

Level

Finding

CNS

Excessive distress responses Excessive sympathoadrenal & pressor responses to central nervous system stimulation Increased tyrosine hydroxylation, norepinephrine release, and a2-adrenoceptor restraint Increasedbrainstemnorepinephrine Variably abnormal concentrations of norepinephrine/adrenoceptors/catecholamine-synthetic enzymes

SNS

Increased activity of pre-ganglionic neurons Increased activity of post-ganglionic neurons Increased ganglionic catecholamine synthesis Ganglion hypertrophy Multiple firing

Terminals

Excessivenorepinephrinerelease during sympathetic stimulation High plasma catecholamine levels Abnormal pre-synaptic modulation of norepinephrine release

Target

Excessive cardiovascular tissue concentrations of norepinephrinehyrosine hydroxylase Sympathetic hyper-innervation Increased expression of nerve growth factor Excessive vasoconstrictor responses Abnormal adrenoceptor numbers Abnormalintracellularmessengers Decreased baroreflex-cardiac sensitivity

Young SHRs haveincreasedsympatheticnervoussystemand adrenomedullary hormonal system outflows at rest, compared with outflows in age-matched Wistar-Kyoto (WKY) rats. Distress augments the strain differences

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between SHRs and WKY rats, again especially in juvenile animals. Renal sympathectomy retards the development of hypertension in SHRs (121,122), and SHRs have excessive renal neural responses during aversive conditions (123-127). Augmented neurogenic sodium retention in SHRs may therefore provide a mechanism whereby excessive acute neurogenic pressor responses lead eventually to fixed hypertension. SHRs have approximately normal renal production of DA but have decreasedsignaltransduction by Dl receptorsinproximaltubulecells (128,129). Asdiscussed in Chapter 2, thisdecreasessodiumtransportand probably biases toward sodium retention. In response to airpuff stress, strain-dependent differences in immunoreactive concentrations of the immediate early gene, fos, reflecting neuronalactivation,becomeevident in thelateral,ventromedial,and dorsomedial hypothalamus, locus coeruleus, rostral ventrolateral medulla, and nucleus of the solitary tract, suggesting augmented responsiveness of centers regulating sympathetic neuronal outflows (1 30). In contrast, nitroprussideinduced hypotension, which markedly increases the number of fos-positive cells in the rostral ventrolateral medulla, does not increase the magnitude of strain differences between SHRs and WKY rats from the difference already present at baseline (13 1). Insufficient evidence about responses of other stress effector systems besides the sympathetic nervous system in SHFb prevents conclusions about whether SHRs have abnormal expression of stress response patterns in general thatmay cause or contribute to development of hypertension. The finding of catecholaminergic abnormalities in juvenile SHRs does not imply that these abnormalities actually contribute to the development of hypertension. For instance, chronic treatment of newborn WKY rats with NGF does not render the rats hypertensive(132). Evidence from studies of effects of sympatholyticproceduresinneonatalorjuvenileanimalshasgenerally supported such a contribution.In neonatal SHRs, administration of antiserum to NGF, combined with guanethidine, completely prevents the development of hypertension (133). PeripheralsympathectomywithNGFantiserumalone preventsthedevelopmentofhypertension in maleSHRs (134), andthe combination of NGF antiserum, guanethidine, and prazosin prevents not only the development of hypertension but also the development of cardiovascular hypertrophy (1 35). Systemic administration of 6-hydroxydopamine alone in neonatalSHRsattenuates by at least one-half increments in mean arterial pressure measured later in life (136,137). Treatment of preweanling SHRs with the al-adrenoceptorantagonist,terazosin,alsodecreasestheamountof hypertension when they reach adulthood (138). These results imply that the developmentofhypertension in SHRsdoesrequirenormalpost-natal development of the sympathetic neurocirculatory effector system.

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The evolution of cardiovascular hypertrophy in SHRs also may depend on catecholaminergic mechanisms. For instance, administration of any of a varietyofcentrallyor peripherally-actingsympatholyticagentstoSHRs prevents or attenuates the development of resistance vessel hypertrophy (133). As noted above, the combinationof NGF antiserum, guanethidine, and prazosin preventsboththevascularandmyocardialhypertrophy (135). Long-term treatment with low doses of catecholamines or with tyramine, which releases endogenous amines, produces myocardial hypertrophy and increased collagen synthesis, without affecting blood pressure or heart rate (139,140). The cardiac hypertrophy from systemic norepinephrine administration appears to depend on agonisticoccupationofboth a 1- andB[-adrenoceptors (141). Whether adrenoceptorsmediatecardiachypertrophyduetoincreasedreleaseof endogenous amines is unknown. Neurogenic Hypertension

Increased sympathoneural outflows contribute to hypertension attending various neurologic syndromes, including baroreceptor deafferentiation (142), hyperdynamiccirculationassociatedwithautonomicepilepsy (143), the Guillain-Barre syndrome (144-146), bladder stimulation in tetraplegia (147), seizures (148,149), intracranial bleeding (150,15 l), intracranial hypertension (1 52,153), and baroreflex failure(1 10). Koch and Mies (1929) probably were the first to describe hypertension related to section of the “buffer nerves” (i.e., baroreceptor deafferentation (142)), a phenomenon confirmed later by many investigators. Subsequent studies in dogs led to the conclusion that baroreceptor deafferentation increases the lability ofbloodpressure,includingexaggeratedpressorresponsestovarious environmental stimuli, without necessarily increasing the mean level of pressure in individuals at rest (1 54). More recent work has questioned this conclusion. Someanimalsbecomeclearlyhypertensiveandothershypotensive,and individual differences may resultfrom concurrent sympathetic afferentor efferent denervation. In ratsandnon-humanprimates,sino-aorticdeafferentation increases blood pressure and plasma levels of norepinephrine (155,156). As noted Chapter 3, lesions of the A1 region of the caudal ventrolateral medulla, nucleus of the solitary tract (NTS), or the rostral hypothalamus cause severe sustained or labile hypertension in rats, mediated by several interacting vasoactive systems. Hypothalamic stimulation can increase blood pressure and sympathoneural activity acutely, but the cardiovascular and autonomic effects depend importantly on the location of the stimulation, and it is unclear whether chronic hypothalamic stimulation produces sustained hypertension. In cats, bilateral NTS destruction elicits labile hypertension, sustained tachycardia, and

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exaggeratedpressorresponsestoconditionedandunconditionedstimuli

(157,158). In rabbits (159) and baboons (156), denervation of the carotid sinus and aortic baroreceptors elicits sustained increases in both variability and mean levels of blood pressure, with increased plasma levels of norepinephrine, the sympatheticneurotransmitter. In humans,baroreceptordebufferingasa consequence of carotid endarterectomy(160) increases blood pressure and indices of sympathetic nervous activity acutely. Bilateral lidocaine blockade of the glossopharyngeal and vagus nerves producesmarkedacutehypertension(1 6 1,162). Anecdotalevidencehas suggestedthatcarotidsinusdenervation in humans,suchasbycarotid endarterectomy or excision of carotid body tumors, can produce sustained hypertension (160,163). Episodesofparoxysmalhypertension,without sustained hypertension, occurred in a patient with a remote history of neck and mediastinal radiation who underwent bilateral carotid bypass surgery (164). In the Cushing reflex, acute intra-cranial hypertension, such as after neurosurgery or subarachnoid bleeding, produces hypertension, bradycardia, and hypoventilation.Diffuselyincreasedsympathoneuralandadrenomedullary outflows cause the hypertension, probably from increased activity of rostral ventrolateral medullary cells(1 52,153). For discussion of the “Jannetta hypothesis” of neurogenic hypertension from neurovascular compressionat sites of entryof medullary cranial nerves, the reader is referred to the section on this topicin Chapter 9. Baroreflex Failure

Recentreportshavedescribedasyndrome of baroreflexfailure, characterized by decreased or absent bradycardia responses to phenylephrine, decreased or absent tachycardia responses to nitroprusside, labile hypertension, and orthostasis- or emotion-evocable episodes of marked increases in plasma catecholamine levels and blood pressure (1 10,165,166). The patients usually have underlying pathology, such as familial paraganglioma syndrome, a history of neck irradiation, a history of surgical section of the glossopharyngeal nerve, or lesions of the NTS (166), although idiopathic cases also occur. Attimes of emotionalexcitement,thepatientsseemtohave hyperadrenergic orthostatic intolerance, and at times of quiescence or sedation neurally mediated syncope. In rare instances, the patient can have unopposed parasympathetic tonus and “malignant vagotonia” (l 67). In acute baroreflex failure, the patients often complain of palpitations, sweating, and headache. The blood pressure increases markedly, occasionally to 300 mm Hg (168), suggesting pheochromocytoma.

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Treatments for baroreflex failure include clonidine (which can exert marked acute depressor responses), a-methylDOPA, and benzodiazepines. Post-operative Hypertension

Severepost-operativehypertensionoftenoccurs in coronarybypass patients;mechanismsofthishypertensionhavenotbeenidentified. Hypertension also occurs frequently after carotid endarterectomy. Consistent with disruption of carotid baroreflexes and release of norepinephrine in the brain and periphery, patients with post-carotid endarterectomy hypertension have increasedcerebrospinalfluidandplasmanorepinephrinelevels (160). In hypertension after repair of coarctation of the aorta, reports have indicated either increased or normal levels of plasma norepinephrine, with excessive pressor responsiveness to exogenous norepinephrine(1 69) Pheochromocytoma

Pheochromocytoma, a rare cause of clinical hypertension, is a tumor of chromaffin cells. Pheochromocytomas occur most commonly in the adrenal gland or along pathways of embryological development from the neural crest, along the aorta to the organ of Zuckerkandl at the aortic bifurcation. The tumor presents clinically as sustained or paroxysmal hypertension, pallor, sweating, headache, anxiety, palpitations, orthostatic hypotension, and hyperglycemia. The orthostatic hypotension appears to result partly from downregulation of a-adrenoceptors on vascular smooth muscle cells (170). Pheochromocytomas are often benign, surgical removal can be curative, andtheassociatedcatecholamine-inducedseverehypertensiveparoxysms, arrhythmias, or cardiomyopathy can be life-threatening. These aspects justify efforts to diagnose pheochromocytoma in patients with suggestive signs or symptoms, despite the rarity of the tumor. Screening tests to detect releaseof catecholamines by the tumor, such as measurements of urinary excretion of “metanephrines” (the sum of all conjugated and unconjugated 0-methylated, non-deaminated metabolites of catecholamines) andofvanillylmandelicacid,aresensitiveandspecific.Patientswith pheochromocytomausuallyhavehighplasmalevels of norepinephrine, epinephrine, or both-most commonly of norepinephrine. The relative valuesof urinary and plasma measurements of catecholamines have been controversial (171). Some hypertensive patients can have high plasma catecholamine levels due to anxiety. Clonidine suppression testing decreases the frequency of false positive results (171). In this test, blood pressure is measured and antecubital venous blood sampled before and three hours after oral clonidine administration.

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Clonidinenormallysubstantiallydecreasesplasmanorepinephrinelevels; patients with pheochromocytoma have a failure of clonidine suppression of plasma norepinephrine. The failure to suppress plasma norepinephrine levels therefore constitutes a positive clonidine suppression test. One can conduct analogous suppression testing using a ganglion blocker(1 72). The occurrence of false negative results using screening biochemical tests for pheochromocytoma presents a more difficult problem. Provocative tests have included administration of tyramine, calcium with pentagastrin, or glucagon. Because these agents can evoke hypertensive crises in pheochromocytoma patients, and since many patients with suspected pheochromocytoma undergo treatment with a-adrenoceptor blockers, clinicians have largely abandoned testing based on the magnitude of pressor responses to drugs. Provocative tests have also used i.v. phentolamine (RegitineTM). This non-specific a-adrenoceptor antagonist decreases blood pressure. In patients with pheochromocytoma, where catecholamines produce hypertension via occupation of a-adrenoceptors on vascular smooth muscle cells, acute blockade of the receptorsevokesalargedepressorresponse.TheRegitineTMtestentails substantial risk, however, not only of excessive hypotension from the drug but also of precipitating catecholamine release by the tumor. Other much safer tests have supplanted the Regitine" test. Our group introduced a schema using plasma levels of catechols for diagnostic testing of hypertensive patients with suspected pheochromocytoma (173). Positiveresultsincludehighbaselinelevelsofnorepinephrine, epinephrine, or L-DOPA; excessive increases in plasma norepinephrine levels after administration of glucagon; and a failure to suppress plasma norepinephrine levels after administration of clonidine. This approach yields conclusive results in about 80% of hypertensive patients with suspected pheochromocytoma. The testing protocol has the advantage of applicability to patients treated with phenoxybenzamine, which blocks or attenuates pressor responses to glucagon but leaves intact responses of plasma levels of catecholamines. Since glucagon administration normally increases plasma epinephrine levels, the neurochemical diagnosis does not depend on epinephrine responses. Consistw e nitinht hter a n e u r o snoa ulporl caf es m a dihydroxyphenylglycol(DHPG),asdiscussedChapter 6, patientswith pheochromocytomausuallyhavehighplasman0repinephrine:DHPGratios (174). Use of this ratio for diagnostic purposes does not improve diagnostic accuracy, because patients with pheochromocytoma can have high plasma levels or urinary excretion of DHPG. Pheochromocytomassecretecatecholaminesepisodicallyintothe bloodstream, but they synthesize and metabolize catecholamines continuously. Adrenal chromaffin cells, including pheochromocytoma cells, contain catecholO-methyltransferase (COMT), and so thecatecholaminesproduced in

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pheochromocytoma cells undergoes substantial metabolism by 0-methylation (175).Thisexplainswhythemeasurementofplasmalevelsoffree (unconjugated) metanephrines (normetanephrine and metanephrine) constitutes the most sensitive biochemical test yet devised for detecting pheochromocytoma (1 76). The superior sensitivity of plasma levels of metanephrines to detect pheochromocytoma becomes especially important in diagnosis of the tumor in patients with a familial predisposition, as occurs in von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia typeI1 (MEN-Ha), and neurofibromatosis. VHL disease, inherited as an autosomal dominant trait, includes a variety of tumors: retinal angioma, cerebellar hemangioblastoma, renal cell carcinoma, and pheochromocytoma. About 1/7 of kindreds have pheochromocytoma. The adrenal gland can harbor a clinically silent pheochromocytoma, discovered during surgery for renal carcinoma (1 77). Because the tumor synthesizes and metabolizes catecholamines, even if release rates into the bloodstream are low, plasma metanephrines can detect the tumor (1 78); other biochemical tests have an unacceptably high frequency of false negative results. In patients with pheochromocytoma, the occurrence of metastases, not the pathologicalappearanceofthetumor,definesmalignancy.Patientswith malignant pheochromocytoma may not have hypertension, and the tumors often 60% of patientswithmalignant occur in unusuallocations.About pheochromocytoma have high plasma levels of the catecholamine precursor,LDOPA (179), whereas patients with benign pheochromocytoma have normal plasma L-DOPA levels. This may result from malignant pheochromocytoma being less well differentiated than benign pheochromocytoma. Plasma L-DOPA in pheochromocytoma probably constitutes a specific but insensitive test for detecting malignancy. Case reports haveindicated that adrenomedullary hyperfunction can cause episodichypertensionandhighplasmacatecholaminelevels,without pheochromocytoma. Of five cases of spontaneous hyper-epinephrinemia(1 80), one patient had suspected adrenal medullary hyperplasia, based on a family history of MEN-2a; two had adrenal cysts, with amelioration of symptoms after surgical removal of the cysts; and two had responses to treatment that suggested hyperdynamic circulation syndrome. In a 30-year-old man with paroxysmal hypertension,highplasmacatecholaminelevels,andpositivemetaiodobenzylguanidine scanning results suggesting an adrenal pheochromocytoma, histopathologicexaminationaftersurgicaladrenalectomyrevealedonly hyperplastic medullary tissue (1 8 1). “Incidentalomas” are incidentally discovered adrenal masses.In one series of89patientswithincidentaloma,32hadstablehypertension(182). In a minority of cases, the masses actually were pheochromocytomas. Hypertension is present in only 1/2 of these cases, and although high plasma levels of

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catecholamines,atbaselineor in responsetoglucagon,characterizemost patients with pheochromocytoma presenting as incidentaloma, false negative results can occur. Whether plasma metanephrines accurately detect pheochromocytoma in this setting remains unknown. The term “pseudopheochromocytoma” has also been used to describe a syndrome of paroxysmal hypertension, flushing, palpitations, and orthostatic intolerance, followedby polyuria or diarrhea (1 83), originally describedby Page as simulating hypothalamic stimulation (184). In contrast with pheochromocytoma,wherepressorepisodesusuallyareassociatedwith catecholamine-induced cutaneous vasoconstriction, in “Page’s syndrome,” the patient appears flushed. Kuchel and co-workers suggested that deficient catecholamine conjugation can produce a syndrome that resembles pheochromocytoma clinically, which they also called “pseudopheochromocytoma.” (1 85). Such patients can have false-positive, large responses of free (unconjugated) plasma catecholamines to glucagon administration (1 86). CARDIAC NECROSIS AND CARDIOMYOPATHY

There are two main forms of cardiac necrosis: coagulation necrosis and necrosiswithcontractionbands.Theformertypicallyoccurs in areasof myocardial infarction-i.e., areas of myocardial cell death due to ischemia without reflow. In coagulative necrosis due to myocardial infarction, the cells die in a relaxed state, and the pathologic changes are not detectable for many hours or even days, when there is a polymorphonuclear infiltrate. Calcification occurs late. In contrast,myofibrillardegeneration(alsocalledmyocytolysis, coagulative myocytolysis, or contraction band necrosis) occurs over a time course of seconds or minutes. Contraction bands reflect the hypercontracted, rather than relaxed, state of the cells. If there is an infiltrate it is mononuclear, and calcification occurs rapidly. On the light microscopic level, mildly affected areas have increased eosinophilic staining of the cytoplasm, with preserved striations;moreseverelyaffectedcaseshavetransformationoftheentire cytoplasm, with dense eosinophilic bands, “contraction bands,” between areas of granular myofibrillar degeneration. Electron microscopy reveals hypercontraction,tearing,anddislocationofcellularmyofibrils.Other pathological findings include mitochondrial deposits of calcium, loss of cellular glycogen, margination of nuclear chromatin, and nonspecific changes of cell death. In less severely affected regions, the finding of small bulges in the cells on either side of the intercalated disk has led to the designation, paradiscal lesion. In more severely affected regions, the entire cell contains coagulated contractile proteins, with clumped mitochondria-a holocytic contraction band

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lesion. Contraction band necrosis appears to arise when large amounts of Ca++ enterlivingmyocardialcells.Thelesionsoccur in theouterregionsof myocardial infarcts and subendocardially. In 1907, only about 12 years after the discovery of the cardiovascular stimulatory effects of epinephrine, Josue demonstrated cardiac necrosis after infusions of epinephrine (1 87). Infusion of catecholamines, stimulation of the central nervous system, the combination of stress and steroids, myocardial reperfusion, the “stone heart” syndrome after heart surgery, and pheochromocytoma all can produce contraction band necrosis, which is also observed in many cases of sudden cardiac death (187-189). The combination of subendocardial damage and arrhythmogenic actions of catecholamines may explain the high frequency of sudden death in patients with stroke, epilepsy, head trauma, intracranial hypertension, and severe emotional distress (190). In rats, contraction band lesions disappear by about 1-2 weeks. Remnants of myocardial cells become condensed fragments, and necrotic areas fibrose. The non-specificity of the resolution of contraction band lesions makes it difficult or impossible to identify catecholamine-induced myocardial damage bya few weeks after the injury. Activation of a-adrenoceptors by norepinephrine, with consequently increased cytoplasmic Ca++ concentrations, appears to be the mechanism of norepinephrine-induced cardiomyopathy and reperfusion injury. Adrenocorticalhormonesrenderthemyocardiumvulnerableto catecholamine-induced necrosis (191,192). Selye showed that injection of large doses of adrenal corticosteroids or analogs increases the frequency of cardiac necrosisafterexposuretoanyofseveralstressors(e.g.,immobilization, bacteremia, surgery, toxins, and vagotomy). The bases for this interaction are unknown.Oneexplanationisthatglucocorticoidsup-regulatecardiac Badrenoceptors. Contraction bands have been observed in up to 80% of all victims of sudden death (188). In an autopsy study of victims of homicidal assault who died despite the lack of sufficient evidence of internal or external injury, contraction band necrosis, without evidence of myocardial infarction, was observed in 1 1 of the 15 cases (193). Cardiacnecrosisalsooccurs in ratssubjectedtoimmobilization, overcrowding, restraint and water immersion, repeated, small electric shocks, and other laboratory emotional stressors (194-200). Electrical stimulation of central neural regions such as the hypothalamus, limbic cortex, and midbrain reticular formation also can produce myofibrillar degeneration, ventricular arrhythmias, or subendocardial necrosis.

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Stroke-Related Myocardial Necrosis

Many studies have reported electrocardiographic abnormalities in patients with acute stroke (201). Burch et al. (1954) considered the triad of prolonged electrocardiographicQTinterval,abnormalTwaves,and U wavestobe distinctive of acute stroke (202). Over 90% patientswithacutestrokehaveelectrocardiographic abnormalities. The most common abnormalities are also changes from previous tracings-QTprolongation,ischemicchanges, U waves,tachycardia,and arrhythmias (203). Patients with embolic strokes have a high frequency of atrial fibrillation and patients with subarachnoid hemorrhage a high frequency of QT prolongation and sinus arrhythmia. Although stroke patients also have a higher frequency of pathologic Q waves and left ventricular hypertrophy than do ageand sex-matched control inpatients, these findings are not new at the time of the stroke. Strokes due to intracranial bleeding are often associated with acute hypertension, arrhythmias, electrocardiographic changes suggesting myocardial ischemia, and increased levels of cardiac isozymes (204,205). In one study, 61% of patients with acute stroke had elevated creatine phosphokinase (CPK) levels, and of patients whohad CPK isozymes measured, 40% had elevated levels, and all patients with intracranial bleedinghad elevated CPK levels (203). Stroke-inducedmyocardialnecrosis is associatedwithgeneralized increases in sympatheticnervousandadrenomedullaryhormonalsystem outflows. The rate of occurrence of cardiac arrhythmias and the extent of increase in cardiac-specific enzymes correlate with plasma levels of catecholamines in stroke patients(150). Highlevelsofcatecholamines in theheartprobablycontribute importantlytothecardiacnecrosisattendingacutestroke.R-Adrenoceptor blockadeamelioratestheelectrocardiographicchanges inpatientswith subarachnoid hemorrhage (206), and adrenoceptor blockade or depletion of catecholamine stores by reserpine can prevent myocardial necrosis producedby intracerebroventricularinjectionofblood.Theextentofmyocardialcell pathology varies inversely with the distance from intramyocardial nerves (207) suggesting that high local concentrations of norepinephrine, released during marked cardiac sympathoneural stimulation, causes contraction band necrosisin patients with intracranial bleeding (208). Inpatientswithpheochromocytoma,persistentlyhighcirculating catecholamine levels can induce cardiac hypertrophy and cardiomyopathy. The cardiomyopathy can progress to a dilated form, producing congestive heart failure. Even at this late stage, however, curative surgical removal of the tumor can reverse the cardiomyopathy (209).

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Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is usually an inherited disease characterized bymassiveovergrowthofthemuscularinterventricularseptum,variable amounts of obstruction of ventricular outflow, a hyper-contractile myocardium, and impaired diastolic filling of the left ventricle. About50% of the patients die suddenly. Pathologically, there is cellular disarray, with patchy areas of necrosis and fibrosis. Hypotheses about the pathogenesis of hypertrophic cardiomyopathy have long imputed abnormalities of cardiac sympathoneural function. Although an early study indicated excessive norepinephrine concentrations in the septum of patients with hypertrophic cardiomyopathy (210), this has not been confirmed. Patients with hypertrophic cardiomyopathy have a few abnormalities of cardiac norepinephrine kinetics, compared with findings in patients with chest pain and normal coronary arteries(21 1).The efficiency of cardiac extraction of circulating 3H-norepinephrine is reduced, whereas that of 3H-isoproterenolis not, and since the latter catecholamine is not a substrate for Uptake-l, this finding suggests decreased neuronal uptake of circulating catecholamines per unit of mass of tissue.Thecardiacarteriovenousincrement in plasmaDHPGlevelsis significantlydecreased.Mostofthefindingscouldbeexplainedifthe hypertrophic myocardium were relatively denervated, with increased traffk in the remaining sympathetic nerves. Chagas’Disease

Chagas’ disease represents a unique form of cardiomyopathy, where abnormalities of cardiac sympathetic nervous system function developin stages (2 12,2 13).Early in the disease, decreased numbers of a-adrenoceptors produce orthostatic hypotension. The adrenergic receptor pathology advances, and nerve and muscle impairment become prominent, with fatigue, dizziness, orthostatic intolerance, and palpitations. High plasma norepinephrine levels at this stage probablyreflectcompensatoryactivation.Inthelaststage,denervationis superimposed on receptor malfunction. Chagas’ disease represents a rare clinical situation where heart failure occurs without increases in plasma norepinephrine levels. The patients have bradycardia, absence of sweating, and weakness. The high frequency of sudden death might result from denervation supersensitivity. NEUROGENETIC DISEASES

Untilrecently,clinicalcatecholamineneurochemistryhasbeenused mainly to examine release of catecholamines as effector chemicals in the brain and periphery, in order to indicate “activities” of central or peripheral neuronal

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systems. The development of assay techniques for simultaneous measurements of concentrations of catecholamines, the catecholamine precursor L-DOPA, and catecholamine metabolites such as dihydroxyphenylglycol (DHPG), dihydroxyphenylacetic acid (DOPAC), methoxyhydroxyphenylglycol(MHPG), homovanillicacid(HVA),andmetanephrines,hasenableddetailed, comprehensive assessments of specific aspects of catecholaminergic finction, including release, neuronal and extraneuronal uptake and metabolism, turnover, and synthesis, as discussed in Chapter 6 . The availability of these simultaneous assays has led in turn to a novel clinical application-delineation of neurochemical patterns associated with specific genetic abnormalities. These patterns can provide potentially important cluestothediagnosis,treatment,andpathophysiologyofneurogenetic disorders. Because adult humans with familial dysautonomia or lacking dopamine&hydroxylasehave a formofsympatheticneurocirculatoryfailure,these neurogenetic disorders are discussed above in the section about autonomic failure syndromes. Genetic Diseases with Specific Catecholaminergic Phenotypes: Synthesis

Asdiscussed in theoverviewchapterabouttheautonomicnervous system (Chapter 2), in mammals all catecholamine biosynthesis stems from a single enzymatic step-conversion of the amino acid tyrosine to the catechol amino acid L-DOPA. Circulating catecholamines seem crucial for normal neural development, since genetic disorders of catecholamine biosynthesis typically producesevereneurologicaldefectsorfetalwastage.Thus,ofmicewith knockout of the tyrosine hydroxylase (TH) gene, approximately 90% die in utero (214). Tyrosine hydroxylation requires tetrahydrobioterin (BH4) as a co-factor fornormalactivity.Inhumans,geneticdeficienciesofBH4synthesisor recycling, while compatible with survival to birth, obviate normal post-natal neurological development, if not recognized and treated appropriately from early infancy.

DHPR deficiency Dihydropteridinereductase(DHPR)catalyzestheconversion of dihydrobiopterin to BH4. BH4 is a required cofactor for hydroxylation not only of tyrosine but also of phenylalanine and tryptophan. BH4 also appears to play a role in maintaining the bioactive (tetrahydro) form of folic acid (215).

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5-CH3

Figure 8-7 Dihydropteridine reductase(DHPR) deficiency. Note the numerous neurochemical consequences of DHPRdeficiency.Aputative alternative pathway mayallowsynthesis of tetrahydrobiopterin(BHq), via conversion of5methyltetrahydrofolate (5-CH3-Hq-folate) to 5-methylenetetrahydrofolate, catalyzed by 5-methyltetrahydrofolate reductase. 3-MT = 3-methoxytyrosine; 5-HIAA = 5hydroxyindoleacetic acid; 5-HT = 5-hydroxytryptamine (serotonin); 5-HTP = 5hydroxytryptophan; COMT = catechol-0-methyltransferase; DHPG = dihydroxyphenylglycol; DOPAC = dihydroxyphenylacetic acid; EPI = epinephrine; LAAAD = L-aromatic-amino-acid decarboxylase; MAO = monoamine oxidase; NE = norepinephrine; PAH = phenylalaninehydroxylase;Phe = phenylalanine; PNMT = phenylethanolamine-N-methyltransferase;TH = tyrosinehydroxylase;TRH = trypotphan hydroxylase; Tyr = tyrosine.

Because of impaired phenylalanine hydroxylation, patients with DHPR deficiency have a variant of phenylketonuria, detecting by neonatal screening. In contrast to classical phenylketonuria (caused by mutations in the phenylalanine hydroxylase gene), where dietary restriction of phenylalanine beginning in infancy protects against mental retardation, patients with DHPR deficiency develop seizures and serious neurodevelopmental delays even with good dietary control of phenylalanine intake(216,2 17).

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TheseclinicalproblemsarisefromdeficientactivitiesofTHand tryptophan hydroxylase and from defective folate metabolism. Corresponding biochemicalconsequencesinclude low cerebrospinal fluid (CSF) levels of metabolitesofdopamineandnorepinephrine(Figure8-7),suchas dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA); low CSF levels of the serotonin metabolite 5hydroxyindoleacetic acid (5-HIAA); and low CSF levels of tetrahydrofolate (21 8,219). Therapy combining phenylalanine restriction with oral administration of L-DOPA, 5-hydroxytryptophan (5-HTP, the precursor of serotonin), and folinicacidappearstoimproveoutcomes in DHPR-deficientpatients (2 18,220,22 1). At least 14 different mutations of the DHPR gene (221-224), located on chromosome 4 (225), have been described. Combinations of neurochemical assessments with mutation detection or functional characterization of abnormal DHPR alleles should help elucidate relationships between genotype and clinical phenotypeinDHPRdeficiency. In onepatient(218),thepretreatment neurochemical findings (low but detectable plasma levels of L-DOPA and normal levels of norepinephrine, despite absent DHPR activity in erythrocytes and fibroblasts) led to the suggestion of a DHPR-independent mechanism for recycling BH4, illustrating how neurochemical analyses in patients with rare disorders can also enhance general understanding of catecholamine metabolism. Defects in GTP-cyclohydrolase I or 6-pyruvoyl tetrahydropterin synthase can also produce atypical phenylketonuria due to defective BH4 synthesis (226). Completedeficiencyofeitherenzymeleadstoaboutthesameclinical syndrome, with seizures, limb hypertonia, intermittent hyperthermia (226), and associatedneurotransmitterabnormalities(227,228).Heterozygosityfor I locusproducesL-DOPA-responsive mutationattheGTP-cyclohydrolase dystonia, discussed on the following page. Deficiency of sepiapterin reductase or of carbinolamine dehydratase, other enzymes in BH4 synthesis and recycling (Figure 2-1 l), should also produce predictableclinicalandneurochemicalabnormalities.Sincecarbinolamine dehydratasecatalyzesareactionthatcanalsooccurnon-enzymatically, individuals with complete absence of this enzyme have mild clinical findings and only transient biochemical changes (229). Cases of sepiapterin reductase deficiency have not been reported to date. L-DOPA-responsive dystonia L-DOPA-responsive dystonia, inherited as an autosomal dominant trait, includes childhood-onset dystonia, abnormal gait, marked diurnal fluctuation (symptoms aggravated in the evening and alleviated in the morning after rest),

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concurrent or later development of parkinsonism, and normal cognitive function. Oral L-DOPA treatment dramatically improves the neurologic symptoms. ThepatternofbiochemicalabnormalitiesinL-DOPA-responsive dystonia-low brain and cerebrospinal fluid levels of dopamine, HVA and BH4 (230-233Fled initially to the hypothesis that the disorder arises from deficient dopamine synthesis due to decreased tyrosine hydroxylation. Genetic linkage analysis localized the putative mutant gene to chromosome 14q (234). Ichinose and co-workers mapped the human GTP-cyclohydrolase gene to the L-DOPAresponsive dystonia critical region (235). The same workers demonstrated GTPcyclohydrolase mutations in patients with L-DOPA-responsive dystonia and severely reduced enzyme activity in affected patients. Numerous other GTPcyclohydrolase mutations have since been reported in patients with L-DOPAresponsive dystonia (236,237), including a splice junction defect that produces skipping of exon 2 and predicts a truncated protein (236). The neurochemical abnormalities in L-DOPA-responsivedystonianotonlyfitthegenetic abnormalities but also predicted the type of genetic defect. Whether an individual possesses one or two mutant GTP-cyclohydrolase alleles determines the resultant neurological phenotype. Patients with autosomal recessive GTP-cyclohydrolase deficiency have atypical phenylketonuria and those with autosomal dominant GTP-cyclohydrolase deficiency have L-DOPAresponsive dystonia.

LAAAD deficiency L-Aromatic-amino-acid decarboxylase (LAAAD) catalyzes the conversion of L-DOPA to dopamine (Figure8-8) and of 5-hydroxytryptophan to serotonin. The enzyme requirespyridoxal-5’-phosphate (vitamin B6). The first case report about deficiency of this enzyme described twins (238),wherebothprobands,products of aconsanguineous(firstcousin) marriage, appeared normal at birth but developed slowly, with hypotonia and abnormal eye and limb movements by 2 months of age. A similarly affected older sibling had died at 9 months old. Both twins had low CSF and plasma levels of monoamines and high levels of L-DOPA and 5-hydroxytryptophan, from which the authors deduced the underlying enzymatic defect. Since the parents each had intermediate LAAAD enzyme activity, the neurochemical findings suggested heterozygosity for a mutant LAAAD allele. Treatment of the affected twins during infancy with pyridoxine, bromocriptine, and tranylcypromine produced some clinical benefit, although at 4 years of age, neural development remained subnormal (239). Characteristic features of LAAAD deficiency include axial hypotonia, hypokinesia, and athetosis, episodes of ocular convergence spasm, oculogyric crises, dystonia, and limb rigidity, and signs of catecholamine deficiency, such

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Fohnlc acld

+

ATP

+NADPH. H+

5-HTP

+NADPH, H+

2/ LAAAD 5-HT

Y A

TYH

t

5-HIAA

DOPA

3”TA

LAAAD

HVA-DOPAC

Figure 8-8 L-Aromatic-amino-aciddecarboxylase(LAAAD)deficiency. LAAAD deficiency results in decreased synthesis of serotonin (5-HT) and catecholamines. See legend for Figure 8-7 for other abbreviations.

as ptosis, nasal congestion, paroxysmal diaphoresis, temperature instability, and blood pressure lability. Abnormal sleep, feeding difficulties, and esophageal reflux are typical. Significant therapeutic benefit was observed in one child treated with a combination of pergolide, trihexyphenidyl, and tranylcypromine, to maximize extracellular fluid concentrations of dopamine and serotonin (240). AlthoughthehumangeneencodingLAAADhasbeenmappedto chromosome 7 (241,242) and cloned, the exact mutation in LAAAD deficiency remains undefined. Two protein isoforms, resulting from alternative mRNA splicing have been identified(243). Neurochemically, as one would predict from the enzyme defect, patients with LAAAD deficiency have high plasma levels of L-DOPA and low levels of dopamine and its deaminated metabolite dihydroxyphenylacetic acid. They also have low levels of serotonin and its deaminated metabolite 5hydroxyindoleacetic acid (Figure 8-8).

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Menkes disease Menkes disease is an X-linked recessive cause of infantile neurodegeneration that results from mutations in a gene encoding a coppertransportingATPase(244-247).Clinicalfeaturesincludeseizures,severe developmental delay, failure to thrive, connective tissue abnormalities such as bladder diverticula and skin laxity, hair abnormalities(“pili tort?’), and death in infancy or early childhood(248). Other syndromes with less severe neurological phenotypes (e.g., “occipital horn syndrome”) have also been associated with mutations at this locus (249). The clinical findings in Menkes disease and its variants result from reduced activities of copper-containing proteins such as ceruloplasmin, cytochrome c oxidase, superoxide dismutase, lysyl oxidase, and dopamine-B-hydroxylase (DBH). Because the patients have impaired intestinal copper absorption, serum copper levels are low after the first 2 months life. of Decreased DBH activity in patients with Menkescauses a distinctive, abnormal pattern of plasma and CSF catechols (250), with high concentrations of LDOPA, dihydroxyphenylacetic acid (DOPAC), and dopamine, low concentrations of dihydroxyphenylglycol (DHPG), and approximately normal concentrations of norepinephrine itself, consistent with compensatory increases in sympathetic nerve traffic and tyrosine hydroxylation. The neurochemical pattern (in particular, elevated ratios of L-D0PA:DHPG and D0PAC:DHPG) providesanexcellentbiochemicalmarkerforthiscondition(250).Thus, analyses of plasma levels of catechols can diagnose or exclude Menkes disease in at-risk infants during the newborn period, when clinical signs are subtle (251) and other biochemical markers unreliable (248,252). The abnormal pattern can also be detected in umbilical cord blood of affected patients, indicating DBH deficiency in utero and suggesting that analysis of catechol levels in cord blood may constitute a rapid, noninvasive test for Menkes disease in at-risk newborns (252,253). Early treatment with parenteral copper improves the clinical outcome in some patients with Menkes disease (253,254). The success of such therapy appears to depend on the particular gene mutation (255,256). Genetic Diseases with Specific Catecholaminergic Phenotypes: Metabolism

Whereas catecholamine biosynthesis occurs mainly, if not exclusively, by a single pathway (tyrosine hydroxylation), catecholamine inactivation occurs by severalalternativepathwaysthatincludeatleast3differentintracellular enzymes-monoamine oxidase, catechol-0-methyltransferase, and monoaminepreferring phenolsulfotransferase. From this, and from the absolute requirement oftetrahydrobiopterinfortyrosinehydroxylation,onemightpredictthat,

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compared with the potentially devastating effect of mutations either in the tyrosine hydroxylase gene itself or in genes encoding enzymes participating in synthesisorrecyclingoftetrahydrobiopterin,defects in genesencoding catecholamine-metabolizingenzymeswouldhavelessseriousclinical consequences. Mutations in genes that encode membrane catecholamine transporters or vesicular amine transporters (VATS) have not been reported, despite cloning of the genes and identification of their chromosomal locations. A recent report described successful generation of mice with a knockout for the membrane dopamine transporter (257). The animals had hyperlocomotion, decreased food intake, abnormal maternal behavior, and an increased likelihood of premature death. Neurochemically, the animals had decreased electrical stimulus-induced dopamine release and decreased tyrosine hydroxylationin dopaminergic neurons. To our knowledge, no report to date has reported knockout or transgenic animals for the membrane norepinephrine transporter or for a VAT.

MAO deficiency Monoamine oxidase (MAO) isoenzymes inactivate catecholamines and their 0-methylated metabolites and also deaminate other biogenic amines such as serotonin. The genes encoding the two subtypes of MAO (MAO-A and MAO-B)lieadjacenttoeachotheronthe X chromosome.Oxidative deaminationofserotonindependsonMAO-A; in vitro,bothsubtypes deaminate L-DOPA, dopamine, and norepinephrine. SeveralinheriteddisordersinvolvingMAOdeficiencyhavebeen described.AkindredofDutchmenwithimpulsivity,aggressiveness,and antisocial behavior had isolated deficiency of MAO-A (258), with a point mutation in exon 8 of the MAO-A gene (259). The patients had increased urinaryexcretionofnormetanephrine,homovanillicacid(HVA),and vanillylmandelic acid (VMA). Patients with Norrie disease, inherited as an X-linked recessive trait, have blindness, deafness, and variable mental retardation. The Norrie disease gene is contiguous with the 2 MAO loci at Xpll.4-pll.3 (3094,3075), the order from centromere to telomere being Norrie disease/MAO-B/MAO-A. Norrie disease patients can have deletions that include the Norrie disease locus and either the MAO-B locus or both MAO loci (260). Two brothers with Norrie disease and selective MAO-B deficiency had minimal neurochemical alterations and no behavioral or psychomotor abnormalities. In contrast, a patient with deletion of all 3 loci had markedly increased levels of 0-methylated amine metabolites and lowlevelsofdeaminatedcatecholamines,withseverementaldeficiency, autistic-like behavior, atonic seizures, and altered peripheral autonomic function (261). These findings imply that MAO-A deficiency produces far more serious

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clinical consequences than does MAO-B deficiency. Some of these differences could depend on the importance of MAO-A in serotonin metabolism, because mice exposed to MAO inhibitors in utero have increased aggressive behavior that is mitigated by blockade of serotonin synthesis (262). Velo-cardio-facial syndrome and DiGeorge syndrome Velo-cardio-facialsyndromeincludescleftpalate,craniofacial abnormalities,learningdisorders,cardiacdefects,andpsychiatricillness in adolescence and adulthood. DiGeorge syndrome includes immunodeficiency, facial dysmorphism, mental disorders, and cardiac defects. Both syndromes have been associated with interstitial deletions of chromosome 22ql1 (263,264). A study of 9 families with recurrent cardiac outflow tract defects found that 5 had transmitteddeletions of chromosome22ql1(265).Chromosome22ql1 includes the locus of the gene encoding catechol-0-methyltransferase (COMT). Thus, one may hypothesize that some patients with the velo-cardio-facial or DiGeorge syndrome may have only one functional COMT allele and decreased COMTactivity(266).Abnormalratiosof0-methylatedtodeaminated metabolitesofcatecholamines in plasmaorurinecoulddetectthis.The relationship between COMT activity and clinical features of either syndrome remains unknown. Von Hippel-Lindau disease Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder featuring hemangioblastomas, cystic tumors, renal cell carcinomas, pancreatic cysts and tumors, epididymal cystadenomas, and pheochromocytomas (267). The patients who have a pheochromocytoma can have false negative results of screening tests based on plasma levels or urinary excretion of catecholamines or catecholaminemetabolites.Measurementofplasmafree(unconjugated) metanephrines (normetanephrine and metanephrine) provides a more sensitive biochemical marker (178). The VHL gene, located on chromosome 3 (3p25), encodes a tumor supressor gene (268-270). Many mutations at different loci in this gene have been documented in individuals with the classic VHL disease phenotype;however,familialpheochromocytomaseemsassociatedwith mutations at specific loci (27 1-273).

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OTHER Guillain-Barre Syndrome

Guillain-Barresyndromeoccasionallyisassociatedwithneurogenic hypertension or supraventricular tachycardia, possibly as a consequence of impaired afferent baroreflex nerves (145). The tachycardia and hypertension are correlated with plasma levels of norepinephrine and with urinary vanillylmandelic acid excretion (274). Seizures

Patients with left temporal lobe complex partial seizures can have cardiac asystole and bradycardia, presumably because left cortical stimulation increases right vagal parasympathetic outflow (275).A cardiac pacemaker may control this life-threatening complication. Quadriplegia

Traumatic destruction of the spinal cord produces low rates of postganglionicsympatheticnervetrafficanddisruptsbaroreflexregulationof sympatheticoutflows.Patientswithquadriplegiafromspinalcordinjury thereforeoftenhavelowplasmalevelsofcatecholamines(147,276)and orthostatic hypotension (277). In contrast to patients with chronic, primary autonomic failure, patients with quadriplegia do not appear to have important post-prandial hypotension (278). Destruction of the spinal cord leaves intact and usually disinhibits local spinal reflexes. Patients with quadriplegia from spinal cord injury therefore have a propensity to acute, neurogenic hypertension from stimuli such as distention of the urinary bladder or stimulation of skeletal muscle. This results not only from disinhibition of spinal reflexes and disruptionof baroreflexes but also from adrenoceptor supersensitivity (279). SUMMARY AND CONCLUSIONS

In several disorders, abnormalities of catecholaminergic function play a primary pathophysiologic role, and treatments targeting those abnormalities constitute mainstays in clinical management of patientswith those disorders. Sympatheticneurocirculatoryfailurepresentsasorthostaticorpostprandial hypotension, with characteristic abnormalities of beat-to-beat blood pressure associated with performance of the Valsalva maneuver. Sympathetic neurocirculatory failure occurs secondarily in diabetes mellitus and infiltrative

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peripheral neuropathy and primarily in pure autonomic failure, the Shy-Drager syndrome, Parkinson’s disease with autonomic failure, dopamine-D-hydroxylase deficiency, and familial dysautonomia. One can distinguish the Shy-Drager syndrome from Parkinson’s disease and autonomic failure, using cardiac sympathoneural scanning. Patients with the Shy-Drager syndrome have normal cardiac sympathetic terminal innervation, whereas patients with Parkinson’s disease and autonomic failure have cardiac sympathetic denervation. Increased sympathetic nervous system activity or reactivity probably occurs during the development of essential hypertension; however, because of thecomplexdeterminationofchronicbloodpressure,thecontributionof sympathetic hyperfunction to clinical essential hypertension remain unclear. Hypertension in pheochromocytoma results from release of catecholamines by the tumor. Catecholamine-induced myocardial necrosiscan occur in the absence of coronary artery disease in patients with stroke due to intracranial bleeding or suffering severe, acutepsychological distress. Thewealth of knowledgeregardingthesynthesisandfateof catecholamines, the availability of sensitive and specific assays for L-DOPA, catecholamines, and most of theirmetabolites, and recent advancesin molecular genetics afford the opportunity to glean new understanding of neurogenetic disorders that involve catecholamine metabolism. The overview in this chapter has presented several examples ratherthan a comprehensive picture of this new application ofclinical neurochemistry.

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36. HoeldtkeRD,Streeten DH. Treatment of orthostatichypotensionwith erythropoietin. N Engl J Med 1993; 329:611-615. 37. Ducla-Soares J, Breitenfeld L, Povoa P, Ferreira M, Carvalho M, Alves M, Bicho M, Sales-Luis Mde L, da Palma-Carlos A. Plasma catecholamines and postural hypotensioninfamilial amyloidotic polyneuropathy of the Portuguese type. ClinAutonRes1991;1:271-274. 38. Nakata T, Shimamoto K, Yonekura S, Kobayashi N, Sugiyama T, Imai K, Iimura 0. Cardiac sympathetic denervation transthyretin-related in familial amyloidotic polyneuropathy:detectionwithiodine-123-MIBG.JNuclMed 1995; 3611040-1042. 39. Carvalho MJ, van den Meiracker AH, Boomsma F, Man in 't Veld AJ, Freitas J, Costa 0, de Freitas AF. Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4dihydroxyphenylserine. J AutonNerv Sys 1997;62:63-71. 40. Comi G, Corbo M. Metabolic neuropathies. Curr Opin Neurol 1998; 11:523-529. 41. Kihara M,MitsuiM, Nishikawa S, Nishimoto K, Takahashi M. Comparison of electrophysiologic and autonomic tests insensory diabetic neuropathy. Clin AutonRes1998;8:213-220. 42. Orchard TJ, LloydCE,MaserRE, Kuller LH. Why does diabetic autonomic neuropathy predict IDDM mortality? An analysisfrom the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Res Clin Pract 1996;34 (S~ppl.):S165-S171. 43. Toyry JP, Niskanen LK, Mantysaari MJ, Lansimies EA, Uusitupa MI. Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis. Diabetes 1996; 45:308-315. 44. Stevens MJ, Raffel DM, Allman KC, Dayanikli F, Ficaro E, Sandford T, Wieland DM, Pfeifer MA, SchwaigerM.Cardiacsympatheticdysinnervation in diabetes: implications for enhanced cardiovascular risk. Circulation 1998; 98:961-968. 45. Weston PJ, James MA, Panerai R, McNally PG, Potter JF, Thurston H, Swales JD. Abnormal baroreceptor-cardiac reflex sensitivity is not detected by conventional tests of autonomic functioninpatientswith insulin-dependent diabetes mellitus. Clin Sci 1996;91:59-64. 46. Watkins PJ.Theenigma of autonomic failure in diabetes. JRCol1 Physicians Lond 1998; 32:360-365. 47. Dunsmuir WD,Holmes SA. The aetiology and managementoferectile, ejaculatory, and fertility problems in men with diabetes mellitus. Diabet Med 1996; 13~700-708. 48. Lehmann R, Borovicka J, Kunz P, Crelier G, Boesiger P, Fried M, Schwizer W, SpinasGA.Evaluation of delayedgastric emptying in diabetic patients with autonomic neuropathy by a newmagneticresonanceimaging technique and radio-opaque markers. Diabetes Care 1996; 19: 1075-1082.

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49. Ziegler D, Schadewaldt P, Pour Mirza A, Piolot R, Schommartz B, Reinhardt M, Vosberg H,BrosickeH, Gries FA. [13C]octanoic acidbreath test for noninvasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function. Diabetologia 1996; 39:823-830. 50. HathawayDK, Abell T, Cardoso S, Hartwig MS,el Gebely S, GaberAO. Improvement in autonomic and gastric function following pancreas-kidney versuskidney-alonetransplantationand the correlationwith quality of life. Transplantation 1994; 57:816-822. 5 1. Straub RH, Zietz B, Palitzsch KD, Scholmerich J. Impact of disease duration on cardiovascular and pupillary autonomic nervous function inIDDM and NIDDMpatients.DiabetesCare 1996; 19:960-967. 52. Navarro X, Sutherland DE,KennedyWR. Long-term effectsof pancreatic transplantation on diabetic neuropathy. Ann Neurol 1998; 44: 149-150. 53. Ejskjaer NT, ZanoneMM,PeakmanM.Autoimmunityin diabetic autonomic neuropathy: does theimmunesystemgetonyournerves?DiabetMed 1998; 15:723-729. 54. ZanoneMM, Burchio S, Quadri R, Pietropaolo M, Sacchetti C, Rabbone I, Chiandussi L, Cerutti F, Peakman M. Autonomic function and autoantibodies toautonomicnervousstructures,glutamic acid decarboxylaseandislet tyrosine phosphatase in adolescent patients withIDDM. J Neuroimmunol 1998; 87:l-lO. 55. Muhr-Becker D, Ziegler AG, Druschky A, Wolfram G, Haslbeck M, Neundorfer B, Standl E, Schnell 0. Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiacautonomicdysfunction.DiabetMed 1998; 15:467-472. 56. Cachia MJ, Zanone MM, Watkins PJ, Vergani D. Reproducibility and persistence of neural and adrenal autoantibodies in diabeticautonomic neuropathy. DiabetMed 1997; 46 (Suppl. 2):S54-S57. 57. MuhrD, Mollenhauer U, Ziegler AG, Haslbeck M, Standl E, Schnell 0. Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy. Diabetes Care 1997; 20: 101 10092. 58. MurphyW,MannR,McGrathBP,Bell C. Neuronal antibodies and autonomic failure.Lancet 1993; 342:563. 59. Hoeldtke RD, Cilmi KM. Norepinephrine secretion and production in diabetic autonomic neuropathy. J ClinEndocrinolMetab 1984; 59:246-252. 60. Kreiner G, Wolzt M, Fasching P, Leitha T, Edlmayer A, Korn A, Waldhausl W, DudczakR. Myocardial m-[123I]iodobenzylguanidine scintigraphy for the assessmentofadrenergiccardiac innervation in patients with IDDM. Comparison with cardiovascularreflex tests andrelationshiptoleft ventricularfunction.Diabetes 1995; 44:543-549.

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pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1970; 1:125-150. 209. Imperato-McGinley J, Gautier T, Ehlers K, Zullo MA, Goldstein DS, Vaughan ED Jr. Reversibility of catecholamine-induceddilatedcardiomyopathyin a child with a pheochromocytoma. N Engl J Med 1987; 316:793-797. 210. Pearse AGE. Histochemistry and electron microscopy ofobstructive cardiomyopathy. Ciba FoundationSymposium. Boston: Little, Brown, and CO, 1964, p. 132. 21 1. Brush JE Jr, Eisenhofer G, Garty M, Stull R, Maron BJ, Cannon RO, Panza JA, Epstein SE, Goldstein DS. Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy. Circulation 1989; 79:836-844. U, Caeiro T, Palmero H. 212. Iosa D, DeQuattro V, De-Ping LeeD,Elkayam Pathogenesis of cardiac neuro-myopathyin Chagas’ disease and the role of the autonomic nervous system. J Auton Nerv Sys 1990; 30:S83-S88. 213. Iosa D, DeQuattro V, Lee DD, Elkayam U, Palmero H. Plasma norepinephrine in Chagas’ cardiomyopathy: a marker of progressive dysautonomia. Am Heart J 1989; 117:882-887. 214. Zhou QY, QuaifeCJ,

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Japanesefamily with hereditary progressivedystoniadoparesponsive dystonia.BiochemBiophysResCommun 1995; 213:645-651. 237. Furukawa Y, Shimadzu M, Rajput AH, Shimizu Y, Tagawa T, Mori H, Yokochi M, NarabayashiH,Hornekiewicz 0, MizunoY,Kish SJ. GTP-cyclohydrolase I gene mutations in hereditary progressive and DOPA-responsive dystonia. AnnNeurol 1996; 39:609-617. 238. Hyland K, SurteesRA, Rodeck C, Clayton PT.Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inbornerror of neurotransmitter amine synthesis. Neurology 1992; 42:19801988. 239. Hyland K, Surtees RA, Heales SJ, Bowron A, Howells DW, Smith I. Cerebrospinal

fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 1993; 34:lO-14. 240. Swoboda KJ, Hyland K, Goldstein DS, Kuban KC, Arnold LA, Holmes CS, Levy HL. Clinical and therapeutic observations in aromaticL-aminoacid decarboxylase deficiency. Neurology 1999; 53: 1205-121 1. 241. Craig SP, ThaiAL,WeberM, Craig IW.Localisation of the gene for human aromatic L-aminoaciddecarboxylase(DDC) to chromosome 7p13-->pll by in situhybridisation.CytogenetCellGenet 1992; 61:114-116. 242. Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL. Human dopa decarboxylase: localization to humanchromosome 7 p l 1 and characterization of hepatic cDNAs.Genomics 1992; 13:469-471.

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243. O’Malley KL,Harmon S, MoffatM,Uhland-Smith

A, Wong S. Thehuman aromatic L-amino acid decarboxylase gene canbe alternatively spliced to generateuniqueproteinisoforms. J Neurochem 1995; 65:2409-2416. 244. Vulpe C, Levinson B,Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a coppertransporting ATPase. Nat Genet 1993; 3:7-13. 245. Mercer JF,LivingstonJ,HallB,PaynterJA,Begy C, Chandrasekharappa S, Lockhart P, Grimes A, Bhave M, Siemieniak D. Isolation of a partial candidate gene for Menkes disease bypositional cloning. Nat Genet 1993; 3:20-25. 246. Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, MonacoAP.Isolationofa candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 1993; 3: 14-19. 247. Das S, LevinsonB,Whitney S, Vulpe C,Packman S, Gitschier J. Diverse mutations in patients with Menkes disease often lead to exon skipping. Am J HumGenet 1994; 55:883-889. 248. Kaler SG. Menkes disease. Adv Pediatr 1994; 41:263-304. Y, SegalNA,GoldsteinDS, 249. KalerSG,GalloLK,ProudVK,PercyAK,Mark Holmes CS, Gahl WA. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet 1994; 8~195-202. 250. Kaler SG, Goldstein DS,Holmes

C, SalernoJA,Gahl WA. Plasmaand cerebrospinal fluid neurochemicalpatterninMenkes’ disease. Ann Neurol

1993; 331171-175. 251. GunnTR,Macfarlane

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S, PhillipsLI.Difficulties in theneonatal diagnosis of syndrome--trichopoliodystrophy. Clin Pediatr (Phila)

1984; 23514-516. 252. Kaler SG, GahlWA,Berry

SA, HolmesCS,Goldstein DS. Predictive value of plasma catecholamine levels in neonatal detection ofMenkesdisease. J InheritMetab Dis 1993; 16:907-908. 253. Kaler SG, Das S, Levinson B, Goldstein DS, Holmes CS, Patronas NJ, Packman S, Gahl WA. Successful early copper therapy in menkes disease associated with a mutant transcript containing asmallIn-framedeletion.BiochemMolMed

1996; 57:37-46. 254. Tumer Z, Horn N, Tonnesen T, Christodoulou J, Clarke JT, Sarkar B. Early copper-histidine treatment for Menkesdisease [letter]. NatGenet 1996; 12:11-13. 255. Kaler SG. Menkes disease mutations and response to early copper histidine treatment. Nat Genet 1996; 13:21-22. 256. Kaler SG, Buist NR, Holmes CS, Goldstein DS, Miller RC, Gahl WA. Early copper

therapyin classic Menkes disease patients withanovel AnnNeurol 1995; 38:921-928.

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257. Giros G , Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference tococaine and amphetaminein mice lackingthedopamine transporter. Nature 1996; 379:606-612. 258. Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA. X-linked borderline mental retardation with prominentbehavioraldisturbance:phenotype, genetic localization,andevidence for disturbedmonoaminemetabolism.AmJHum Genet 1993; 52:1032-1039. 259. Brunner HG,NelenM,BreakefieldXO,RopersHH,van Oost BA.Abnormal behaviorassociated with a point mutation in thestructuralgenefor monoamine oxidase A. Science 1993; 262578-580. 260. Lenders JWM, Eisenhofer G, Abeling NGGM, Berger W, Murphy DL, Konings CH, Wagemakers LMB, Kopin IJ, Karoum F, van Gennip AH, Brunner HG. Specific genetic deficiencies of the A and B isozymes of monoamine oxidase are characterized by distinct neurochemical and clinicalphenotypes.J Clin Invest 1996; 97:lOlO-1019. 261.Collins FA, Murphy DL, Reiss AL, Sims KB, Lewis JG, Freund L, Karoum F, Zhu D, Maumenee IH, Antonarakis SE. Clinical, biochemical, and neuropsychiatric evaluation of a patientwith a contiguousgenesyndromedueto a microdeletion Xpl1.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes. Am J Med Genet 1992; 42:127-134. 262. Cases 0, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC. Aggressive behavior and altered amountsof brain serotoninandnorepinephrineinmicelacking MAOA. Science 1995; 268:1763-1766. 263. Scambler PJ, Kelly D, LindsayE,Williamson R, Goldberg R, Shprintzen R, Wilson DI, Goodship JA, Cross IE, Burn J. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 1992; 339:1138-1139. 264. FrankeUC, Scambler PJ, Loffler C, Lons P, Hanefeld F, Zoll B,Hansmann I. Interstitial deletionof 22qll in DiGeorgesyndromedetected by high resolution and molecularanalysis.ClinGenet 1994; 46:187-192. 265. Wilson Dl, GoodshipJA,Burn J, Cross IE, Scambler PJ. Deletions within chromosome 22ql1 in familialcongenitalheartdisease.Lancet 1992; 340~573-575. 266. Dunham I, Collins J, Wadey R, Scambler P. Possible role for COMT in psychosis associated with velo-cardio-facial syndrome. Lancet 1992; 340: 1361-1362. 267. Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 1995; 194:629-642.

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T, Kuzmin I, ModiW, Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260:1317-1320. 269. Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer. JAMA 1995; 273564-570. S, Samid D, Duan DS, Gnarra 270. Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu JR, Linehan WM. Silencing of the VHL tumor-suppressor gene by DNA methylationinrenalcarcinoma. Proc NatlAcadSci U S A 1994; 91:97009704. 271. Gross DJ, Avishai N, Meiner V, Filon D, Zbar B, Abeliovich D. Familial

pheochromocytoma associated witha novel mutation in the von HippelLindaugene. J ClinEndocrinolMetab 1996; 81:147-149. 272. Crossey PA, Eng C, Ginalska-Malinowska M, Lennard TW, Wheeler DC, Ponder BA, Maher ER. Molecular genetic diagnosis of von Hippel-Lindau disease in familialphaeochromocytoma.JMedGenet 1995; 32:885-886. 273. Neumann HPH, Eng C, Mulligan LM.Von Hippel-Lindaudiseaseand pheochromocytoma. J AmMedAssoc 1996; 275:280. MA. Estimation of plasmaandurinary 274. Ahmad J, Kham AS,Siddiqui catecholamines in Guillain- Barre syndrome. Jpn J Med 1985; 24:24-29. 275. Locatelli ER, Varghese JP, Shuaib A, Potolicchio SJ. Cardiac asystole and bradycardia as a manifestation of left temporal lobe complex partial seizure. AnnInternMed 1999; 130581-583. dopamine: studies 276. Christensen NJ, Mathias CJ, Frankel HL. Plasma and urinary during fasting and exercise andintetraplegicman.EurJ Clin Invest 1976; 6~403-409. 277. Mathias CJ, Christensen NJ, Frankel HL, Peart WS. Renin release during head-up tilt occurs independently of sympatheticnervousactivityin tetraplegic man. Clin Sci 1980; 59:251-256. Watson LD, Short DJ,FrankelHL,Mathias CJ. 278. Baliga RR, CatzAB,

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Mysterious or Controversial Entities Patients with signs or symptoms suggesting some form of combined cardiovascular, neurological, and psychiatric disorder represent a large proportion ofanyinternist’smedicalpractice.Thesepatientsoftenposediagnostic, therapeutic,andmanagementchallenges.Correspondingly,patient-oriented clinical researchers tend to avoid these conditions or focus their attention on the facets relevant to their experience and expertise, andso large gaps in knowledge persist. Treatment is often empiric, symptomatic, or based on untested notions. The patients and their doctors can become frustrated, and the patients often try “alternative” medical modalities such as “holistic” practitioners and “herbal” remedies. For several of these entities, mechanistic hypotheses impute a role of catecholaminergic systems. This chapter considers research evidence about several ofthese hypotheses. Manydifferentdiagnosticappellationshavebeensuggestedfor psychoneurocardiologicsyndromes-hyperdynamiccirculationsyndrome, hyperkineticheartsyndrome,vasoregulatoryasthenia,hypernoradrenergic hypertension,mitralvalveprolapsesyndrome,chronicfatiguesyndrome, neurocirculatory asthenia, soldier’s heart, effort syndrome, hyperventilation syndrome,DaCosta’ssyndrome,somatizationpsychogeniccardiovascular reaction, psychophysiologic cardiovascular disorder, nervous heart complaint, psychogenic cardiac non-disease, panic disorder, and psychogenic autonomic dysfunction (1,2). The length of this list probably indicates not so much the varietyofpsychoneurocardiologicconditionsasignoranceabouttheir pathophysiologic mechanisms. Common complaints of patients with functional psychoneurocardiologic disorders include breathlessness, palpitations, fatigue, sweating, pain in the chest, limbs, or total body, paresthesias, faintness, and anxiety. The following sections discuss some of these entities in clusters“(1) postural tachycardia (POTS), chronic orthostatic intolerance, and hyperdynamic circulationsyndrome; (2) chronicfatiguesyndrome,neurasthenia,and neurocardiogenic syncope; (3) mitral valve prolapse-dysautonomia syndrome; and (4) reflex sympathetic dystrophy, fibromyalgia, and complex regional pain syndrome. Although the discussion presents the rationale for this parcellation, the reader should keep in mind that these clusters may not constitute distinct 525

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nosologic entities and that within clusters real pathophysiological differences someday may emerge. POSTURAL TACHYCARDIA SYNDROME (POTS), CHRONIC ORTHOSTATIC INTOLERANCE (Col), HYPERDYNAMIC CIRCULATION SYNDROME, NEURASTHENIA, AND HYPERADRENERGIC ORTHOSTATIC INTOLERANCE

As these designations indicate, patients with the postural tachycardia syndrome(orposturalorthostatictachycardiasyndrome,POTS)have an excessive increase in pulse rate during orthostasis-by more than 30 bpm to a heart rate exceeding 120 bpm (3,4). Da Costa’s case descriptions of “irritable heart” in Civil War soldiers included patients with orthostatic tachycardia and palpitations (5), associated with exercise intolerance, fatigue, chest pain, and dizziness. Most cases evaluated in modem medicine involve relatively young (14-45 years old) women (fema1e:male ratio about5:l). Despite the fact that the initial increase in heart rate during orthostasis dependsmainlyonparasympatheticwithdrawal,patientswithPOTShave approximately normal cardiac vagal function, as indicated by the magnitude of respiratory sinus arrhythmia or responses of heart rateto the Valsalva maneuver. Theorthostatictachycardiausuallyoccurswithoutorthostatic hypotension, defined by a decrease in blood pressure exceeding 20 mm Hg systolic or 10 mm Hg diastolic (6). The finding of orthostatic hypotension does not exclude a diagnosis of POTS, and, as discussed below, delayed orthostatic hypotension can occur in this condition (7). Indeed, Lewis’s report about “effort syndrome” in World War I soldiers commented on post-exercise hypotension (8). After essential hypertension, chronic orthostatic intolerance probably is the most common disorder of blood pressure regulation (9). Robertson has suggestedtwoformsofchronicorthostaticintolerance (CO1)-”partial dysautonomia” and “hyperadrenergic orthostatic intolerance” (1). Both are also referred to as POTS or “sympathotonic orthostatic intolerance.” According to thisdistinction,inpartialdysautonomia,incomplete,mildautonomic dysfunction compensatorily activates sympathetic outflows to other regions, via baroreflex mechanisms, whereas in hyperadrenergic orthostatic intolerance, a constant diffuse increase in sympathetic outflows overrides baroreflex inhibition. As discussedbelow,thesesyndromesdifferfromneurocardiogenic syncope (neurally mediated syncope), in that patients with neurocardiogenic syncope have sympathetic inhibition, at least during acute episodes (IO). In contrastwithbaroreflexfailure,patientswiththesesyndromeshave approximatelynormalarterialbaroreflex-mediatedheartrateresponses.In inappropriate sinus tachycardia, the heart rate is increased to 100 bpm or more

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even under resting conditions (1 1). Radiofrequency ablation of the sinus node is considered for patients resistant to treatment with B-adrenoceptor blockers (12). Symptoms associated with POTS include exercise intolerance, dyspnea on exertion, chest pain atypical for angina pectoris, episodic or persistent fatigue,andpanidanxiety.Symptomsthoughttosuggesthyperadrenergic orthostaticintoleranceincludecool,sweatyextremitiesandmigraine-like headache. Clinicians often attribute these symptoms to physical deconditioning, psychosomatic disorders, blood volume depletion, or even malingering. The possibility of blood volume depletionor excessive pooling of blood in thelegsduringorthostasishasdrawnparticularattention.Indeed, hypovolemia was notedin the first case report of postural tachycardia syndrome, by Rosen and Cryer in 1982 (1 1). Their patient responded to the salt-retaining steroid, fludrocortisone, and a high-salt diet. A subsequent study of 11 patients with orthostatic intolerance found decreased blood volume as the only clear cardiovascular abnormality (13), and treatment with fludrocortisone normalized the responses to tilt in 4 of 5 patients. In another small series, 4 of 6 patients with orthostatic intolerance and orthostatic tachycardia had low plasma volume (14).

Acrosspatients,thetachycardicresponsetoorthostasiscorrelates negativelywithbloodvolumeandplasmareninactivity,suggestingthat hypovolemiaoccurscommonly in chronicorthostaticintoleranceand is associated with inappropriatelylow activity of the renin-angiotensin-aldosterone system (9). The response to infused normal saline can be dramatic in POTS patients, temporarily ameliorating their orthostatic symptoms. Streeten has emphasized orthostatic tachycardia and delayed orthostatic hypotension resulting from a progressive, exaggerated decline in blood volume duringorthostasis,asmanifested by alargerthannormalincrease in radioactivity in the calf after injection of erythrocytes tagged with 99Tcpertechnetate (15). Consistent with excessive blood pooling in thelegs or splanchnic bed during orthostasis, inflation of a military antishock trousers (MAST) suit substantially reduces the tachycardic response to orthostasis in patients with POTS (16). Of several possible mechanisms, Streeten has favored venous denervation, because the patients have augmented decreases in foot venous distensibility in response to norepinephrine, as one might expect from local denervation supersensitivity(1 7). Although one might expect hypovolemia at baseline and exaggerated venous pooling of blood during orthostasiss in chronic orthostatic intolerance, the patients usually have normal central venous pressure at baseline and normal decreases in central venous pressure during orthostasis (1 8). Relatively small increments in peroneal skeletal muscle sympathetic activity can occur. Because of the increased activity at baseline, the physiological meaning of a small increase during orthostasis seems unclear.

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Patients with POTS often have increased plasma norepinephrine levels. Indeed, according to one suggestion, criteria for diagnosing chronic orthostatic intolerance include an upright venous plasma norepinephrine level of600 pg/ml ormore (19); however,whetherincreasedsympatheticnervousoutflows constitute a primary abnormality or compensatory response is unknown. When the patient is at supine rest, the rate of peroneal muscle sympathetic nerve traffic is somewhat increased (1 8). Total body, forearm, and cardiac norepinephrine spillover areapproximately normal but can be increased. During exposure to lower body negative pressure, and especially during i.v. infusion of yohimbine, some patients with POTS have marked increases in cardiac norepinephrine spillover, associated with clinically evident panic and large increases in arterial plasma epinephrine levels. Other patients, however, have normal responses to yohimbine. This probably reflects heterogeneity in the patient population. is to The first step in management of chronic orthostatic intolerance search carehlly for reversible causes, such as diabetes, weight loss, prolonged bed rest, debilitating diseases, and medications. Medical treatments for POTS generallyhaveattemptedtoincreasebloodvolume(e.g.,i.v.fluids, fludrocortisone, high-salt diet), block cardiac B-adrenoceptors (e.g., atenolol), decrease exaggerated sympathetically-mediated norepinephrine release (e.g., clonidine, a-methylDOPA, moxonidine), or enhance vasoconstriction (e.g., midodrine,ergotamine,octreotide).Othertreatmentsincludevenous compression hose, calfmuscle resistance training, and exercise. In the hyperdynamic circulation syndrome, resting tachycardia, labile, predominantly systolic hypertension, and increased heart rate responsiveness to isoproterenol are associated with increased catecholamine levels at rest and during provocative maneuvers (20-22). B-Adrenoceptor blockers or benzodiazepines ameliorate the syndrome. It is unclear whether patients with this syndrome have an increased frequency of subsequent development of established hypertension. Episodes of tachycardia and systolic hypertension can be associated with remarkable blotchy flushing of the face, nape, and upper chest (22,23), the emotional facial flushing possibly reflecting active sympathetic vasodilation (24). “Neurasthenia,” a term introduced by Beard in 1867, refers to a syndrome initially described by Da Costa in Civil War soldiers and subsequently by Osler, MacKenzie, and Paul Dudley White (25). The syndrome consists of a large number of symptoms, including breathlessness, palpitations, precordial chestpain,fatigue,dizziness,exertionaldyspneaandfatigue,excessive sweating, trembling, flushing, dry mouth, paresthesias, irritability, and exercise intolerance (26). Family members often have a similar syndrome. The multiplicity of symptoms in these patients contrasts with the dearth of signs of disease,whichallarenon-specific-relativetachycardiaand

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tachypnea, facial and neck flushing, slight tremor, excessive palmar sweating, a functional heart murmur, and hyperactive deep tendon reflexes, with generally normalrestingbloodpressure,Therearenocharacteristiclaboratoryor electrocardiographic findings. Injections of epinephrine can evoke these symptoms. 8-Blockade often normalizesthecardiovascularandsomaticfindingswithoutaffectingthe emotionalsymptoms.Drugssuchascaffeinecanproducetachycardia, tachypnea, tremor, and diaphoresis in patients with neurocirculatory asthenia. These drugs are thought to increase sympathetic outflow by actions in the brain, whereas exogenous epinephrine produces tachycardia directly. Caranasoshashypothesizedthatexcessivecentralstimulationof sympathetic outflows, rather than augmented responsiveness to adrenoceptor agonists, produces the symptoms in patients with neurocirculatory asthenia(27). Rosenman (1990) has suggested that patients with neurocirculatory asthenia have a biological anxiety disorder associated with mitral valve prolapse (25), discussed below. Most modemresearch about neurocirculatory asthenia has beenconducted in Russia. Meerson et al. reported increased baseline epinephrine excretion, normalbaselinenorepinephrineexcretion,andexcessivenorepinephrine responses to stress (28). More than 1/2 of the patients were reported to develop arrhythmias during adrenergic stress responses but not during exercise. Western cardiovascular researchers rarely use the term. Patients with neurocirculatory asthenia do not appear to have an increased risk of organic heart disease or other medical illnesses. MITRAL VALVE PROLAPSE-DYSAUTONOMIA SYNDROME

Some patients with mitral valve prolapse complain of chest pain or pressure, exertional dyspnea, palpitations, orthostatic faintness, fatigue, poor exercise tolerance, pallor, sweating, anxiety, and panic (25). To the patients and their doctors, this constellation can suggest autonomic “imbalance.” Patients with mitral valve prolapse seem to have an increased prevalence of anxiety disorders,although it remainsunclearwhethertheprolapseandpossibly adrenergically-associated anxiety are coincidental. Although early reports noted increased plasma norepinephrine levels in patients with mitral valve prolapse, studies in the late 1980s failed to confirm boththepsychiatricandbiochemicalassociations (29). Onestudynoted increased heart rate and plasma norepinephrine levels and exaggerated tachycardic responses to isoproterenol in patients complaining of dysautonomic symptoms, regardless of the presence of mitral valve prolapse (30). Lenders et al. found no differences in plasmacatecholaminelevelsamonggroupsofmitralvalve

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prolapse patients with or without symptoms and healthy control subjects, at (3 l). rest, during head-up tilt, or during isometric exercise Rosenman has suggested that some of the excessive “sympathicotonic” responsiveness of symptomatic patients with mitral valve prolapse syndrome may result from abnormal processing of baroreceptor information or from hypovolemia, which would augment sympathoneural responses to orthostasis (25). According to Rosenman’s hypothesis, functional mitral valve prolapse results from decreased ventricular volume compared to the size of the mitral orifice. The decreased ventricular volume would in turn result from deficient blood volume produced by an abnormality of sodium homeostasis; this would stimulate sympathetic nervous system outflows compensatorily. Alternatively, since patients with mitral valve prolapse syndrome tend to be thin for their height, with a narrow anterior-posterior chest diameter, and occasionally have pectus excavatum, theymay on a constitutional basis have decreased ventricular volume compared to mitral annulus area. Regardless, hyperadrenergic activity would be associated with mitral valve prolapse not because of a neurocirculatory disorderorbecauseofanxietybutbecauseofaspecifichemodynamic abnormality eliciting appropriate autonomic responses. This pathophysiologic mechanism would in essence subsume mitral valve prolapse-dysautonomia syndrome as a subset ofPOTS. NEUROCARDIOGENIC SYNCOPEI NEURALLY MEDIATED SYNCOPE / CHRONIC FATIGUE SYNDROME

Acute, marked decreasesin sympathetic neural outflows characterize noncardiacsyncope(neurocardiogenicsyncope,neurallymediatedsyncope, vasodepressor syncope, the common faint), by far the most common cause of suddenlossofconsciousness in thegeneralpopulation (10,32-35). Sympathoinhibition, coupled with increased circulating epinephrine levels (3639), produces decreases in vascular resistance, especiallyin skeletal muscle, and decreased total peripheral resistance, without compensatorily increased cardiac output (40), causesthebloodpressuretoplummet.Thepatientfeelsfaint (presyncope) or actually loses consciousness (syncope). Althoughsymptomsandsignsconsistentwithincreasedcholinergic outflows (nausea, abdominal cramps, sweating) often precede the vasodepression, and although vagal bradycardia can accompany it, these do not always occur, and anticholinergic agents often fail to prevent acute episodes. Neurocardiogenicsyncopeseemsmorelikelytooccur in relativelyyoung women than in elderly men, after mssing a meal such as lunch, in a warm environment,whilestanding,afterisotonicexercise,orduringasituation eliciting a classically conditioned or unconditioned emotional response.

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Physiologicalandneuroendocrinecorrelatesofneurocardiogenic vasodepression have received considerable research attention; however, studies so far have failed to identify predisposing factors. Independent of acute episodes, the patients have normal values for physiological and neurochemical variables, including power spectral analysis of heart rate variability (4 1,42), although some reports have implicated increased parasympathetic (43) or decreased sympathetic (44) cardiac “tone” at rest. Plasma levels of norepinephrine are normal; levels of the adrenomedullary hormone, epinephrine, may be increased (45). Peroneal muscle sympathetic activity is normal (35). Accordingtothe“collapsefiring”hypothesisofneurocardiogenic syncope, a combination of increased cardiac contractility and decreased cardiac filling leads to stimulation of inhibitory neuronal afferents to the brain and consequently to vasodepression (32,46,47). Patients with cardiac transplants and therefore denervated hearts, however, can have typical acute vasodepressor reactions (48,49). “Collapse firing” of inhibitory afferents in remnant recipient atria could still occur(50). In a key test of the collapse firing hypothesis (IO), patients with a history of frequent episodes of non-cardiac syncope had attenuated responses of directly recorded sympathetic nerve traffic and plasma norepinephrine levels during tilting, with no evidence for a burst of increased sympathetic outflow, sudden decrease in central venous pressure, or increased cardiac inotropic state prior to thesyncope. In afollow-upstudy (51), thesameinvestigatorsfoundthat treatment with clonidine, which reduces sympathetic neuronal outflows and inhibits norepinephrine release from sympathetic nerve terminals, decreased tolerancetotilt in patientswithahistoryofrecurrentneurallymediated syncope, and treatment with yohimbine, which exerts opposite effects from clonidine,preventedsyncope in mostofthepatients.Thesestudieshave challenged the view that generalized sympathetic activation precedes recurrent neurally mediated syncope. According to anotherview, clinical non-cardiac syncope occurs mainly as a result of elicitation of a particular pattern of central autonomic outflows from the brain, especially during distressing situations where the individual can neither “fight” nor “flee” (52). Consistent with this view, in one of our patients, who was supine at the time, arterial plasma epinephrine levels had already begun to increase and plasma norepinephrine levels to decrease before the onset of hypotension, demonstrating that diffuse sympathoinhibition and adrenomedullary stimulation preceded the spontaneous vasodepression.In three otherpatients,whoweresupineatthetime of theepisode,theplasma epinephrine:norepinephrineratio was higher than before or after the episode. This pattern of sympathoinhibition and adrenomedullary stimulation has been reported in patientswithtilt-inducedvasodepression,priortotheonsetof syncope (53). “Collapse firing” not only does not explain the occurrence of

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neurocardiogenicsyncope in supinepatientsbutalsodoesnotexplainthe prominent adrenomedullary stimulation preceding the vasodepression. We evaluated rates of entry of norepinephrine into arterial, coronary sinus, and forearm venous plasma (norepinephrine spillovers), as indices of total body, cardiac, and forearm release of norepinephrine from sympathetic nerves, and we conducted thoracic positron emission tomographic scanning after administration of the perfusion imaging agent 13N-ammonia and then the sympathoneural imaging agent 6-[18F]fluorodopamine, 'in patients with a history of neurallymediated syncope, normal volunteers, and patients with persistent sympathetic neurocirculatoryfailure. In patientswithsyncopeorpresyncope,cardiac norepinephrine spillover averaged about 1/4 normal (unpublished observations). All thepatientshadhomogeneousmyocardialperfusionanddetectable myocardial 6-[18F]fluorodopamine-derivedradioactivity during thoracic positron emission tomographic scanning. These findings indicate that, independent of acute episodes, patients with a history of repeated episodes of non-cardiac syncope or presyncope have tonically suppressed release of norepinephrine from intact cardiac sympathetic nerve terminals. Several types of treatment can prevent acute episodes in patients with recurrent neurally mediated syncope (54). These include cardiac pacing (55-57), sympathomimetic amines (58,59), midodrine or other a-adrenoceptor agonist (60-62), 8-adrenoceptor blockers (63,64), fludrocortisone (65), i.v. saline or oral salt loading (66,67), and yohimbine (51). Opiate antagonists often do not help (68). Currently no pathophysiology-based rationale exists for choosing among these sometimes seeminglycontradictory treatments. Patients with the chronic fatigue syndrome have persistent, disabling fatigue without established cause for more than 6 months (69). Although at first thought to result from prolonged infection with Epstein-Barr virus, which producesmononucleosis,patientswithchronicfatiguesyndromedonot necessarily have evidence for prior Epstein-Barr virus infection, and many cannotrecallanantecedentviralillness.As in POTSand in mitralvalve prolapse-dysautonomia syndrome, patients with chronic fatigue syndrome or frequent episodes of neurocardiogenic syncope usually are relatively young women. Reports about a high frequency of neurocardiogenic syncope and acute vasodepressor reactions during provocative tilt table testing have supported the view that chronic fatigue syndrome often includes and may result from a form of dysautonomia(70-72).Thetendencytoneurallymediatedpresyncopeor syncope in patients with chronic fatigue syndome seems to contrast with a tendencytosympathetichyperactivity in patientswithchronicorthostatic intolerance; however, no generally accepted means to distinguish the two have appeared.Preliminaryfindingssuggestthatpatientswithchronicfatigue syndrome and a positive tilt table test have decreased cardiac spillover Of

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norepinephrine, whereas patients with POTS have normal or increased cardiac norepinephrine spillover. Treatment ofneurally mediated syncope andchronic fatigue syndrome can be disappointing. Fludrocortisone, midodrine, or a 8-adrenoceptor blocker may decrease the frequency of presyncopal episodes, with unknown effects on the fatigue. Pursuing the hypothesis that sympathoinhibition-especially in the heart-underlies the sense of chronic fatigue, sympathomimetic amines such as d-amphetamine and methylphenidate may merit consideration. Carotid Sinus Syncope

Physical manipulation of the region of the carotid sinus in the neck has long been thought to evoke circulatory abnormalities such as bradycardia, arrhythmias,hypotension,andsyncope. In contrastwithneurocardiogenic syncope, carotid sinus syncope seems to occur mainlyin elderly patients. Surprisingly little is known about the mechanism of clinical carotid sinus syncope.Althoughvagalcardioinhibitionusually is prominent,hypotension independent of bradycardia can occur(73,74). The mainstays of treatment of carotid sinus syncope are irradiation of the neck, surgery, cardiac pacing, and medical treatment with vasoconstrictors and fludrocortisone (73,74). REFLEX SYMPATHETIC DYSTROPHY, FIBROMYALGIA, AND COMPLEX REGIONAL PAIN SYNDROME

Simonovsky coined the term “reflex sympathetic dystrophy” (RSD), to refer to structural damage in myocardium after prolonged stimulation of sensory nerves in the arm, a phenomenon he considered to result from an abnormal sympathetic reflex (75). The term has been expanded to include severe limb pain that develops after seemingly minor trauma and is disproportionate to the injury. RSD, renamed complex regional pain syndrome (CRPS) type I (76), now refers to post-traumatic pain that (1) develops regionally distal to the site of injury; (2) exceeds in magnitude and duration the expected clinical course of the inciting event; (3) progresses variably over time; (4) is associated with nonspecificsymptomsandsignssuchasalteredskincolor,temperature,or sudomotor activity, allodynia, disuse atrophy, or edema; and (5) in contrast with CRPS type I1 (formerly called causalgia), occurs in a distribution different from that resulting frominjury to a single peripheral nerve. The pathogenetic basis of RSD has been and remains both controversial and unclear. Some authors view the syndrome as mainly inflammatory (77,78); however, flow cytometry analysis does not differ between RSD patients and

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healthy control subjects (3), and treatment with non-steroidal anti-inflammatory drugs is probably ineffective( 5 ) . Others view RSD as a neurocirculatory disorder, with the pain mediated in some way by altered sympathetic neurovascular function. A pathogenetic role for increased sympathetic neuronal outflows can explainimprovement of painby sympathetic blocks or sympathectomyin some patients (1 5,69,79,80); however, neurophysiological and neurochemical studies have failed to support increased post-ganglionicsympatheticnervetraffic in RSD (35,81,82), and a disappointingly large proportion of patients with chronic RSD have recurrence of pain after surgical or chemical sympathectomy(69,83-85). Neurocirculatory concepts have alternatively posited partial sympathetic denervation. This might secondarily increase expression of nerve growth factor (86), which bya variety of mechanisms could increase efficiency of pain transmission or norepinephrine-induced stimulation of nociceptors. Denervation supersensitivityofvascularsmoothmusclecellswouldalsodevelop, augmenting vasoconstrictor responses to sympathetic activation. These processes could then help to explain improvementin pain by sympatholytic procedures or administration of a-adrenoceptor blockers (1 1). Animal models of chronic constriction injury to peripheral or spinal nerves often feature histological (87) or neurochemical (88) evidence of local denervation. Placebo-controlled studies of patients with RSD, however, have failed to confirm amelioration of the pain by sympathetic block (89) or a-adrenoceptor blockade (90,91), questioning the notion of “sympathetically maintained pain,” at least in patients with chronic RSD. The syndrome is thought to evolve in stages, the early stage characterized by localburningpain,swelling,increasedsweating,andincreasedskin temperature; and the late stage by cool skin, allodynia, tropic skin and nail changes, muscle atrophy, osteoporosis, and contracture of the limb. Thepain in RSDoftenrespondsacutelytolocali.v.instillationof guanethidine(“Bierblock”)intothebloodlesslimb,localinjectionofan anesthetic in the region of a sympathetic ganglion, or local intradermal or i.v. injection of the a-adrenoceptor blocker phentolamine (92). Moreover, brachial intra-arterialinfusionofnorepinephrineintoanaffectedarmelicitsan exaggeratedlocalvasoconstrictorresponse (93), andbrachialinter-arterial infusion of phentolamine can alleviate the pain temporarily. These findings have led to the use of surgical sympathectomy to produce longer-lasting benefit. WhetherRSDasencounteredclinicallyresultsfromabnormal sympathetic nervous system activity has been unknown. Patients with RSD have decreased, rather than increased, plasma norepinephrine levelsin the venous drainage of the affected limb (81). Research attention therefore has begun to focus on possible abnormalities of adrenoceptors, including adrenoceptors on nociceptor afferents (94). Our recent findings indicate generally independent

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mechanisms of chronicpain and sympathetic dysfunction after traumatic damage to peripheral nerves in patients with reflex sympathetic dystrophy (unpublished observations). ThepaininRSDcanspreadtotheoppositelimb,orcanspread throughout the body. In fibromyalgia, the patient has generalized pain, which can include atypical chest pain. Manipulation of trigger points can precipitate the pain, and emotional distress increases the frequency of complaints of pain. Thepathophysiologicalbasisofpain in fibromyalgiaremainsmysterious. Patients with fibromyalgia have normal rates of peroneal sympathetic nerve traffic (95). POST-TRAUMATIC STRESS DISORDER

In the Bible, among the ancient Hebrews all able-bodied adult males had to serve in the military. An exception to such service was the conscript with a “faint heart.” As noted above, Da Costa noted cases of “irritable heart,” aform of functional cardiovascular disorder, in Civil War soldiers ( 9 , and Osler, MacKenzie, and Paul Dudley White subsequently reported similar cases in soldiers ofWorld War I and World War I1 (25). During and after theVietnam conflict, clinicians noted again an incidence of disability after psychological trauma. This led to the designation, “posttraumatic stress disorder” (PTSD), beginning about 1980 (96). This rapidly received publicity and acceptance. Since the same symptoms and signs can develop in individuals independently of military exposure, current research and clinical practice considers this syndrome as inducible by any source of sudden, unexpected, extreme distress. The diagnosis of PTSD depends mainly on psychological criteria, such as vigilance, fear, sensitivity to threat, helplessness, exaggerated startle, sleep disturbance, intrusive memories, dissociation phenomena, and numbing. The intrusive symptoms and exaggerated startle typically develop only weeks after the trauma, suggesting a maladaptive psychobiological state. Severalneurobiologicsystemshavebeenstudied in patientswith PTSD-sympatheticnervous,adrenomedullaryhormonal,hypothalamicpituitary-adrenocortical, hypothalamic-pituitary-thyroid, and endogenous opioid (97). The following discussion focuseson the catecholaminergic systems. Underrestingconditions,patientswithPTSDhavenormalifnot decreasedplasmalevelsandtotalbodyspilloversofnorepinephrineand epinephrine (98,99). During exposure to trauma-related laboratory stressors (e.g., a combat movie), however, the patients have enhanced heartrate, blood pressure, and plasma epinephrine responses (99,100). An issue in this research is the constitution of the control group, which should consist of people who have undergone similar psychological trauma but have not developed PTSD, rather

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than consist only of age- and gender-matched normal volunteers. It is also possible that increased plasma norepinephrine levels in some PTSD patients may relate to concurrent depression(101). In response to the yohimbine challenge test, most patients with PTSD have exaggerated noradrenergic responses (102). Perhaps more importantly, the drugoftenelicitsorintensifiesthedisablingsymptomsofPTSD,suchas flashbacks, intrusive traumatic thoughts, numbing, or grief, and can evoke frank panic. These findings support the view that release of norepinephrine in the brain can precipitate or worsen the psychiatric manifestations acutely. Patients with PTSD who have taken over-the-counter yohimbine orally also have noted acute worsening of their symptoms (103). In contrastwithresponsesoflaboratoryanimalstoacutedistressing stimuli and of humans to laboratory mental challenges, where plasma levels of norepinephrine, epinephrine, and ACTH usually increase, patients with PTSD have evidence for peripheral noradrenergic activation, often measuredby plasma levelsorurinaryexcretionof methoxyhydroxyphenylglycol (MHPG) but decreasedadrenocorticalsecretion,measuredbyplasmalevelsorurinary excretion of cortisol (1 04, l OS), although studies have not agreed consistently on these points (106). The research usually has failed to consider the separate regulation of the sympathetic nervous and adrenomedullary hormonal systems and the fact that MHPG production depends complexly on many factors besides releaseofcatecholamines in the“sympathico-adrenalsystem”;somehave presumed erroneously that urinary excretion of MHPG has a mainly central neural origin. PTSD inpatients have been reported to have increased 24-hour urinary excretion rates of dopamine and norepinephrine, with results about epinephrine less clear (107,108). Although these findings have been interpreted in terms of “increasedsympatheticarousal” in PTSD, in humansurinarydopamine excretion depends on non-neuronal synthesis of dopamine in the kidneys and is onlydistantlyrelatedtosympatheticnervousoutflows;andurinary norepinephrine excretion probably depends at least partly on norepinephrine release in the kidneys. CATECHOLAMINES AND HUMAN ESSENTIAL HYPERTENSION

Accordingtoalong-heldbutunprovenclinicalnotion,excessive “sympathico-adrenal” activity or reactivity contributes to the pathogenesis of clinical primary hypertension. Decadesbeforeepidemiologicstudiesshowedthatevenmoderate hypertension shortens life span and increases cardiovascular morbidity, surgical sympathectomy successfully ameliorated severe hypertension in a substantial proportion of patients (1 09). After pharmacotherapy superseded neurosurgeryin

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the treatment of hypertension, many effective antihypertensive agents were found to work by interfering with sympathetic neurotransmission, blocking cardiac or vascular adrenoceptors, or stimulating central neural adrenoceptors, implicating adrenergic mechanisms in the hypertensive process. According to one conceptual model( 1 lo), four factors produce increased sympathetic outflow and increased total peripheral resistancein clinical primary hypertension:baroreflexresetting,geneticconstitution,stress,andreninangiotensin-aldosterone system activation in the brain and periphery. Complex interactions among circulating levels of humoral factors such as an endogenous digoxin-like substance, steroids, and epinephrine; structural adaptive changes in vascular walls; endothelium-derived relaxing and contracting factors (e.g., nitric as oxideandendothelins);membraneandintracellularmechanismssuch adrenoceptor numbers and types, second messengers, ion channels, and protein phosphorylationallwouldincreasesympathoneuraloutflow,leadingtoan abnormal renal function curve, the long-term determinant of high blood pressure (1 11). Theimportantissue in consideringthissortofmodelisnotthe individualcomponents,sincetheyseemtochangecontinuallywiththe discovery of additional vasoactive substances, but the “goal-directedness’’ of the entire mosaic. What homeostats regulate the effectors, and how and why do the homeostats reset? In a manner analogous to spontaneously hypertensive rats, patients with essential hypertension can have abnormalities of catecholaminergic function at virtually all levels of the sympathetic neuraxis (Table 9-1). As in spontaneously hypertensive rats (SHRs), these abnormalities are more apparent or are only detectable in relatively young patients, suggesting a role in the development of the hypertension. When studied at rest, patients with established essential hypertension, considered as a whole, do not have increased directly recorded peroneal skeletal muscle sympathetic activity (SMSA). A proportion of patients with borderline or mild hypertension do have excessive SMSA at baseline (1 12-1 15); and it appears that Japanese hypertensives can have increased SMSA regardless of the age of the compared groups (1 16- 1 18), just as many studies of Japanese hypertensives have reported increased plasma norepinephrine levels. Exposure to stressors such as the cold pressor test, unloading of cardiopulmonary “low pressure” baroreceptors, or unloading of arterial baroreceptors seems to augment differencesbetweenhypertensiveandnormotensivecontrolsubjects ( 11 4 , 1 1 5 , 1 1 9 ~ a l s oanalogous to findings in SHRs. Plasma Catecholamines

Analytical reviews have summarized the voluminous literature about plasma norepinephrine levels in clinical hypertension (120,12 1). Distributions

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Table 9-1 Multiple Loci of Abnormalities of Catecholamine Systems in Human Essential Hypertension

Level CNS

Finding

PNS

Decreased baroreflex-cardiac sensitivity Increased heart rate Decreased power of high-frequency variability of heart rate Decreasedsalivation

SNS

Inverse relation between baroreflex-cardiac sensitivity and plasma norepinephrine Increased response of skeletal sympathetic nerve activity for a given change in cardiac filling Increased skeletal sympathetic nerve activity during various laboratory challenges (e.g., cold) Increased depressor response during ganglionblockade Increased spillover of norepinephrine into arterial plasma Decreased Uptake- 1 activity Increased pressor and plasma catechol responses during ~ ( 2 adrenoceptor-blockade Increased cardiac and renal norepinephrine spillover Increased power of low-frequency variability of heart rate

Target

Cardiac hypertrophy related to plasma norepinephrine Excessive vasoconstrictor responses Abnormalintracellular messengerdca Decreased acetylcholine-induced vasodilation Increased crl-adrenoceptor-mediated responses Decreased P-adrenoceptor-mediated responses Increased renal vasomotion and responses to adrenoceptor blockade

Excessive increases in arterial norepinephrine spillover during mental challenge High plasma norepinephrine and epinephrine during real-life distress Increased CSF norepinephrine and cerebrovascular norepinephrine spillover

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Positive correlation between plasma norepinephrine and plasma renin activity Decreaseddopamineexcretioninsalt-sensitivepatients

Abbreviations: CNS = central nervous system; PNS system; SNS = sympathetic nervous system.

=

parasympathetic nervous

of antecubital venous plasma norepinephrine levels in hypertensive patients are widerandshiftedsignificantlytowardshighervaluesthandistributions in normotensivecontrolsubjects,butwithsubstantialoverlapbetweenthe distributions (122), indicating the absence of a discrete hypernoradrenergic subgroup. After taking into account several possibly confounding factors, including body-mass index, individual maximum physical work capacity, urinary sodium excretion,andanxietyscores,relativelyyoungpatientswithborderline hypertensiondoseemtohaveincreasedantecubitalvenousplasma norepinephrine concentrations, compared to valuesin age-matched normotensive subjects (1 14,115,123-126). The sympathetic hyperactivity may relate to the development ofcardiovascular hypertrophy (127). Studies of regional kinetics of catecholamines have indicated increased cardiac and renal spillovers of norepinephrinein young hypertensives (128-130). In contrast, forearm norepinephrine spillover seems normal. Total body spillover of epinephrine may be statistically increased in mild essential hypertension, even when total body and forearm spilloverof norepinephrine are normal (131). Some hypertensive patients have increased spillover of norepinephrine intointernaljugularvenousplasma(132,133),andmoststudiesabout cerebrospinal fluid norepinephrine in primary hypertension have noted increased levels in hypertensive patients, consistent with increased norepinephrine release in the central nervous system. In some patients with primary hypertension, a transition occurs from a neurogenic to a non-neurogenic basis for the high blood pressure. Thus, the magnitudeofincrease in totalbody,cardiac,andrenalspilloverof norepinephrine in hypertensive patients varies inversely with age (128,129,132,134).Sincenormotensivesubjectswithafamilyhistoryof hypertension have higher rates of norepinephrine spillover into arterial plasma than do normotensives without a family history of hypertension(1 35), increased sympathetically-mediated norepinephrine release might contribute to or provide a marker for thelater development ofhypertension in humans.

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Pharmacologic Profiling

Given the large number of factors regulating blood pressure, and the likely heterogeneity of clinical hypertension, the contribution of increased autonomic activity to essential hypertension must vary widely across individual patients. Using a pharmacologic blockade method to estimate the neurogenic component, Korner et al. (136) found an increased autonomic contribution to totalperipheralresistance in hypertensives,butwith 60% to 80% of the observed difference from that in normotensives due to non-autonomic factors. AS discussed previously, compensatory activation of other pressure-regulatory systems could have led to underestimation of the contribution of the autonomic component. This and other limitations have led to abandonment of the use of ganglionic or adrenoceptor blockade to estimate autonomic tone from effectson blood pressure or peripheral resistance. Combinedassessmentsofneurohormonalfactorsandhemodynamic responses to adrenergic drugs can improve the accuracy of identifying patients with a sympathoneural contribution to blood pressure. Hypernoradrenergic patients have augmented depressor responses to clonidine, atenolol, or combined a-and R-adrenoceptor blockade and augmented pressor responses to yohimbine (137-139). Hypernoradrenergic hypertensives also tend to have increased plasma reninactivity(PRA),andwhereasmostpatientswithbothhighplasma norepinephrine levels and increased PRA respond well to treatment with a Radrenoceptor blocker or a combineda-and R-adrenoceptor blocker, they respond less well to a diuretic (140-144). The combination of high baseline levels of norepinephrine and PRA, a large depressor response to clonidine, and a large pressor response to yohimbine therefore may identify patients with an increased sympathoneural contribution to blood pressure better than does any of these measures in isolation. The value of this profiling, both in therapeutic decision-making and in predicting cardiovascular morbidity, is unknown. Hypertensive patients with elevated plasma norepinephrine concentrations do appear to respond well to relaxation therapy for hypertension (145). Patients with established hypertension often have exaggerated increments in blood pressure or total peripheral resistance after administration of any of a varietyofvasoactivedrugs,includingnorepinephrine.Excessivepressor responsiveness in hypertensives probably results from a complex combination of pre-synapticandpost-synapticfactors.Moststudieshavenotassessed simultaneously more than one of these factors. The “yohimbine challenge test” is a step in this direction (139). Among young patients with borderline or mild hypertension, some have normal pressor responses and normal responses of arterial norepinephrine levels during yohimbine infusion; some have augmented pressor responses for a normal increment in plasma norepinephrine; and some

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haveaugmentedincrements in plasmanorepinephrinelevels,withpressor responses appropriate for the increases in norepinephrine levels. Thus, the yohimbinechallengetestmaydistinguishpatientswithpressorhyperresponsiveness due to increased sympathetically-mediated norepinephrine release from patients with pressor hyper-responsiveness due to increased post-synaptic responsiveness for a given amount of norepinephrine release. Patientswithessentialhypertensiondonotappeartohaveoverall increased responsiveness of isolated arteriolar smooth muscle to norepinephrine. Moststudieshavefoundnormalorevendecreasedresponsiveness,after exclusion of geometric factors such as wall thickness:lumen ratios.

Stress Responses Many studies have reported excessive catecholaminergic, pressor, or vasoconstrictor responses to a variety of laboratory stressors in young patients withborderlineormildhypertension.Amongborderlinehypertensive adolescents, those with excessive physiologic responses to mental challenge have enhanced plasma catecholamine responses as well as a higher risk for subsequent progression to established hypertension during a long-term followup(146).Inoneofthefewstudiesaboutcatecholamineresponsesof hypertensives to other than laboratory stressors, Low et al. reported that during laryngoscopy prior to elective vascular surgery, hypertensives had markedly larger increases in plasma norepinephrine levels than did normotensive patients, and plasma epinephrine levels increased onlyin the hypertensive group (147). Analogous to the findings described above in SHRs, excessive renal vasoconstrictor responses during emotional stress in hypertensives would be expected to contribute to a tendency to retain sodium; and several groups have reported augmented renovascular responses in hypertensive patients (148- 15 1). As part of defense reactions, sympathetically-mediated vasoconstriction could augment sodium retention, by several mechanisms, including renin-angiotensinaldosterone system activation. If there is a hypertensive personality, probably only a minority of patients have it. Young patients with mild neurogenic hypertension (characterized by high plasma levels of catecholamines or plasma renin activity and sensitivityof blood pressure to autonomic blockade) tend to have anger, suppressed hostility, oranxiety(139,140,152). In across-sectionalstudyofnewlydiagnosed, untreated hypertensive and normotensive control subjects, anxiety, depression, hostility, and anger expression did not differ between the groups, whereas “alexithymia” (referring to inappropriate affect, difficultyin verbal description of feelings, absence of fantasies, and acting on impulse) constituted an independent correlate of hypertension (153). Analysis of the literature about suppressed hostility, the Type A behavior pattern, a constellation of neuroticism, anxiety

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and depression, inability to deal with life stresses, and alexithymia has indicated that although personality factors may characterize certain subgroups of patients, there is no convincing evidence that any of these factors actually relates causally to the development of hypertension(1 54). In a prospective study of personality factors as predictors of hypertension development in young (18-24 year old) normotensiveandborderlinehypertensivesubjects,stress-inducedpressor responses, indices of sympathoneural activity, and psychological factors only weakly predicted blood pressure classification at a meanof 30 months of followup (155). The largest pressure increases in pressure occurred in subjects with suppressed aggression. The Epinephrine Hypothesis

Accordingtothe“epinephrinehypothesis”forthedevelopmentof essentialhypertension(156-158),highcirculatingepinephrinelevels in hypertensive patients increase neuronal uptake of epinephrine, and subsequent sympathetic stimulation co-releases neuronal epinephrine with norepinephrine, the released epinephrine activatingpre-synaptic R-adrenoceptors and augmenting further norepinephrine release. The hypothesis therefore views epinephrine as an amplifier of sympathetically-mediated pressor responses. Recent clinical studies havefailedtosupporttheviewthatphysiologicallyactiveamountsof circulating epinephrine augment vasoconstrictor or norepinephrine spillover responses to subsequent sympathetic stimulation (159,160). Salt-Sensitive Hypertension and the L-DOPAIDopamine Natriuretic System

Many groups have studiedpossible pathophysiologic mechanisms of saltsensitive hypertension, generally referring to hypertensive patients in whom blood pressure increases by more than 3 to 10 mm Hg between a low- and highsalt diet. In healthy people and in experimental animals, salt deprivation tends to increase and salt loading tends to decrease plasma norepinephrine levels. Several reports have noted a failure to suppress plasma norepinephrine levels normally during dietary salt loading in salt-sensitive hypertensives; and other reports have indicated higher plasma norepinephrine levels in salt-sensitive than in salt-resistant hypertensives or normotensive control subjects even during normalsaltintake.Thesefindingsareconsistentwiththesuggestionthat enhancedsympathoneuralresponsivenesscontributestosaltsensitivity. Althoughdirectlyrecordedskeletalmusclesympatheticactivity(SMSA) decreases during dietary salt loading (1 12), and renal norepinephrine spillover increases during dietary salt restriction (161), no study has compared responses

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of either SMSA or renal norepinephrine spillover to alterations in dietary salt intake in salt-sensitive and salt-resistant hypertensives. Several groups have hypothesized that an imbalance between the antinatriuretic catecholamine, norepinephrine, and the natriuretic catecholamine, dopamine, causes or contributes to salt sensitivity (162-170). In a study of responsesofurinaryL-DOPAanddopamineexcretionduringdietarysalt restriction and loading in salt-sensitive and salt-resistant hypertensive inpatients, salt-sensitive patients had a higher mean rate of L-DOPA excretion and a lower urinary dopamine:L-DOPA ratio than salt-resistant patients, regardless of dietary salt intake, suggesting deficient renal uptake or decarboxylation of L-DOPA in salt-sensitive patients (17 1). Abnormalities of dopaminereceptors also can contribute to hypertension. Asnotedabove,SHRshaveapproximatelynormalrenalproductionof dopamine but have decreased signal transduction by D l receptors in proximal tubulecells,decreasingsodiumtransportviatheNa+-H+exchangerand Na+/K+ATPase activity(1 72). Mice with knockout of either D the l A receptor or D3 receptor gene have hypertension(1 73,174). According to one concept (1 75), lack of Dl receptors interferes with the ability of dopamine to function as an autocrine/paracrine factor at proximal tubular cells, and lack of D3 receptors interferes with the ability of dopamine to restrain norepinephrine release from renal sympathetic nerves, both abnormalities contributing in decreased excretion of a sodium load. In humans, administration of the D l agonist, fenoldopam, increases urinary sodium excretion in both hypertensives and normotensives (176).SincethedrugdoesnotincreasefractionalexcretionofLi+in hypertensives, up-regulation of distal D l receptor function might offset a defect in proximal D l receptor function.

Baroreflexes Resetting of the cardiovagal limb of the arterial baroreflex accompanies virtually all forms of experimental and clinical hypertension, including essential hypertensioninhumans(177,178).Alterationsinbaroreflexfunction in essential hypertension could be primary or secondary. Parmer et al. (1992) reported lower mean arterial baroreflex-cardiac gain in normotensives with a familyhistoryofhypertensionthan in thosewithout a familyhistoryof hypertension(179),suggestingthat low arterialbaroreflexsensitivitycan indicate a risk for the development of hypertension rather than simply result fromhypertension.Markhasproposedthatincreasesinskeletalmuscle sympathetic activity (SMSA) in mild hypertension do not result from impaired arterial baroreflexes but from increased central sympathetic outflow (180). These viewsarenotnecessarilycontradictory.Forinstance,stimulationofthe paraventricular nucleus, which projects to sympathetic pre-ganglionic neurons,

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inhibits single unit responses of cells in the nucleus of the solitary tract that are activated by stimulation of arterial baroreceptors (18 1). Whether patients with essential hypertension have alterations in arterial baroreflex-vascular or arterial baroreflex-sympathoneural gain has been less clear. Several studies have reported evidence for baroreflex-cardiac resetting in young hypertensives,withoutevidenceforbaroreflex-vascularorbaroreflexsympathoneural resetting(177,182). Matsukawa et al. reported decreased arterial baroreflex-mediated inhibition of SMSA after phenylephrine administration, with normal reflexive stimulation of sympathoneural activity after injection of nitroglycerine, a mechanistic combination that would tend to elevate blood pressure (1 15). When lower body negative pressure is used to hold central venous pressure constant, borderline hypertensives have similar changes in SMSA to those in normotensive control subjects when arterial baroreceptors are stimulated or inhibited by infusionsof nitroprusside or phenylephrine (1 19). Patients with mild or borderline essential hypertension appear to have increased cardiopulmonary baroreceptor reflex gain, since during unloading of cardiopulmonary baroreceptors by application of non-hypotensive lower body negative pressure (LBNP), hypertensives have larger increments in SMSA for any given decrease in central venous pressure than do normotensive control subjects (1 19). Increased cardiopulmonary baroreflex gain could offset a central neural abnormality in regulation of sympathetic vascular tone, and LBNP might unmask the abnormality. In established hypertension, or hypertension associated with myocardial hypertrophy and increased stiffness, the restraining influence of the cardiopulmonary baroreceptors could decline (1 83). This would help to explain positive correlations between plasma norepinephrine levels and severity of left ventricular hypertrophyin some studies. Neurovascular Compression

Beginningabout1980,anovelputativemechanismofneurogenic hypertension, advanced mainly by Jannetta and colleagues at the University of Pittsburgh, has aroused interest and debate (184). According to the Jannetta hypothesis, aging-related changes in the architecture of local arteries, such as elongation and formation of stiffened loops, leads to pulsatile neurovascular compression of cranial nerve roots in the lower brainstem, eliciting hyperactive dysfunctionoftheaffectedcranialnerve.Thishasbeenproposedasa mechanism for trigeminal or glossopharyngeal neuralgia, hemifacial spasm, tinnitusandvertigo,andessentialhypertension.Jannettahascarriedout microsurgical decompression procedures in numerous patients, claiming cure of “essential” hypertension in many cases. Such claims continue to the present time (185).

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Recently, a different group reported positive results of neurovascular decompression to treat refractory essential hypertension in selected patients with (1 86). A third group magnetic resonance imaging evidence for such compression reported a case of trigeminal and glossopharyngeal neuralgia, left hemifacial spasm, and hypertension, with pre-operative magnetic resonance angiographic evidence for an ectatic left vertebral artery and intra-operative discovery of multiple neurovascular compressions, Microvascular decompression not only relieved the neuralgias but also normalized the blood pressure (187). A fourth group also reported positive results of microvascular decompression in four patients (1 88). Studies by severalgroupshavegenerallyconfirmedthatpulsatile compression of the rostral ventrolateral medulla (RVLM) increases blood pressure. In rats, this manipulation increases blood pressure and heart rate, splanchnic nerve traffic, and plasma levels of norepinephrine and epinephrine. Abolition of the pressor response by the ganglion blocker, hexamethonium, indicates dependence of the response on sympathetic neuronal outflows(1 89). A remarkable autopsy study of humans reported that in contrast with control subjects or patients with renovascular hypertension, all of 24 patients withessentialhypertensionhadneurovascularcompressionintheleft ventrolateral medulla (190). The same group of investigators, in a single-blind study,obtained in vivo evidencebymagneticresonanceimagingfor neurovascular compression in the left ventrolateral medulla in most patients withessentialhypertension (191). Othersudiesusingmagneticresonance imaging have disagreed about the frequency of neurovascular compression ofthe left RVLM in patients with essential hypertension and about the specificity of such a finding (1 89,192,193). The relative paucity of clinical trials of microvascular decompression, ethical limitations that preclude “sham” surgery, the statistical phenomenon of regression to the mean, and potential observer biases prevent firm conclusions about the frequency of neurovascular compression in the left ventrolateral medullaasacauseofessentialhypertensionandabouttheefficacyof microvascular decompressive surgery. Perhaps clonidine suppression testing (137) canidentifyindividualcaseswhereincreasedsympatheticneuronal outflows, associated with “hyperactive dysfunction” of the rostral ventrolateral medulla, cause or contribute to the hypertension. Cardiovascular hypertrophy in hypertension does not appear to relate as directlytobloodpressureasonemightexpect.Oneexplanationforthis discrepancy is that sympathetic activity can contribute to cardiac and vascular hypertrophyeven in theabsenceofalterations in bloodpressure.Among borderlinehypertensives,baselineplasmanorepinephrinelevelscorrelate positively with minimum forearm vascular resistance (127), consistent with the view that increased sympathoneural activity contributes to the development of

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vascularhypertrophy.Severalstudies by Coreaandco-workers (194-196) reported positive correlations between plasma norepinephrine levels and severity of left ventricular hypertrophyin hypertensives. In young hypertensives, arterial plasma norepinephrine levels correlate positively with the extent of limitation in (197). arteriolar dilation and arterial distensibility Although associations between plasma norepinephrine levels and cardiac hypertrophy are consistent with a sympathoneural contribution to cardiovascular hypertrophy in hypertension, another explanation for these relationships is that impaired cardiac function resulting from ventricular hypertrophy may recruit sympathetic outflow compensatorily to maintain hemodynamic homeostasis. In patients with essential hypertension, the extent of alterations in left ventricular massandgeometrymarkedlyinfluencesprognosis (198). No studyhas considered the possible prognostic implications of high plasma norepinephrine levels in patients with hypertension-associated left ventricular hypertrophy. Research about linkages, mutations, or polymorphisms of genes related to catecholamine synthesis or inactivation in clinical hypertension are in their infancy. A positive association between a tyrosine hydroxylase microsatellite marked and essential hypertension has been reported (199); however, no study has examined the relevance of this association to sympathetic neuroeffector function. STRESS AND CARDIOVASCULAR DISEASE

Catecholamines contribute to values for every known risk factor and epidemiological feature of coronary heart disease-hyperlipidemia, hypertension, nicotiniceffectsofsmoking,obesity,insulinresistance,andtheType A behavior pattern-and catecholamines can precipitate acute events in coronary patients. Despite suggestive evidence from studies of laboratory animals, the role of chronically repeated episodes of stress or of abnormal “coronary-prone” behavior or personality in the development of clinical coronary heart disease remains controversial; and a catecholaminergic link, while rational, remains unproven. At least theoretically, sympathetic nervous system or adrenomedullary hormonal system activation can accelerate the development of atherosclerosis, by a variety of mechanisms. Catecholamine-induced hemodynamic changes that increase peak blood flow velocity and heart rate increase the likelihood of turbulence and therefore might increase endothelial cell turnover and arterial wall damage. Since epinephrine mobilizes free fatty acids, the catecholamine might indirectly inhibit production of high density lipoproteins, via transformation of excess free fatty acids to triglycerides in the liver and inhibition of lipoprotein lipase by high triglyceride levels. Catecholamines might catalyze production of cholesterol esters in arterial walls (200). Thus, in rabbits on a normal diet(201),

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and monkeys on a high-cholesterol diet (202), injections of norepinephrine or epinephrine can produce aortic sudanophilic lesions. Moreover, emotional distress seems to increase serum cholesterol levels subacutely or chronically, in humans and laboratory animals (203-207). In a famous study of tax accountants, serum cholesterol levels peaked about April 15 (208). In a longitudinal study of Johns Hopkins medical students, the stress of examinations was associated with increased cholesterol levels (209). Although long-term emotional distress probably does bias towards increased circulating lipidlevels,themagnitude,timecourse,mechanisms,andinter-individual consistency of this effectin humans remain incompletely understood. In laboratory monkeys on a high cholesterol diet, social instability and dominanceinteracttoaccelerateatherosclerosis(210-212).Cynomolgus monkeys subjected to psychosocial stress (the threat of capture and physical handling by the investigator while the animals were in their social groups), that have relatively large heart rate responses, also have more extensive coronary atherosclerosis than those with small heart rate responses (213). In zoo animals, crowding and social perturbation increase the frequencyof atherosclerosis (214).

Life Events Until the late 196Os, scientific support for a causal link between stress and the development of chronic cardiovascular disease depended mainly on collectionsofcasereports. In 1967,HolmesandRahe(21 5 ) publisheda “Schedule of Recent Experience” to quantify major life changes and their relationship to illness in general. The authors proposed that the sum of the life changes requiring adjustment would predict subsequent illness. In the inventory, subjects reviewed a checklist of positive and negative life experiences, such as marriage, divorce, birth or death of a close family member, loss of employment, and relocation. The 43 life events were ranked numerically, with death of a spouse rated 100, divorce 73, marital separation 65, a jail term 63, death of a close family member 63, loss of employment 47, and so forth. The subjects wereasked to think back over a specific time interval and report events during that interval. The total score was compared with health outcomes, such as visits to a doctor. Studies using this approach generally found thatrecalled life changes preceded the recalled onsetof illness (2 16). The approach using life change rating scales accepts Selye’s notions that stresscancontributetoanyofawidevarietyofdiseases,dependingon “conditioningfactors”operating in theindividualandtheextentand appropriateness of the stress response; and that stress is the sum of all the LLwear and tear” in an individual. This approach has proven very popular, and an abundance of lay literature purports to instruct the reader about how to quantify stress and calculate risk.

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The IOW predictability of morbid events or mortality has led to reliance on retrospective or case-control analyses in testing the validity of rating scale results. The retrospective approach has inherent potential for biases to influence or even determine the results. For example, subjects stricken with serious illness probably try to identify preceding factors in their lives that could have caused theirdisease.Case-controlapproacheshavewell-knownandinescapable limitations. One is that they provide no information about the actual increasein riskduetothe loss, sincethiswouldrequireacomparisonbetweenthe incidence of death after the loss with the incidence of death in the absence ofthe loss-i.e., a predictive study design. Another problem with the rating scale approach is that the same events may have different psychological impacts in different people. This could be especially relevant in studies of people with the “TypeA” pattern, in which the stressor itself is not so important as the patient’s interpretation of and response to the stressor. A more appropriate life experience inventory would take into account the impact of the experienceson the individual. To date, no prospective study has determined whether taking into account both the events and their personal impact improves the predictability of life change scores in terms of cardiovascular risk. Someofthelistedlifechangescanthemselvesindicateunderlying disease. In the rating scale of Holmes and Rahe, the occurrence of personal injury or illness receives a score of 53, change in living conditions 25, change in work conditions or hours 20, and change in sleeping habits 16. In myocardial infarction patients, these associations alone can explain a relationship between self-reported life changes and health outcomes. Available epidemiologic literature has been inconsistent about whether life change inventory scores predict any specific cardiovascular morbid events. ReportsbasedonlongitudinalstudiesofSwedishmenhavesupported an association between stressful life events and mortality. In one such study of 1016 men born in the city of Goteborg in 1933, life events in the year before the baseline examination were associated with all-cause mortality during 7 years of follow-up (217). Some events associated with increased mortality included concern about a family member, moving the household, feelingsof insecurity at work, financial problems, lower emotional support, and living alone. After statistical adjustment for smoking, emotional support, and self-perceived health, life events remained correlated with mortality. In two other population studies of menby the same group, psychological stress was defined ina questionnaire as a feeling of tension, irritability or anxiety, or as having sleeping difficulties as a result of conditions at work or at home. In one study, after a mean follow-up of about 12 years, 6% of men with the lowest stress ratings had either developed a nonfatal myocardial infarction or died from coronary artery disease, compared with 10% of men with the highest

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stress ratings; the odds ratio was 1.5 after controlling for age and other risk factors;however,norelationbetweenlifeeventsandself-perceived psychological stress was foundin another sample of 732 men of similar age. After major life crises, such as the death of a spouse, mortality transiently increases. Mortality following bereavement may not necessarily result from coronary heart disease (21 8). The mechanism of increased mortality in this setting remains obscure. Catastrophic,unexpectednaturaldisasterstemporarilyincrease cardiovascular mortality. During the first three days after the Athens earthquake of 1981, fatal cardiac events increased by 50% and deaths from atherosclerotic heart disease by about loo%, compared with corresponding periods in 1980 and 1982 (219). After the Loma Prieta San Francisco area earthquake in 1989, the incidence of myocardial infarction did not appearto increase, whereas after the Northridge Los Angeles area earthquake of 1994, the incidence of myocardial infarction did increase. One explanation for this difference is that the latter earthquake took place in the early morning hours(220). An oft-quoted report by Graham noted a high frequency of hypertension in soldiers after a year or more of desert warfare (22 1). With two months of rest, however,bloodpressurenormalized in virtuallyallthesubjects.Whether chronic neurotic illness incited by wartime stress causes or contributes to chronic cardiovascular disease remains unsettled and controversial (222,223). In civilians, all modern wars have been associated with temporarily increased cardiovascularmorbidityormortality (224). Forinstance,whenIsraeli populaticn centers underwent Iraqi “Scud” missile attacks in 1990, the only reported deaths resulted from cardiac causesin elderly people, and the frequency of myocardial infarction and sudden death suddenly increased (225). “Coronary Prone” Behavior Pattern

According to the theory of the “Type A coronary-prone behavior pattern,” the Type A individual’s style of reaction to stress constitutes an independent coronary risk factor. The theory therefore shifts emphasis from stressors that may accelerate development of atherosclerosis to aspects of the individual’s personalitythatincreasecoronaryrisk.AlthoughFriedmanandRosenman introduced and popularized the Type A theory, William Osler presaged it in his characterization of the typical coronary patient as “not the delicate neurotic but therobust,thevigorousinmindandbody,thekeenambitiousman,the indicator of whose engineis always full speed ahead” (226). The Type A behavior pattern includes time urgency, competitiveness, and aggressiveness. Results of The Western Collaborative Group Study (WCGS) of 3,524 men followed prospectively for 8-1/2 years provided convincing evidence for the existence and pathophysiological significance of this pattern (227). After

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taking into account all other known major risk factors, Type A subjects had a two-fold greater risk of developing overtischemic heart disease than did subjects without Type A behavior. Findings of the Framingham study tended to confirm the WCGS results (228). Afterwards, however, several studies subsequently failed to support the Type A theory. These studies usually stratified patients in terms of the existence of the Type A patternandthentestedtheassociationwiththeextentof angiographically demonstrable coronary atherosclerosis. The results of the Multiple Risk Factor Intervention Trial (MRFIT) were very damaging to the Type A theory, since this prospective study of 3000 healthy men failed to reveal increasedsusceptibilitytodevelopcoronarydisease in Type A subjects (229,230). If only a portion of the Type A pattern actually were related to coronary risk, this would help to explain the inconsistent findings. Friedman, Rosenman, and co-workers emphasized the constellation of aggressiveness, time urgency, and competitiveness. Williams and co-workers concentrated on the specific componentofangerorhostility(231,232).Reanalysisofthestructured interview data from the MRFIT trial indicated that, whereas the global Type A patternfailedtopredictthedevelopmentofcoronaryarterydisease,the component of hostility did (233). A 25-year study of law students found that thescoreonthehostilityscalecomponentoftheMinnesotaMultiphasic Personality Inventory did predict mortality during the follow-up period (234).A 30-year longitudinal study, however, did not find that hostility scores predicted coronary disease or mortality (235). Statistical reanalysis of the original WCGS data of Friedman and Rosenman confirmed that when responses in the structured interview by 250 subjectswhosubsequentlysufferedheartattackswere compared with responses by 500 subjects who remained healthy, hostility ratings predicted overt coronary heart disease, whereas after exclusion of the hostility component, no other component of the coronary prone behavior pattern was predictive (236). Whether hostility, lack of social support, or joyless striving are “toxic” components of the TypeA pattern has not yet been resolved. Eliot, Buell, and co-workers suggested that patterns of hemodynamic response during emotional stress, rather than the Type A pattern itself, might explain the association between cardiovascular morbidity and stress (237). These investigators categorized patients as “hot reactors” or “cold reactors”, based on theoccurrenceofexcessivehemodynamicresponsestoapaneloftests, includingmathematicalproblems,competitivevideogames,andthecold pressor test. The authors provided anecdotes in which myocardial infarction patients with abnormal hemodynamic responses underwent reinfarction within twoyears,andpatientswithlargeincreases in totalperipheralresistance

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subsequently suffered cardiovascular catastrophes; however, the report did not test scientifically the predictive value of the “hot reactor” categorization. Arelatedviewholdsthatstress-relatedcoronaryriskresultsfrom excessive catecholaminergic responses that elicit pathologic hemodynamic patterns. Since the “hypertensive personality” and the Type A pattern seem to share a component of hostility, and considering the association between this personality characteristic and elevated norepinephrine and plasma renin activity levels in hypertensives, one might hypothesize that catecholamines mediate the increased coronary risk in hostile Type A individuals. Type A men have been reported to have exaggerated responses of plasma catecholamine levels during mental arithmetic (238) or during challenges perceived as personally threatening (239,240).Ameta-analysissummarizedresultsfrom33experimentsand concludedthatTypeAindividualshaveabout3-foldlargerplasma norepinephrine responses and about 4-fold larger epinephrine responses during exposure to various laboratory and clinical stressors than do Type B individuals (24 1). Although the neuroendocrine mediator hypothesis can explain increased coronary risk in people with the hostile Type A pattern, the pathophysiologic meaning of excessive catecholamine responsesin the long-term development of coronary disease remains unknown.

Job Stress as a Risk Factor for Cardiovascular Disease Literature about occupational stress and cardiovascular disease has referred frequently to the “Karasek hypothesis,” in which job settings involving both largedemandsandlittleautonomy(i.e.,latitude in decision-making)are associated with especially increased cardiovascular risk (242-244). Investigators have listed excessive overtime, monotonous assembly line labor, unrealistic timeschedules,morethanonejobatatime,toolittle(ortoomuch) responsibility, and conflicts with supervisors or fellow employees, as relevant job-related stressors affecting cardiovascular health (245). This would fit with the view that emotional stress contributes to heart disease when thereis a sense of lack of control or inability to cope. Analogously, it has been proposed that increased work demand, job dissatisfaction, and lack of control increase coronary risk (246). Syme (247) hypothesized that job elements related to increased cardiovascular risk include tight scheduling with an impossibility of meeting time requirements, social isolation, and interpersonal provocation producing anger and impatience. For instance, Japanese who acculturated after they immigrated to the San Francisco of coronary heart disease than those who did not Bay area had higher rates acculturate. Studies about the relationship between the amount of “inherent” stress of occupations andrisk of coronary heart disease have suggested increased

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coronary risk in general medical practitioners as opposed to specialists, sea officers, blue-collar workers as opposed to white-collar workers, police officers, and self-employed individuals as opposed to employees. For most of these studies, the effects of self-selection and of behavioral factors such as cigarette smoking, intake of alcohol, fat, salt, and caffeine, obesity,andsedentarinessprobablycomplicated-ifnotartifactually influenced-the results. For instance, in a cross-sectional study of urban bus drivers,aftercontrollingfor 12 confounding variables, no relationship was detected between job strain or demands or decision latitude and hypertension (248). In a prospective study of blue-collar male workers, multivariate logistic regression analysis revealed that status inconsistency (low reward at work) and “immersion” (high intrinsic effort at work) constituted independent factors predicting cardiovascular events (249). Other identified risk factors included hypertension, left ventricular hypertrophy, and hyperlipidemia. TheKarasekhypothesisremainscontroversial(249-253). A major problem in this line of research is the assessment of the amount of distress experienced by individuals who self-select their employment. The study of Cobb and Rose (254) exemplifies this problem. Air traffic controllers had excessive rates of hypertension, diabetes, and other risk factors that would be expected to contribute to the development of coronary heart disease. The union of air traffic controllers staged a strike at least partly because of the position that the controllers should be compensated for the increased risk due to the stress inherent in theirjob.Relativelyfewpeople,however,becomeairtraffic controllers. In a free society, perhaps individuals who feel a thrill holding for a few minutes the lives of hundreds of people in their hands, or who smoke cigarettes and drink coffee, or who prefer a sedentary job, tend to become air traffic controllers; for them thejob may not be distressing but stimulating. A similar limitation applies to the use of case-control studies to uncover relationships between job stress and heart disease. Schnall et al. (1990) (250) screened blood pressure in 2556 male employees at 7 work sites; 87 cases of hypertension and a random sample of 128 controls were studied further. After adjusting for age, race, body-mass index, type A behavior, alcohol intake, smoking, sodium excretion, education, the work site, and the physical demand of the job, job strain-defined ashigh psychological demand and low decision latitudeonthe job-was associatedwithhypertensionandincreasedleft ventricular mass index. The case-control method is cross-sectional in design, rendering interpretations in terms of cause and effect most difficult and risky (255). For instance, the results of Schnall et al. (1990) did not exclude the possibility that patients with elevated blood pressure-perhaps in response to publicity about the topic-tended to report more stress on their jobs. Brody and Natelson (256) concluded that there is no compelling evidence that chronic

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stress alone, in an otherwise healthy individual, causes hypertension that is sustained after removal of the stressor. The inadequate number of prospective studies prevents drawing firm conclusions about the role of chronic emotional stress in the development of heart disease.

Heart Rate as a Risk Factor Many prospective studies have reportedan association between heart rate at rest and subsequent cardiovascular morbidity and all-cause mortality. For instance, the British Regional Heart study followed a cohort of 7735 men for 8 years who were aged 40-59 years old at baseline (257). Among the 75% of subjects who had no evidence of ischemic heart disease at baseline, after adjustment for all other factors, those with a resting heart rate of 90 bpm or more had more than 3-fold increased relative risk of mortality from ischemic heart disease or sudden cardiac death. Similarly, among 1827 men and 2929 women, aged 40-80 years,followedfor12years,heartrateindependently predicted all-cause and cardiovascular but not cancer-related mortality (258). In a 12-year study of 763 white men and 1175 women aged 65 years or older, in men heart rate predicted cardiovascular mortality; in women the results were not statistically significant (259). Basesfortheincreasedcardiovascularriskassociatedwithresting A hypothesisforfuturetesting is thatthe tachycardiaremainobscure. tachycardia reflects recruitment of sympathetic outflow to the heart to maintain normalcardiacperformance in thesettingofsub-clinicalleftventricular dysfunction. SUMMARY AND CONCLUSIONS

The mechanisms and even the existence of many common disorders remain mysterious and controversial. This chapter considers several that may involve abnormal autonomic function. After essential hypertension, chronic orthostatic intolerance is viewed as the most common disorderof blood pressure regulation. A group of conditions, lumped together here as chronic orthostatic intolerance, postural tachycardia syndrome (POTS), or hyperdynamic circulation syndrome, feature weakness, orthostaticintolerance,andrapidpulserate.Thiscombinationsuggestsa contribution of blood volume depletion in at least some subjects, possibly relatedtoinappropriatelylowlevelsofactivityoftherenin-angiotensinaldosteronesystem. In thehyperdynamiccirculationsyndrome,resting tachycardia, labile, predominantly systolic hypertension, and increased heart rate responsiveness to isoproterenol are associated with increased catecholamine

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levelsatrestandduringprovocativemaneuversandameliorationby 8adrenoceptor blockersor benzodiazepines. Some patients with mitral valve prolapse complain of chest pain or pressure, exertional dyspnea, palpitations, orthostatic faintness, fatigue, poor exercise tolerance, pallor, sweating, anxiety, and panic. Plasma catecholamine levels in patients with mitral valve prolapse and the above symptoms do not or fromhealthycontrol differfromthose in patientswithoutsymptoms subjects. Acute, marked decreasesin sympathetic neural outflows characterize noncardiac syncope (neurocardiogenic syncope, vasodepressor syncope, neurally mediated syncope, the common faint), by far the most common cause of sudden loss of consciousness in the general population. Patients with a chief complaint of repeated episodes of neurally mediated syncope have low rates of cardiac norepinephrine spillover, with intact sympathetic terminal innervation. Tonic suppression of cardiac sympathetic outflow could contribute to a tendency to faint, by limiting norepinephrine release in situations where maintenance of blood pressure depends on sympathetically-mediated increases in cardiac rate and contractility. A neuroendocrine pattern combining adrenomedullary stimulation with more generalized sympathoinhibition may constitute the proximate cause of vasodepressor reactionsin predisposed individuals. Reportsaboutahighfrequencyofneurocardiogenicsyncopeacute vasodepressor reactions during provocative tilt table testing have supported the view that chronic fatigue syndrome often includes and may result from a form of or syncope in dysautonomia. The tendency to neurally mediated presyncope patients with chronic fatigue syndrome seems to contrast with a tendency to sympathetichyperactivity in patientswithchronicorthostaticintolerance; however, no generally accepted means to distinguish the two have appeared. Reflex sympathetic dystrophy, renamed complex regional pain syndrome (CRPS)type I (58), nowreferstopost-traumaticpainthat (1) develops regionally distal to the site of injury;(2) exceeds in magnitude and duration the expected clinical course of the inciting event; (3) progresses variably over time; (4) is associated with non-specific symptoms and signs such as altered skin color, temperature, or sudomotor activity, allodynia, disuse atrophy, or edema; and ( 5 ) occurs in a distribution different from that resulting from injury to a single peripheral nerve. Whether RSD is associated with abnormal sympathetic nervous system activity has been unknown. Mechanisms of chronic pain and sympathetic dysfunction after traumatic damage to peripheral nerves appear to occur generally independently. The diagnosis of post-traumatic stress disorder (PTSD) depends mainly onpsychologicalcriteria,suchasvigilance,fear,sensitivitytothreat, helplessness,exaggeratedstartle,sleepdisturbance,intrusivememories, dissociation phenomena, and numbing, In response to yohimbine, most patients

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withPTSDhaveexaggeratednoradrenergicresponses,associatedwith flashbacks, intrusive traumatic thoughts, numbing, grief, or frank panic. These findings support the view that release of norepinephrine in the brain can precipitate or worsen the psychiatric manifestations acutely. Patients with established essential hypertension, considered as a whole, do not have increased values for indices of sympathetic nervous outflows. Cardiac, renal, and cerebrovascular spillovers of norepinephrine, however, are increased in relativelyyoungpatients,consistentwitharoleofincreased sympathetic neuronal outflows in the development of the hypertension. Patients with hypernoradrenergic hypertension have a combination of high plasma norepinephrine levels and exaggerated changesin blood pressure in response to adrenoceptor-active drugs. Catecholamines contribute, at least theoretically, to values for every known risk factorand epidemiological featureof coronary heart disease. The role of chronically repeated episodes of stress or of abnormal “coronary-prone” behavior or personality in the development of clinical coronary heart disease remains controversial; and a catecholaminergic link, while rational, remains unproven. The literature about occupational stress and cardiovascular disease remains controversial. Most studies do not give adequate consideration to the problem of self-selection bias.

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8. Lewis T. The Soldier’s Heart and the Effort Syndrome. London, England: Shaw Sons, 1919. 9. Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni

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Hypovolemia in syncopeandorthostaticintolerance role of the reninangiotensinsystem. Am J Med 1997; 103:128-133. T, Snell M, Jarai Z , 10. Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai Ananthram V, Robertson RM,Robertson D. Sympathetic and baroreceptor reflex function inneurally mediated syncope evoked by tilt. JClin Invest 1997; 99:2736-2744. 1 1 . Rosen SG, Cryer PE.Posturaltachycardia

syndrome. Reversal of sympathetic hyperresponsivenessandclinicalimprovement during sodiumloading. Am J Med 1982; 72:847-850. 12. Lee RJ, Kalman JM, Fitzpatrick AP, Epstein LM, Fisher WG, Olgin JE, Lesh MD, Scheinman MM. Radiofrequency catheter modification of the sinus node for “inappropriate” sinus tachycardia.Circulation 1995; 92:2919-2928. 13. Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann InternMed 1986; 104:298-303. RK. Orthostatic intolerance and orthostatic tachycardia: a 14. Khurana heterogeneousdisorder. Clin AutonRes 1995; 5:12-18. 15. Streeten DH, Anderson GH Jr, Richardson R, Thomas FD. Abnormal orthostatic changes inbloodpressureandheartrateinsubjectswithintact sympathetic nervous function: evidence for excessive venous pooling. JLab Clin Med 1988; 111:326-335. 16. Streeten DH, Scullard TF. Excessive gravitational blood pooling caused by impairedvenoustoneisthepredominantnon-cardiacmechanism of orthostaticintolerance.Clin Sci 1996; 90:277-285. 17. Streeten DH. Orthostatic intolerance. A historical introduction to the pathophysiologicalmechanisms. Am JMedSci 1999; 317:78-87. 18. Furlan R, Jacob G, Snell M, Robertson D, Porta A, Harris P, Mosqueda-Garcia R.

Chronicorthostatic intolerance: a disorder with discordantcardiacand vascular sympathetic control.Circulation 1998; 98:2154-2159. 19. Jacob G , Biaggioni I. Idiopathicorthostaticintolerance and posturaltachycardia syndromes.AmJMedSci 1999; 317:88-101. 20. FrohlichED, Tarazi RC,DustanHP.Hyperdynamicbeta-adrenergiccirculatory state. Arch Int Med 1969; 123:l-7. 21. Frohlich ED. Beta-adrenergic blockade in circulatory regulation of hyperkinetic states. Am J Cardiol 1977; 27:195-199. 22. Goldstein DS, Keiser HR. Neural circulatory control in the hyperdynamic circulatory state syndrome. AmHeartJ 1985; 109:387-390. 23. Kuchel 0, Cusson JR, Laroachelle P, Buu NT, Genest J. Postureand emotioninduced severe hypertensive paroxysms with baroreceptor dysfunction. J Hypertension 1987; 5:277-283.

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of the left lateral medulla oblongata for severerefractoryneurogenic hypertension. Neurosurgery 1998; 43:l-6; discuss. 186. Geiger H, Naraghi R, Schobel HP, Frank H, Sterzel R B , Fahlbusch R. Decrease of blood pressure by ventrolateralmedullarydecompression in essential hypertension. Lancet 1998; 352:446-449. 187. Platania N, Nicoletti GF, Barbagallo G, Albanese V. Concurrent trigeminal and glossopharyngeal neuralgia, hemifacial spasm and hypertension by neurovascular compression. Case report. J Neurosurg Sci 1997; 41:303-307. 188. Saglitz SA, Gaab MR, Assaf JA, Naraghi R, Kleineberg B. Neurovascular compression at the left ventrolateral medulla as an etiological factor for arterialhypertension.ExpClinEndocrinolDiabetes 1997; 105 Suppl 2:9-11. 189. Morimoto S, Sasaki S, Miki S, Kawa T, Itoh H, Nakata T, Takeda K, Nakagawa M, Naruse S, Maeda T. Pulsatile compression of the rostral ventrolateral medulla in hypertension. Hypertension 1997; 29:514-518. Walter GF, Kleineberg B. Arterial hypertension and 190. Naraghi R,GaabMR, neurovascular compression at the ventrolateral medulla. A comparative microanatomicalandpathologicalstudy. J Neurosurg 1992; 77:103-112. 191. Naraghi R, Geiger H, Crnac J, Huk W, Fahlbusch R, Engels G, Lufi FC. Posterior fossaneurovascularanomalies in essentialhypertension.Lancet 1994; 344: 1466-1470. 192. Watters MR, Burton BS, Turner GE, Cannard KR. MR screening for brain stem compressioninhypertension.Am J Neuroradiol 1996; 17:217-221. 193. Colon GP, Quint DJ, Dickinson LD, Brunberg JA, Jamerson KA, Hoff JT, Ross

DA. Magnetic resonanceevaluationofventrolateralmedullary compression in essentialhypertension. J Neurosurg 1998; 88:226-231. 194. CoreaL, Bentivoglio M, Verdecchia P, Motolese M. Role of adrenergic overactivity and pressure overload in the pathogenesis ofleft ventricular hypertrophyinborderline and sustainedessentialhypertension inman. Clin Sci 1982; 63:379~-381s. 195. Corea L, Bentivoglio M, Verdecchia P, Motolese M. Plasma norepinephrine and left ventricular hypertrophyin systemic hypertension. Am J Cardiol 1984; 53:1299-1303. 196. Corea L, Bentivoglio M, Verdecchia P. Echocardiographic left ventricular

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197. Chadwick RS, Goldstein DS, Keiser HR. Application of a pulse wave theory to modulation of the human brachial arterialdicroticwave in aging and essentialhypertension. Am J Physiol1986; 151:Hl-HI I . 198.KorenMJ,DevereuxRB,Casale PN, SavageDD,Laragh JH. Relation of left ventricular mass and geometry to morbidityandmortalityinuncomplicated essentialhypertension.AnnIntern Med 1991;114:345-352. 199.SharmaP,HingoraniA, Jia H,AshbyM,HopperR, Clayton D,BrownMJ. Positiveassociation of tyrosinehydroxylasemicrosatellitemarker to essentialhypertension.Hypertension1998; 32:676-682. 200. Sacks FM, Dzau VJ. Adrenergic effect on plasma lipoprotein metabolism. Am J Med 1986;80:71-81. 201. Helin P, Lorenzen I, Garbarsch C, Matthiessen E. Arteriosclerosis in rabbit aortia inducedby noradrenaline. Atherosclerosis 1970; 12: 125- 132. 202. Kukreja RS,DattaBN,CakravartiRN.Catecholamine-inducedaggravationof aortic and coronaryatherosclerosis in monkeys.Atherosclerosis 1981; 40:291-298. 203. Grundy SM, Griffin AC. Effects of periodic mental stress on serum cholesterol levels.Circulation1959;19:496-498. 204. CatheyC,JonesHB,NaughtonJ,HammarstenJF,Wolf SG. The relationship between life stress to concentration of serum lipids in patients with coronary artery disease. Am J Med1962;244:421-441. 205. Taggart P, Carruthers M. Endogenous hyperlipidemia induced by emotional stress of racing driving. Lancet 1971; 1:363-366. 206.WertlakePT,WilcoxAA,HaleyMI,PetersonJE.Relationship of mentaland emotional stress to serumcholesterollevels.Proc SOCExp BiolMed1958; 97:163-168. 207. Wolf SG. History of the study of stress and heart disease. In: Beamish SG, ed. Stress and Heart Disease. Boston: Martinus Ninhoof, 1985:3-16. 208. FriedmanM,RosenmanRH,CarrollV. Changes in theserumcholesteroland blood clotting time inman subjected to cyclic variation of occupational stress.Circulation 1958; 17:852-861. 209. Thomas CB,MurphyEA. Further studies on cholesterol levels in the Johns Hopkins medical students: Effect of stressat examinations. J ChronDis 1958; 8:661-669. 210. Clarkson TB, Manuck SB, Kaplan JR. Potential role of cardiovascular reactivity in artherogenesis. In: Matthews KA, Weiss SM, Detre T,Dembroski TM, Falkner B, Manuck SB, Williams RB Jr, eds. Handbook of Stress, Reactivity, & Cardiovascular Disease. New York: Wiley, 1986:35-47. 21 I . Kaplan JR, Manuck SB, Clarkson TB. Social status,environment, and atherosclerosis in cynomolgus monkeys.Atherosclerosis 1982; 2:359-368.

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218. Clayton PJ, Darvish HS. Course of depressive symptoms following the stress of bereavement. In: BarrettJ, Rose RM,KlermanGL,eds. Stress and Mental Disorder. New York: Raven Press, 1979: 219. Trichopoulos D, Katsouyani K, Zavitsanos X, Tzonou A, Dalla-Vargia P. Psychological stress and fatalheart attack: the Athens (1981) earthquake naturalexperiment.Lancet1983;1:441-444. 220. BrownDL. Disparate effects of the 1989 Loma Prieta and 1994 Northridge earthquakesonhospitaladmissionsforacutemyocardialinfarction: importance of superimposition of triggers. Am Heart J 1999; 137:830-836. 221. Graham JDP. High blood pressure after battle. Lancet 1945; 1:239-240. ,222. BlizardDA, Liang B,EmmelDK.Blood pressure, heart rate, and plasma catecholamines under resting conditions inrat strains selectively bred for differences in response to stress. Behav Neural Biol 1980; 29:487-492. 223. Tennant C. Psychological stress andischaemicheartdisease:an evaluation in the light of the diseases’ attribution to warservice.Aust N Z J Psychiatry 1982; 16131-36. 224. Boman B. Psychosocial stress and ischemic heart disease. Aust N Z J Psychiatry 1982; 16:265-278. 225. Meisel SR, Kutz I, Dayan KI, Pauzner H, Chetboun I, Arbel Y, David D. Effect of Iraqi missile waron incidence of acute myocardial infarction and sudden deathin Israelicitizens.Lancet1991;338:660-661,1991. 226. Osler W. The Lumleian lectures on angina pectoris. Lancet 1910; 1:697-699 and 83. 227. Rosenman RH, Brand RJ, Jenkins CD, Friedman M, Straus R, Wurm M. Coronary heart disease in the Western Collaborative Group Study: Final fohw-up experience of 8 1/2 years. J Am Med Assoc 1975; 233:872-877.

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S, Scotch N, KannelWB.Therelationshipof psychosocialfactors to coronaryheart disease intheFraminghamStudy. 11. Prevelence of coronary heart disease. Am J Epidemiol 1978; 107:384-402. A. Hostility,riskofcoronaryheart disease and 229. Shekelle R,GaleM,Ostfeld mortality. Psychosom Med 1983; 45: 109-1 14. 230. Shekelle RB, Hulley SB, Neaton JD, Billings JH, Borhani NO, Grace TA, Jacobs DR, Lasser NL, Mittlemark MB, Stamler J. The MRFIT behavior pattern study. 11. Type A behavior and incidence of coronary heart disease. Am J Epidemiol

1985; 122:559-570. 231. Barefoot JC, Dahlstrom WC, Williams RB. Hostility, CHD incidence, and total mortality: a 25-year follow-up study of 255 physicians. PsychosomMed 1983; 45:59-63. 232. Suarez EC, Williams RB. Situational determinantsofcardiovascularand emotional reactivity in high-andlow-hostilemen.PsychosomMed 1989; 5 1 1404-418. 233. DernbroskiTM, Costa PT.Assessmentofcoronary-pronebehavior.Acurrent overview. Ann Behav Med 1988; 10:60-63. 234. Barefoot JC, DodgeKA, Peterson BL, Dahlstrom WC. The Cook-Medley

hostility scale: item conent andability to predict survival. PsychosomMed 1989;51:46-57. 235. Hearn MD, Murray EM, Luepker

RU. Hostility, coronary heart disease, and total mortality: a 33-year follow-upstudyofuniversity students. JBehavMed

1989; 12:105-121. 236. HeckerMH,ChesneyMAB,Frautschi

N. Coronary-prone behaviors in the WesternCollaborativeGroupStudy.Psychosom Med 1988; 50:153-164. 237. Eliot RS, Buell JC. Utilization of a new objective, non-physical stress test. In: BearnishRE,SingalPK,DhallaNS,eds.StressandHeartDisease. Boston: Martinus Nijhoof Publishing, 1985:116-126. 238. Williams RB, Lane JD, Kuhn CM, Melosh W, White AD, Schanberg SM. Type A behaviorandelevatedphysiologicalandneuroendocrineresponsesto cognitive tasks. Science 1982; 218:483-485. 239. Glass DC, Krakoff LR, Contrada R, Hilton WF, Kehoe KM, Collins C, Snow B, Elting E. Effect of harassment and competition upon cardiovascular and plasma catecholamine responses in type A and type B individuals. Psychophysiology 1980; 17:453-463. SB. Acute psychophysiologic reactivity and risk of 240. Krantz DS,Manuck cardiovascular disease: areview and methodologic critique. Psycho1 Bull 1984; 961435-464. 241. DeQuattro V, Loo R, Foti A. Sympathoadrenal responses

to stress: the linking of type A behavior pattern to ischemic heart disease. Clin ExpHyper 1985; 7:469-481.

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T. Job decision latitude, job demands, andcardiovascular disease: aprospectivestudy of Swedish men. Am J Pub Health 1981; 71:694-705. 243. Karasek RA, Theorell TG, Schwarts J, Pieper C, Alfredson L. Job Psychological factorsandcoronaryheartdisease: Swedish retrospective findings and U.S. prevalence findings using a new occupational inference method. Adv Cardiol 1982; 29:62-67. 244. Langosch W, Brodner G, Borcherding

H. Psychological and vocational longterm outcomes of cardiac rehabilitation with post-infarction patients under the age of forty.PsychotherPsychosom 1983; 40:115-128. 245. Beamish RE, Singal P,K, Ganguly PK. Stress, catecholamines and heart disease. In: Ganguly PK, ed. Catecholamines and Heart Disease. Boca Raton: CRC Press, 1991:231-244. DG, 246. Byrne DG, Byrne AE. Anxiety and coronary heart disease.In:Byrne Rosenman RH, eds. Anxiety and the Heart. New York: Hemisphere Publishing Corp, 1990:213-232. 247. Syme SL. Socioenvironmentalfactorsinheartdisease.In:BeamishRE,Singal PK,DhallaNS, eds. Stress and Heart Disease.Boston: Martinus Nijhoof Publishing, 1985:60-70. SL. Job strainand 248. Albright CL, WinklebyMA,RaglandDR,FisherJ,Syme prevalence of hypertension in a biracial population of urban bus drivers. Am J PublichHealth 1992; 82:984-989. 249. Siegrist J, Peter R, Motz W, Strauer BE. The role of hypertension, left ventricular hypertrophy and psychosocial risks in cardiovascular disease: prospective evidence from blue-collar men. Eur Heart J 1992; 13 Suppl D:89-95. 250. Schnall PL, Pieper C, Schwartz JE, Karasek RA, Schlussel Y, Devereux RB, Ganau A,Alderman M,WarrenK, Pickering TG. The relationship between “job strain,”workplacediastolicbloodpressure,andleftventricular mass index. Results of a case-control study. J Am Med Assoc 1990; 263:1929-1935. 251. Pieper C, LaCroix AZ, Karasek RA. The relation of psychosocial dimensions of work with coronary heart disease risk factors: a meta-analysis of five United States data bases. Am J Epidemiol 1989; 129:483-494. 252. Hlatky MA, Lam LC, Lee KL, Clapp-Channing NE, Williams RB, Pryor DB, Califf RM, Mark DB. Job strain and the prevalence and outcome of coronary artery disease. Circulation 1995; 92:327-333. 253. BeilinLJ.Stress,coping,lifestyleandhypertension:aparadigmforresearch, prevention and non-pharmacologicalmanagement of hypertension. Clin Exp Hypertens 1997; 19:739-752. 254. Cobb S, Rose RM. Hypertension, peptic ulcer, and diabetes in airtraffic controllers. J AmMed Assoc 1973; 224:489-492. 255. Pickering TG, Gerin W. Reactivity and the role of behavioral factors in hypertension. Acriticalreview.AnnBehav Med 1990; 12:3-16.

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256. Brody MJ, Natelson BH. Task Force 3: Behavioral mechanisms in hypertension.

Circulation1987;76:Suppl 1:I-S95--1100. 257. Shaper AG, Wannamethee G, Macfarlane PW, Walker M. Heart rate, ischaemic heart disease, and sudden cardiac death in middle-aged British men. Br Heart J 1993; 70:49-55. 258. Mensink GB, Hoffmeister H. The relationship between resting heart rate and allcause, cardiovascular and cancer mortality. Eur Heart J 1997; 18: 1404-1410. 259.PalatiniP, Casiglia E, Julius S, PessinaAC.Highheartrate:ariskfactorfor cardiovascular death in elderly men. Arch Intern Med 1999; 159:585-592.

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IO Future Trends CLINICAL NEUROCARDIOLOGY AND INTEGRATIVE MEDICINE Patients with known or suspected neurocardiologic disorders force their clinicians to think continually in integrative terms, because neurocardiologic disordersusuallyreflectaninherentlycomplex,dynamicinterplayof psychology, neurochemistry, and pathophysiology. Diagnosticiansintentonlyonconfirmingorexcluding“organic” diagnoses in these patients-on separating “mind” from “body”-fail to take into account the integrative nature of most neurocardiologic disorders. Because diagnosis by exclusion can determine only what the patient does not have, this approach can defeat much of the purpose of clinical management. For instance, standard neurological evaluation of a patient with repeated episodes of syncope mightcenteronexcludingaseizurefocus in thetemporallobe.Standard cardiologic evaluation of the same patient might center on excluding abnormal intra-cardiac conduction. Once standard testing proves negative, the frustrated consultants may end involvement in the case and dismiss the patient as having a “psychosomatic” disorder, for which only non-specific treatment or “reassurance” would seem indicated. In fact,thepatientmighthaveanidentifiableneurochemicalor physiological abnormality that predisposes to neurocardiogenic syncope, and superimposed acute distress, via patterned neuroendocrine activation, might set into motion a positive feedback loop that would cause rapid declines in blood pressure and cerebral perfusion and precipitate loss of consciousness. The predisposed patient might have tonically decreased cardiac sympathetic outflows or augmented restraint of norepinephrine release from cardiac sympathetic terminals.Duringdistress-inducedadrenomedullaryactivation,resulting in decreased skeletal muscle and total peripheral vascular resistance, absence of a compensatory,sympathetically-mediatedincrease in cardiacoutputmight precipitate syncope (Figure 10-1). Thinking integratively, keeping in mind the principles of homeostat operation and interactions among relevant homeostatic systems, the clinician can inferpossiblepathophysiologicalmechanismsandconductappropriate individualizeddiagnosticteststoconfirmorrefutethehypothesized mechanisms.Forinstance,totesttheschema in Figure 10-1, theclinician 575

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7-

+zit-* Barostat

L

-I

I

Baroreceptors

Figure 10-1 Application of a homeostatic systems approach to the problem of the pathophysiology of neurally mediated syncope. Superimposed on tonic inhibition of norepinephrine release from terminals of the sympathetic nervous system (SNS), acute activation of the adrenomedullary hormonalsystem (AHS) and occupation of inhibitory cholinergic receptors on sympathetic terminals could decrease total peripheral resistance (TPR) while preventing compensatory increases in cardiac output (CO). This would reduce blood pressure (BP) and initiate a positive feedback loop. c1 l = c1 I-adrenoceptors; R2 = R2-adrenoceptors; X = vagus nerve.

might look for attenuation or absence of during orthostasis-induced forearm vasoconstriction,coupledwithadrenomedullaryactivationasindicated by plasma epinephrine levels. Moreover,absent a diagnosis,oreven a rationalpathophysiological mechanism, no specific treatment can emerge from the evaluation, whereas a physiologically acceptable explanation can lead to specific, pathophysiologybased treatment. Thus, the schema in Figure 10-1, if confirmed by appropriate neurocardiologic testing, would indicate treatment with an a]-adrenoceptor agonist to supportperipheral vascular resistance and a B2-adrenoceptor blocker to attenuate epinephrine-induced skeletal vasodilation.

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The same principlesmay render “integrative medicine” more scientific, by enabling the derivation of non-circular hypotheses that observation or experience can test. Perhaps even more importantly, applying these principles can also demonstrate that some hypothetical explanations, because of untestability, are not scientific at all. The term, “integrative medicine,” has gained currency partly by vague and variable definitions; however, the popularity of integrative, holistic medicine may reflect its positive nature. In contrastwith“traditional”or“Western” medicine, which emphasizes diagnosis and treatment of diseases, integrative medicineemphasizespromotionofwellness, by maximizing,oratleast claiming to maximize, homeostatic regulation of the many apparent steadystatesthatcharacterizehealthyindividuals.Thus,atraditionalpsychiatrist diagnoses depression and prescribes antidepressants to the depressed patient, whereasaholisticpractitionerattempts,admittedlywithlimitedscientific validation, to increase the sense of well-being and psychological resilience. A traditional internist diagnoses infection and prescribes antibiotics, whereas a holistic practioner attempts to promote immune surveillance and competence. The principles of homeostat operation apply in both approaches. TOWARD A NEW MEDICAL SCIENCE

The last three decades have witnessed the remarkable ascendance of molecular biology and molecular genetics, which by now have outdistanced integrativephysiology in theraceformoney,personnel,space,and programmatic priorities. The following discussion offers the view that the present struggle continues an ancient dispute about what medical scientific knowledge is and about how one should go about acquiring it. The resolution will not be by victory for either side but by merging of the two disciplines into a new one. Molecular medical science uses a stepwise, regressive, essentially linear approach to acquire knowledge about causes of disease (Figure 10-2). One identifies the proximate preceding step, then the next proximate step, and so on, in a seemingly neverending quest to identify one or perhaps a few “first causes” of clinical phenomena. Suppose a disease has several L‘causes,’’and suppose that for the most common ones, feedback loops, modulators, and parallel pathways complicate the picture. Using molecular genetic approaches, the exact mutation associated with a rare inherited form of the disease could be identified. One might justify the search for the rare mutant gene, not only because of the potentialto identify a first cause but also because the information gained could apply later to the other more complex, more common pathways.

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Moreover, one might presume that, after identification of a defective gene, reversal of the steps in the discovery process might “explain” the disease. Even if all patients with a particular disease shared the same mutation, however, this would not imply that all people with the mutation would develop the disease-exactlybecauseofthemultiplefeedbackloops,modulators,and parallel pathways, operating at genetic, molecular, cellular, and systemic levels, that characterize living organisms. For instance, the mutation might lead to the disease only in the setting of another mutation, or dysfunction of a membrane ion channel, or a deformed cell structure, or failure of an organ. The lack of a word to describe the conceptual foundation of integrative physiology has led to the proposition here of a neologism: “homeostatism.” Homeostatism uses a feedback-dependent(i.e., circular) approach to the apparent steady-statesthatcharacterizealllivingthings.Theprincipleunderlying homeostatism is that organisms maintain their internal environment by the operation in parallel of adaptive, feedback-regulated systems. Via negative feedbackregulation,comparatorhomeostats,andmultipleeffectors,adult organisms maintain levels of monitored variables within prespecified ranges. Accordingtothehomeostaticconcept,growth,senescence,disease,and, ultimately,organismicdeathresultfrominstabilityintroduced by positive feedback loops-upward and downward spirals rather than circles-leading to new apparent steady-states. A strength of the homeostatic model lies in predicting the emergence of complex phenomena, based on processes such as compensatory activation of alternative effectors, effector sharing, and homeostat resetting. The emergent phenomena can include shifts among apparent steady-states, evocable even from near-randomperturbations (1). Aweaknessofthemodelisitsessential circularity, with few or no simple causal chains or cascades, and with the possibility that diseases might arise from flaws in systems as wholes. Thefollowingtabulationcontraststhemolecularandhomeostatist approaches to disease causes, mechanisms, and treatments. In the table, the term, “linear schema,” refers to unidirectional chains (or cascades)ofmolecularevents.Anexamplecomesfromadiscussionof molecular bases of exocytosis: Munc18 binds syntaxin prior to priming. rSec6and4Sec8mayinteractwiththe Rab3a GTPase and the syntaxin complex prior to vesicle priming. Syntaxin stabilizes Q- and N-type Ca2+ channels in the closed state ...A core complexof proteins consisting ofsyntaxin,synaptotagmin,VAMP,and SNAP-25 anchor the vesicle to the

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presynaptic membrane. Complex I or I1 may regulate the rate of exocytosisby competing with a-SNAP for binding to syntaxin. After a-SNAP is able to bind syntaxin, NSF (an ATPase)bindsa-SNAPandhydrolyzes ATP,whichdisruptsthesyntaxin-core complex ...Ca2+ binds to synaptotagmin, andpossiblytootherCa2+-responsive proteins to trigger fusion...(2). Ananalogouslinearmolecularcascadefollowsbindingofreleased neurotransmitters to membrane receptors (3) The majority of current molecular neuroscience research uses this type of schema, which ignores completely the central determinants of release of the effector compound and the consequences of cellular activation on those determinants. In contrast, “circular schema” refers to loops, where afferent information about levels of monitored variables leads to centrally regulated alterations in activities of parallel effector systems. Thisnot only helps to explain phenomena that one might otherwise find impossible to comprehend but also can lead to otherwise underivable mechanistic hypotheses, as exemplified below. With mutation, the etiologic trail appears to end. The trail begins with the clinical findings, then intermediate neurochemical or enzymatic phenotypic changes follow, and at the end of the trail lies the seeming first cause, the genetic defect. Of course, the medical scientific quest for how a genetic defect actually causes a clinical disease-the pathophysiologic trail-only begins here, and even the etiologic trail only appears to end with the identification of a mutation, because this still leaves unanswered why the mutation occurred where and when it did and howit escaped detection and correction. Ahomeostaticexplanationforthesamediseasemightfocusonan alternative pathway for generating a missing co-factor independently of a disabled gene. No amount of analysis of mutations of the gene itself could lead to the hypothesis of an alternative biosynthetic pathway for generating such a co-factor.Thiswouldrequirehomeostaticthinkingbasedoninformative neurochemistry. Agenetherapistmightrecommenddevelopingsomeformofgene therapytocorrectorbypassthegeneticdeficiency.Ahomeostatistmight recommend treatment that would increase synthesis via the putative alternative pathway. The former treatment would be largely independent of whether the defect led to the disease directly, such asby absence of synthesis of an enzyme, or indirectly, such as by compensatory activation of a shared effector system,

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Table 10-1 Molecular vs. Homeostatist Approaches

Molecular

Homeostatist

Regressive Linear schema Serial Etiology Mutation model for cause Gene therapy Computer-aided design No “goals”

Emergent Circular schema Parallel Pathogenesis Evolutionary model for cause Organismic treatment Chess computer algorithm Apparent purposefulness

leading to worsening of an independent pathologic state. The latter treatment wouldbelargelyindependentofwhether a singlemutation,complex interactionsbetweenepigeneticandgeneticfactorsduringembryological development, or entirely environmental (e.g., toxic) exposures caused the gene deficiency. Both types of treatment, at least in theory, could work. Politicians, bureaucrats, and science reporters seem to have taken on the belief that molecular genetics holds the key to future acquisition of medical knowledge, partly because of the potential to discover first causes of disease. The genotype is the disease, and pathogenetic mechanisms are secondary. This view, which ignores the myriad adaptive responses organisms express and depend on continuously in life, has arisen partly from the choice-so far-by molecular geneticists to study rare inherited diseases that seem to entail the least complexitynecessitatedbythemultipleadaptivechangesrequiredfor homeostasis. Thus, the finding that mice with genetic absence of dopamine-8hydroxylase die during fetal development (4), yet patients with absence of the same enzyme ( 5 ) survive to adulthood, poses a perplexing problem. Not long ago, the same politicians, bureaucrats, and science reporters would have subscribed to the belief that learning all the mechanistic pathwaysin a disease and predicting rational, beneficial treatments constitute all that one can learn from medical scientific research. The phenotype is the disease, and first causesliewithintheprovinceofmetaphysics,notscience.Butduring

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REDUCTIONIST / LINEAR ‘Envlronrnent‘

Disease

Genetic Mutation or Polyrnorphlsrn

HOMEOSTATIST Genetic-Environmental

LInteractions

Effector

Feedback

Systems

Figure 10-2 Reductionist vs. homeostatist models.

embryological development, post-natal growth, pubescence, and senescence, relatively long periods when steady-states are not maintained, the genes may act fairly directly. So far, homeostatists have chosen for study complex common diseases involving “dysregulation,” with mutations viewed as anomalies only distantly related to pathogenetic mechanisms. For a moleculargeneticist,genotypicchangesandtheirlinear consequencesexplaininheriteddiseasesand,sincemostdiseasesinclude hereditarycomponents,canapplytomostdiseases.Forahomeostatist, interactions and feedback regulation of simultaneously acting homeostatic systems explain what maintains organisms in life and what goes wrong in most diseases. A genetherapyadvocatemightfocusonidentifyingthegenetic mutation, replacing the defective gene, or setting up a factory to provide the missing protein encoded by the gene, thereby curing the disease. This seems straightforward, but, so far at least, it simply has not worked in practice.

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T o a homeostatist, the goal of treatment is to counter the pathophysiological mechanism of the disease. This also seems straightforward, but theoretically the goal is impossible to attain, Scientific medicine attempts to explaindiseasesby a continuingprocessofformulatingandtesting pathophysiologic theories, which can be disproven but not proven. This means thatourunderstandingofmechanismsofdiseaseswillalwaysremain incomplete.Consequentlywemustalwaysremainskepticalaboutthe appropriateness of any mechanistic treatment--consider the patients who during thecourseofmedicalhistoryhavesufferedfrom“rational”bloodletting, trephination, and cupping. The molecular approach in medical research offers several attractions. Genetic studies seem capable of revealing etiologic truths, whereas integrative studies, requiring complex experimental designs, large numbers of subjects, longitudinal studies, and statistics, yield only pathophysiologic suggestions. Gene therapy seems direct and curative, whereas mechanistic treatments require “profiling”torationalizeindividualtherapyandrequireexpensivedrug development,includingstudiesofbioavailability,pharmacodynamics,and efficacy. Above all, studying one system or one gene is always easier and cheaper than studying more than one simultaneously, and studying effects of a drug or a knockoutof a gene encoding an endogenous substance is always easier and cheaper than studying the function of a homeostatic system. Even a cursory glance at Table10-1 would convince one that the dialectic between molecular and integrative medicine is not new; rather, it continues centuries-old, fundamental disputes about philosophies of science-reductionist vs. emergent, linear vs. circular, atomistic vs. organismic, phenomenological vs. purposive. Both types of concept explain phenomena in terms of relatively fewbasicprinciples,andbothleadtohypothesesthatobservationor experimentation can test. Thus, both types of approach are scientific. Research in both traditions should continue, with the expectation that from the creative friction at their interface, future breakthroughs will arise. AccordingtoHegel’sdialectic,thesisandantithesisresulteventually in synthesis. These considerations lead to the hope and prediction that molecular geneticists will begin to expand their theoretical horizons to include feedbackregulated, interacting, adaptive systems that operate in parallel and will consider not only direct genetic programming but also genetic “algorithms” (analogous to thesimulationsencoded in achesscomputer’ssoftware).Geneticistswill recognize that humans depend on nervous, endocrine, and autocrine/paracrine systems to maintain apparent steady-states-to keep us alive-since the time lags for transcriptional responses obviate direct genetic actions (6). Physiologists, in turn,willapplynewgenetictoolstoexaminethe homeostaticrolesofthebody’s“stress”systemsandwillconsidermore seriously genetic constraints on the functioning of those systems. In neurology,

Future

583

“genotypers,” who identify defects but remain ignorant about how those defects leadtodiseases,willjoinforceswith“phenotypers,”whoidentify neurochemical or behavioral phenotypes but remain ignorant about the genetic and molecular bases. The future of clinical science therefore is neither in molecular genetics nor in integrative pathophysiology but in building bridges between the two. Common, modern-day diseases will be found to be mainly disorders of regulation, only complexly and indirectly related to genetic changes. Most of the genetic contribution to disease in adults will be found to result not from direct genetic orders but from subtle genetic advice, which has afforded a survival advantage in evolution. Consider diseases of senescence. Aging-related increases in susceptibilitiestocardiovascular,neurologic,oncologic,and immunologic diseases have always limited our lifespan and always will. One maysearchforraregeneticmutationscausingprematuredegeneration. Alternatively, however, one may recognize that our bodies have been designed to protect and propagate genes, not to live indefinitely (6). Accordingly, one may hypothesize that groups of genes bias toward accelerated neuronal loss in the elderly because they enhance protection and propagation of genes in the younger reproducers. Perhaps the same homeostatic systems that organisms rely on to counter acute threats earlyin life cause senescence by the accumulation of toxic byproducts of the actions of those systems(7). Forinstance,parkinsonism in theelderlyappearstoresultfrom cumulativeinjurytodopaminergiccells,possiblybecauseoffreeradicals generated over the years during oxidative deamination of released dopamine (8). In the young, this enhanced release could enable rapid initiation of locomotion orofotherbehaviorsrelevanttosurvival.Analogously,cardiovascular hypertrophy, and consequently susceptibility to stroke and cerebrovascular ischemia in theelderly,couldresultfromprolongedbombardmentof adrenoceptors or continuous “revving” of vesicular engines (9, lo), enhancing adaptive fight-or-flight responses in the young at the cost of chronic changes in cardiovascular architecture. Thisgenetic-evolutionaryperspectivealsoleadstotherapeutic hypotheses. If chronic oxidative deamination of dopamine led to toxic injury to dopaminergic cells, then long-term blockade of that deamination in individuals with a genetically determined high rate of oxidative deamination could prolong the average useful life of human nervous systems. Analogously, disconnecting geneticallydeterminedsympathoadrenalhyperreactivityfromchronic cardiovascular hypertrophy could prolong the average useful life of human circulatory systems. A person’s genes link that person not only with hisher family, not only with the family of man, but with all things that have ever lived. This surely is a basis for the fascination of genetics. As amazing as the detail of the genetic

Chapter 10

584

instructions, however, are the uses to which those instructions are put by living things to maintain organismic integrity so well for so long. The genes are life’s blueprint; ongoing information processing and compensatory adjustments enable life to go on. Whatisbeingproposedhere, in conclusion,isnothinglessthana redirectionofmoleculargenetics,molecularbiology,andintegrative physiology, to focus on the real “first causes” of many modern diseases of adults: the loss of “wellness,” for which both health and disease depend on geneticalgorithmsdeterminingthedevelopmentandadaptiveregulation of homeostatic systems. In the words of E. R. Weibel, Complexity has its own laws. Our challenge ...is todiscoverthelaws of complexity that determine the coordinated function of the body’s parts and the new qualities that emerge from this integrated function (( 1l), p. 295). The principles of homeostat operation described and illustrated in this book seem simple, yet feedback regulation, multiple effectors, effector sharing, and homeostat resetting can explain many phenomena in clinical neurocardiology and, more generally, in integrative medicine. Walter Cannon, in his classic monograph, The Wisdom of the Body, used results of many studies based on catecholamine systems to derive the main ideas he wished to convey (12). The author of the present book has done about the same thing.

REFERENCES 1. Yates FE. Self-organizing systems. In: Boyd CAR, Noble D, eds. The Logic of Life.

NewYork:OxfordUniversityPress,1993:189-218. 2. Tigley DW. Synaptic-vesicle release: New pieces of a puzzling process. J NIH Res 1995; 7:46-49. 3. PremontRT,Koch WJ, IngleseJ, Lefiowitz RJ.Identification,purification,and characterization of GRK5, a member of the family of G protein-coupled receptorkinases. J BiolChem1994;269:6832-6841. 4. ThomasSA,MatsumotoAM,PalmiterRD.Noradrenalineisessentialformouse fetaldevelopment.Nature1995;374:643-646. 5 . Biaggioni I, GoldsteinDS,Atkinson T, RobertsonD.Dopamine-beta-hydroxylase deficiencyinhumans.Neurology1990;40:370-373. 6. Dawkins R. The Selfish Gene. New York: Oxford University Press, 1989. 7. Nesse RM, Williams GC. Why We Get Sick. New York: Times Books, 1994.

Future 8. Gotz ME, Kunig G, Riederer P,YoudimMB.

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Oxidative stress: free radical productioninneuraldegeneration.PharmacolTher 1994; 63:37-122. 9. Eisenhofer G , Esler MD, Meredith IT, Dart A, CannonRO, Quyyumi AA, Lambert G, Chin J, Jennings GL,GoldsteinDS.Sympatheticnervousfunctioninhuman heart asassessed by cardiacspillovers of dihydroxyphenylglycoland norepinephrine. Circulation 1992; 8 5 : 1775-1785. 10. Eisenhofer G, Rundqvist B, Friberg P. Determinantsofcardiactyrosine hydroxylase activity duringexercise-inducedsympatheticactivation in humans.Am J Physiol 1998; 43:R626-R634. 1 1 . Weibel ER. The future of physiology. News Physiol Sci 1997; 12:294-295. 12. Cannon WB. The Wisdom of the Body. New York: W.W. Norton, 1939.

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Index -AA I cells, 146, 147, 149, 151, 154, 155,

160,161,162,167,168,170, 175,178,183,232,302,485 (see also CVLM) AI adenosine receptors, 47,4485 A2 cells, 154, 160, 161, 167, 168, 170, 172,175,178,183 (see also NTS) A5 cells, 143, 144, 145, 146, 147, 151,

156,168,178 A6 cells, 154, 161, 162, 164, 168, 169,

172, 173, 178,183 (see also Locus ceruleus) Abel, J.J., 3 Accentuated antagonism, 104, 108 ACE (Angiotensin-converting enzyme), 18,233-236,482 Acetylcholine, 6, 8, 23, 26-28, 29, 52, 61 effects of, 28,29,32 receptors, 29,33,36 catecholaminereleaseand,45, 47 sympathetic neurotransmission and, 38 Acetylcholinesterase, 28,29 Acidosis, 97,247, 294,307 ACTH (corticotropin, adrenocorticotropin), 205, 21 5, 227-228,229,230,232,236, 237,254,307,315, 318, 319, 536 Adaptation energy, 201, 202,203 Adenosine, 47,48,49,50, 85, 395,443 Adie’s syndrome, 15, 341,

Adrenaline (see Epinephrine) Adrenoceptors, 7, 8, 54, 61, 70-78, 80, 83,91, 107, 171, 173, 177,237, 280,358, 363, 364,432,477, 483,535,538,577,584 a-,7,48,50,64,65,66,67,7174, 77, 80, 81, 83, 90, 107, 177, 280,308,364,428, 432, 460, 461,466,476,477,488,489, 492,494 al-,35, 51, 75, 77, 78, 80, 81, 90, 96, 177-179, 18 1, 184, 230, 308,356, 358, 374, 428,436, 445,484,486,538,576 a2-, 42, 43, 47, 71-74, 77, 81, 83,85, 86, 91, 92,106,155, 157,172,174,176,178-181, 183,184,229,232,238,239, 280,308, 361, 362, 372,374, 375,400,440,479,483 R-, 35,66,74-76,81,83,90, 93,102,107,177,178,181, 234,280,303,349,365,373, 428,432, 440, 441, 442, 443, 445,460,492,529,538,543 81-, 77, 80, 94, 182,485 R2-, 7, 9, 47, 75, 78, 82, 85, 89, 102,181, 182,230,291,576 B3-, 76,441 intracellular mechanisms, 7174, 107, 176,365 Adrenochrome, 369 Adrenomedullary hormonal system (AW, activation in asphyxiation, 306 circulatory activation in collapse and shock, 307 activation in distress, 246, 321 activationinhemorrhage,300302 587

588

Index

activation glucoprivatton, in 304-306,372 acttvation in pain, 308, 321 Aging adrenomedullaryfunctionand, 103 parasympathetic function and, 101

sympathetic nervous system function and, 101-103 Aggression, 159, 256,310,314, 543 Ahlquist, R.P., 8 Air traffic controllers, 553 Alarm, 174,200-201,205,248,261 Aldehyde dehydrogenase, 55,56,370 Aldosterone, 61, 73, 80, 82,84,85, 107,213,214,217,222,233236,257,258,259,283,284, 285,286,289,295-299,300, 301,303,320,321,432, 435, 482,528,538,542,554 Alprazolam, 440 Amphibia, 257 Amygdala,147,151,154, 155, 156, 159,160,162,163-164,165, 167, 183,281,315 Amyloid polyneuropathy,463 Anemones, 257 Anger,208,209,244,311-313,314, 315,317,323,428,429,438, 542,55 1,552 Anginapectoris,8,14,223,226,251, 290,430-432,440,456,528 Angiotensin I1 (AII), 47,61, 80, 82, 85, 95, 107, 160,163,213,214, 217,222,233-236,257,259, 283,284,285,286,289,295, 296,297,298,299,300,301, 303,320,321,432,435,482, 483,528,538,542,554

circumventricular in organs, 165,235 baroreflex effects of, 235 cardiac filling and, 296, 300 dietary salt intake and, 295 dipsogeniceffect of, 163,236, 299 modulationofnorepinephrine release by, 47 Angiotensin-converting enzyme (ACE), 18,233,234,235,483 Animal spirits, 1 Anoxia, 48, 97,306,424 ANP (atrial natriuretic peptide, atriopeptin, atrial natriuretic factor), 213, 217, 219, 234, 257,283,295,296,298,299, 301,303,320,432,433 Anxiety,14,15,17,83, 93, 94,141, 164,172,174,228,243,246, 248,250,291,310,314-316, 321,336,340,344,360,361, 363,364,425,437,439-441, 488,526,528,530,531,540, 542,549,555 AP (see Area postrema) Aplysia, 242,255 APUD(amineprecursoruptakeand decarboxylation) cells, 258 Area postrema (AP), 84, 143, 15 1, 165, 166, 167,232,235 Aristobulus, 436 Arrhythmias, 8, 14, 80, 82,90,91, 141, 219,343,360,424,425,426429,437,438,441,488 myocardial infarction and, 426429,444,492,493,530,534 sudden death and, 436-438 Arterioles, 35, 233,256,371 Ascorbic acid, 44

589

Index

Asphyxiation, 306-307, 320,379 Associative learning, 242 Atherosclerosis, 16, 344, 431, 432, 546,547,549,550 ATP (adenosinetriphosphate), 9, 1 I , 31, 45, 47, 48, 49, 51, 53, 60, 74, 106,435,443,580 as cotransmitter, 45,47-50, 106 Uptake-l and, 54 ATPase, 63, 65, 80, 84, 435, 500, 544, 580 Atrial natriuretic peptide (see ANP) Atriopeptin (see ANP) Atropine, 7, 30,33,34,67, 101, 104, 106,350,352,356,365,396, 428 Attention, 158, 173, 174, 184,294,309 deficit disorder, 141 Autocrine/paracrine, 1 I , 13, 62, 64, 65, 84,107,108,140,235,257, 258,319,380,384,481,544, 583 Autonomic epilepsy, 486 Autonomicfailure,13,14,16,18,92, 21 1, 223,282,285,317,337, 338, 339, 340,345,347,350, 355,363,365,378,381,384, 388, 393, 396 , 397, 399, 400, 456,457,458,459,460,461, 462,464,465,469-480,495, 503 (see also MSA, PAF, Parkinson’s disease) peripheralneuropathyand,15, 461 Autonomicnervoussystem, 1, 4, 5, 8, IO, 20, 23,24, 25, 33, 104, 105, 140,142,162,227,280,469, 472, 495 (see also Sympathetic nervous Parasympathetic nervous

system) AV3V (anteroventral third ventricle regionofthehypothalamus), 163, 165, Avoidance learning, 240, 243,248, 262 AVP (arginine vasopressin, anti(see diuretichormone,ADH) Vasopressin) -B-

Baroreceptors, high-pressure (see Baroreflex, arterial) Baroreceptors, low-pressure (see Baroreflex, cardiopulmonary) Baroreflex,78,80, 81, 179,182,212, 217,224,226,235,257,285, 365,366,367,503,527 amygdala and, 163 arterial, 101, 160, 162, 213, 215,235,246,282,284, 357, 358,365,527,544 autonomic failure and, 367, 473,478 cardiopulmonary, 97, 235, 236, 284,357,359,545 CVLM and, 182, 184 defense reaction and, 162,246 failure, 15, 363, 481, 486, 487, 527 inhypertension,152,225,246, 359,481,484,487,538,539, 544,545 NTSand,68, 138, 150,152, 160, 163,235 PVN and, 160 RVLM and, 143, 147, 163 sensitivity,95,282,357-360, 400,429,462,484,539,544 vasopressin and, 165, 231, 232,

590

Index

302 adrenomedullary response to Barostat, 138, 212, 217, 222, 224, 225, hypoglycemia and,304 231, 236, 283, 289, 321, 357, adrenomedullary response to 481 pain and, 308 Bednucleusof thestriaterminalis anti-fatigue effect of (BNST), 148, 159,281 epinephrine and,83 Benzodiazepines, 14, 364, 487, 529, bioassay measurements of 554 adrenomedullarysecretionand, Bereavement, 550 313,368 Bernard, Claude, 2, IO, 24, 137, 199 denervation sensitivity and, 77 fight-or-flight responses and, Biofeedback, 259 Blood-brain barrier, 29, 43, 83, 84, 90, 310,315 92, 95, 139, 165, 177, 183, homeostasis 260, and, 23, 199 sham rage and,315 361,384,390,398 stressand, 199, 205, 260, 26 Blushing, 245 279 BNST (see Bed nucleusofthestria sympathico-adrenal system and, terminalis) 24,35, 105, 142, 199,279 (see Bradbury-Eggleston syndrome “voodoo death” and,318 Pure autonomic failure) Carbidopa, 43. 92, 390, 393,474 Brattleboro rats, 232, 254 Cardiacfilling, 176, 226, 230, 234, Bretylium, 86-87 257, 283, 286, 289, 295, hypotensive effect of, 87 300, 306, 345, 357, 358, norepinephrine release and, 67, 368,400,433,455,532,539 85,86, 87 Cardiac necrosis, 491,492,493 pain and, 87 Cardiomyopathy, 141,490-493,494 ventricular fibrillation and, 87 hypertrophic, 438,493 pheochromocytoma and, 360, -C488,493 Carotid endarterectomy, 487,488 Cl cells (see RVLM) Carotid sinus,212,214,307,487 C2 cells, 168, 175 baroreceptors, 357 Caffeine, 15,48,93, 94,530, 553 nerve, 137, 147, 148 3’-5’-adenosine (cyclic CAMP syncope and, 15,534 monophosphate), 9,3 I , 34, 49, 201 64, 66, 74, 75, 76, 84,“Catatoxic,” 93, 94, Catechol, 38,41,52. 90, 92, 369, 104,440,44 1 389,46 1,495,500,539 Cannon, Walter B., 6, IO,7,23,81,83, 0-methyltransferase (see 165,204,225,246,313,585 COMT) adrenomedullary response to Catecholamme, 3, 8-9,1 1 , 12-13,41, cold and, 292

591

Index 42,52,54,55,56,60,70,83, 88,90, 91, 92,96,97,98, 140 administration, 54, 88 blood-brainbarrierfor,43, 83, 84,92,398 central neural, 141, 150, 166 circulating,56,83,218,291, 3 15,429,439,493,494 clearance, 97, 102,460 definition, 41, 89 effects,5,43,66,70, 71, 76, 78-85,97,99, 107 “gut-bloodbarrier”for, 3, 1113,258,382 levels,12,93,97, 100, 108, 152,153,159,218,232,254, 290,304,307,315,316,361, (cyclic 364,423,435,439,445,461,guanosine 484,487,488,490,493,529, 530,552,554 metabolism, 12, 41, 52, 54, 5558, 92, 93 non-neuronal, 1 I , 12,25,6266, 107 pathways, 140 responses, 17, 152 receptors (see Adrenoceptors) release, 44, 46, 5 1, 60, 86, 91,with 105, 108,162, 164,230,489 synthesis,38,41,43,51,57, 62,88 system,12,24,55,103,105, 108

translocation of, 42, 60 turnover, 40 uptake, 52, 54, 55, 93, 97, 107, 494,495 Catecholaminergic,12,13,147,148, 150,151,154,160,166,171, 175,177,258,352,423,433,

480,483,485,542,547,552, 556 cells, 166, 184,469 centers, 164 function,14-16,140,335,368, 421,455,483,495,503,538 neurons, 17 1 pathways, 140,23I , 308 phenotype, 352,494,499 systems, 1 I , 20, 171, 207, 222, 227,228,232,234,257,258, 308,318,526,536 cerebrospinal fluid (CSF), 13, 43, 238, 395,438,460,466,473,476, 488,496,497,498,500,539, 540 c-fos, 147 (see also Fos) cGMP monophosphate), 31, 32, 67, 104 Chagas’ disease, 15,493 Cholinergic effectsonsympatheticnervous outflows, 105 sympathetic inhibition of function, 103-104 (see also Accenuated antagonism) interactions catecholamines, 103-105 receptors (see Muscarinic receptors; Nicotinic receptors) stimulation of adrenomedullary secretion, 105 “tone,”396

Chromaffincells,38,43,44,50,51, 57, 60, 61, 105, 108, 141, 258, 360,488,489 Chromogranin, 45, 50,51, 106 Chronic fatigue syndrome, 16, 337, 350,365,527,532,534,556

592

Circadian rhythms,100 Circulatorycollapse,227,307,320, 379,437, Circumventricular organs, 83, 139, 141,165, 166,235,259 Classical conditioning, 241,255 Clearance, 375, 397,460 of catecholamines, 97,102,460 of norepinephrine, 101, 102, 373,375,376,377,458 Clonidine, 54, 176, 232,465,487, 529, 532 adjunctiveanalgesiaand,179, 180,465 a2-adrenoceptors and, 180, 239,374,480 depressorresponseto,17,180, 184,363,374,541 effectsof,94,179,180,183, 239,361,473,480 growth hormone levels and, 239,473,480 in heart failure, 436 hypernoradrenergic hypertension and, 17, 363, 541, 546, as an imidazoline, 54,180 norepinephrine levels and, 374, 488,489 sedative effect of, 94 suppression test, 360-362, 364, 374,400,488,489,546 sympatheticnervetrafficand, 180 Coarctation of the aorta, 337, 340, 344, 488 Cocaine, 6, 15, 54,356 cardiotoxicity from, 54 LC firing and, 176 Uptake-lInhibitionby,54, 88,

Index

107 Cold, 50, 255, 290, 292-294, 321, 336, 539 exposureto, 83, 97, 172,223, 226,292,293,320,366,441 pressor test, 293, 538, 551 immersion, 294 intolerance, 255,290,336, 339 reactor, 55l “Collapse firing,” 349, 531 Compensatoryactivation, 10, 17, 23, 219-220,233,236,261,279, 302,304,308,368,424,435, 441,494,541,579,580 Complex Regional Pain Syndrome (CRPS), 87, 308, 465, 526, 533-535,555 COMT (catechol-0-methyltransferase), 12, 41, 53, 56, 57, 58, 59, 61, 66,370,383,389, 394, 397, 398,434,489,496,502 inhibitors, 93, 390 Conditionedresponse(CR),172,173, 242,243 Conditioned stimulus (CS),242,427 Conditioningfactors,203,206,249, 548 Conjugation, 258,382,491 Contractionbandnecrosis,491,492, 493 Controlled variable, IO, 21 I , 212,217 Coral, 255 Coronary arteries, 431,437,494 spasm in, 43I , 432 Coronaryheartdisease,13,251,429, 439,440,547,550,551, 552, 556 spasm and, 431-432 Corticotropin (see ACTH) Corticotropin-releasing hormone (see

593

Index

CM) Cortisol, 215 201, (see also Glucocorticoids) q-adrenoceptors and, 179 depression and,204 distress and,25 1, 3 15 exercise and, 3 19 feedback inhibition by, 217 glucose regulation and, 304, 464

HPA system and,227-230 post-traumatic stress and,536 subordinate status and,319 CO-transmission, 47-51 CPK (creatine phosphokinase), Crawford, A.C., 4 CR (see Conditioned response) otropin-releasmg CRH hormone), 73, 161, 170,172, 174,176, 181, 208,229,232, 237 Cruri/ragiurn, 284 Crying, 158,246

CS (see Conditioned stimulus) CT (central tegmental tract), 170 Cushing reflex,486 Cutaneous, 245,292,310,312,322, 349,353

blood flow, 67,352,439 nociceptor, 155, 157 sympatheticactivity, 290,358, 365

vasoconsctriction, 79, 80, 81, 285,288,292,293,491

CVLM(caudalventrolateralmedulla), 67,68,69,143,145, 150,151,152,156,157, 161,167,183,184,302, 486 Cyclosporin, 337

147-149, 160, 469,

-DDA (see Dopamine) Darwin,Charles, 207,244,25

1, 252, 262,310,311,314,317 Dawkins, Richard, 254, 260,482 DBH (dopamine-13-hydroxylase), 4344,86,230

conversion to norepinephrine and, 43,44, 106, 175 deficiency of, 15, 92, 291, 352, 391,393,465-467,468,503, 58 1 exocytosis and,45,89

familial dysautonomla and, 495 Menkes disease and,43,500 pure autonomic failure and, 458 “Defeatreaction,” 317-318 (see also “Giving up reactlon”) Defense reaction, 156, 246, 3 16, 542 centralneuroanatomyof, 161, 163,315

circulatory pattern In, 1G 1, 3 15 hypertenslon and, 246,249 Deoxyglucose, 15 1 adminlstration of, 305-306 autoradiography and, 15 1 effects of, 305,367 Depression, 14,141,179,204,336, 438-439,578

catecholamme theory of, 375 central nervous, 29 “giving up” and,3 18 hypertension and, 542 myocardial, 21 8 norepinephrineand, 174,208, 438,537

reserpine and, 375 treatment of, 337

594

hdex

Desensitlzation, 75, 76-78, 107,432 heterologous, 77 homologous, 77 Desipramine, 177,459,465 3H-labelled, 177 epinephrine and, 88 pain and, 465 Uptake-lblockadeby,54, 88, 395 Determinism, 2 (dihydroxyphenylglycol, DHPG DOPEG), 57, 59, 370, 434, 494,496 aldehyde reductase and, 12, 55, 56 autonomic failure and, 459 DBH deficiency and, 43,466 DOPA levels and, 43, 391, 392, 468,500 DOPAC levels and, 393,500 MAO and, 12,55,392 norepinephrine turnover and, 12, 53,59,387, 389,401,494 pheochromocytoma and, 489 inplasma, 386-387, 392,394, 395,459,460,465,468,494 DHPR (dihydropteridine reductase), 40,393 deficiency of, 16, 40, 494-496, 491 gene, 497 Dlabetes, 14, 202, 21 I , 227, 335, 336. 441,552 autonomlc neuropathy and, 396, 456,461,462-464, 502,528 “metabolic syndrome” and, 442-444

painful neuropathy in, 464-465 Dmylglycerol (DG), 3 I , 34, 74 Diazepam, 94

Dietary salt intake,295-296 DOPA-dopamine system and, 65,543 hypertension and, 204 neuroendocrine responses in, 296

plasma norepinephrine and, 543 renin-angiotensin system and, 295,320 skeletal muscle sympathetic acitivity and, 543 DiGeorge syndrome, 501 Dihydroxyphenylacetic acid (see DOPAC) Dihydroxyphenylalanine (see DOPA) Dihydroxyphenylglycol (see DHPG) Diseases of adaptation, 201-202, 203, 208,249 Dishabltuation, 165, 203, 248, 319 Distress 10, 94,141,156,166,172, 173,199,206,207, 208,239251, 284, 309-319, 321,352, 436,553 adrenomedullaryactivationin, 246,248,299,309,315,320, 379,576 angina pectorls and, 429 arrhythmias and, 437,438,444 aversiveness and, 240 barostat resetting and, 152 communication and, 243,248 conditioned response and, 243 consciousnessand,239,248, 261,439 definition of, IO, 239, 247, 248, 249,250,261 depression and, 3 18,439 drive and, 243 emotional, 25, 80, 8 1, 204, 207, 222,228,251,256,294, 309,

lndex

315, 320, 322,366,429,436, 437,438,444,468,492,548 fetal, 97 gastrointestinal system and, 3 13 glucose levels and, 80 homeostat resetting and, 152, 245,246-247,482 HPA axis and, 3 18 hypertension and, 484,539 infant crying and, 245 memory and, 164, 165, 184, 247 myocardialinfarctionand,427, 444 myocardial necrosis and, 504 neuroendocrine pattern in, 245, 246,309 novelty and, 308 pain and, 172,214, 308,536 post-traumatic stress disorder and, 536,537 Selye and, 201, 202, 204, 216, 248,249 sexual activlty and, 239 sudden death and,436,437 sweating and, 352, 353 syncopeand,183, 3 17,532, 576 Diuresis,64, 80, 85,200,231,296, 297,298,300,461 DNB (dorsal noradrenergic bundle, dorsalbundle,DB),169,173, 179 Dobutamine, 54, 72 DOCA (deoxycorticosterone), 163, 203 Dominance vs. submlssiveness, 245, 254,256,319,548 DOPA (L-dihydroxyphenylalanme, LDOPA), cerebrospinal fluid, 43, 498,

595

500 circulating, 17, 65, 66, 235, 296,381,382,384,385,386, 390,401 oral, 18,393,497 plasma, 11, 12,43,380,381, 387-392, -responsivedystonia, 1 6, 496497 sources, 12 TH activityand,12,42,382, 390,391,392 DOPA decarboxylase (see LAAAD) DOPAC(dihydroxyphenylaceticacid), 53,370,383,394,434,494, 496 aldehyde dehydrogenase and, 55,56,57 in CSF, 496 6-Fluoro-, 398 MAO and, 55,56,57,392 Menkes disease and, 500 in plasma, 58, 62,392-393, 500 in urine, 62 Dopamine (DA), 11 in brain, 167, 170-171, 184, 379 conjugation of, deficiency, 170 pathways, 168, in plasma, 1 I , 13, 64, 379-380, 391,395,401 receptors 78, 84, 182,298, 384 renalDOPA-dopaminesystem and, 63-65, 107,298 sulfate, 13,380-385, urine, 385-386 Dopamine-B-hydroxylase (see DBH) DOPS (L-dihydroxyphenylserine), 92, 46 1,467,476,477

596

Index

Dorsal bundle effect, 173

-EEarthquake, 550 EDRF(Endothelium-derivedrelaxing factor) (see Nitric oxide) Effectorsystem, 5, 10, 203,208,210, 215,216,222,233,239,247, 254,257,259,261,279,287, 300,319,388,422,455,482, 485,580 Effectors, alternative, 23,233,279, 579 multiple, 10, 19, 213, 219, 221, 223,279,300,579,585 sharingof, IO, 214,222-223, 224,579,585 interactions among, 304 Endorphin,179,237,238,302, 304, 308,3 18,320,322 Endothelins, 70 Endothelium-derived relaxing factor (see Nitric oxlde) Endoxin, 213, 303 Enkephalin, 45, 50, 143, 160, 175, 236, 237 EPI (see Epinephrine) Epinephrme (EPI, adrenaline), 3, 4, 6, 8, 38, 41,97,103,204,238, 257,281,289,291,312,316, 353,368,370,380,393,430, 433,442,445,497,531,537, 548 adrenoceptors and, 70, 107, 177 adrenomedullary system and, 7, IO, 1 1 , 61, 63, 64, 85, 103, 107, 108, 162,215,256,314,369, 401,578 adrenomedullary secretion of,

38,86,256,289,3 16 anti-fatigue effectof, 79, 83 R2-adrenoceptorsand,47,85, 88,578 C l cellsand, 144, 154,175, 183 Cannon and, 6, 82, 307, 369 central nervous system and, 175, 177 circulatorycollapseand, 307, 322 corticotropine-releasing

hormoneand,208,228,229, 230 co-transmission, 47, 544 discovery of,3,369 distress and, 228, 246, 250, 294,3 16 effects of, 9, 61, 79, 81-83, 107, 108, 223,234,256,368,427, 493,548 “epinephrinehypothesis”and, 542 “fight-or-flight” and, 23, 158 glucagon and, 8, 238, 304, 465, 490 glucose counter-regulation and, 238,256,290,304-306,465 glycogen and, 8,79, 8 I , 216 hemorrhage and, 300-304 hypertension and, 539, 540, 541,543 metabolismof,12,55,56,58, 371,395,401 pain and, 308 panidanixetyand, 3 15,440, 530 pheochromocytoma and, 98, 395,401,489-490 in plasma, 5 I , 62, 88, 93, 105,

597

Index 158,228,229,230,237,238, 246,251,254,285,289,292, 293,295,299,300,303,304, 307,314,318,352,364,369, 379,395,401,434,442,489, 530,533,540,542,553 PNMT and, 58, 61-62, 63, 143, 175,230,547 renin-angiotensin-aldosterone system and, 234, spillover, 103,238, 537,541 stress and, 207, 228, 237, 537 syncope and, 19, 317,322,350, 531-533 synthesis of, 61, 259,353, 371 Type A and, 17,553 Uptake- 1 and, 5 1 Ethology, 252 Eustress, 201,202 Exercise, 101, 222, 246, 256, 286-288, 306,308,318, 319, 321,352, 367,428,431, 435, 439,457, 459,528,530,531,532 bicycle, 288,319, 352 “centralcommand”and,226, 287 epinephrme and, 103, 25 I , 288, 290 handgrip, 67 homeostat resetting and, 226 intoleranceof,528,530,531, 556 isometric, 223,531 isotonic, 287,289,459, 532 norepinephrine and, 102, 172 sympathoneuraleffectsof,60, 223,306,320,321,352,426 treadmill, 48 Exhaustion,201,202,204,248,261, 318

EXOC~~OSIS, 44-46, 49, 50, 51, 87, 388, 580 Extinction, 172, 173 -F-

Fainting (see Syncope) Familialdysautonomia(FD),15,339, 341,391,467-469,503 Fastigial nucleus, 284, Fatlgue,chronlc (see Chronicfatigue syndrome) Feedback regulation, 19,217, 261, 580, 583,586 Fetus, sympathetic function in,96 “Fight-or-flight,”23,207,245,249, 308,310,315,585 Fluorodopamine, 18, 19, 398-402, 460, 466,476,478,479,480,481, 534 Fluorometaraminol, 427 Folkow, Bjorn, 249,260,484 Fos, 147, 151,486 -G-

G-protein, 8, 29, 30, 3 I , 32, 34, 48, 49, 54, 71, 74,75,77,104,106, 107 GABA (gamma-aminobutyric acid), 47, 54,85, 143, 153, 176 Gain, baroreflex (see Baroreflex) Galen, 1-2 Ganglionic blockade,232,298,305,348, 349,364 blockersktimulants, 85-86 neurotransmission, 37-38 GeneralAdaptatlonSyndrome(GAS), 200,201,203,204,248,261

Index

598

Generators, 216 “Givingup”reaction,204, 314, 317, 322 Glucagon, 143,398 epinephrine levels and, 239, 305 glucoseand, 8, 215,216,239, 305,321,322,466 levels, 306 stimulation test, 362, 400, 488, 490 Glucocorticoid, B-adrenoceptors and, 231,494 effects of,201,228,23 1 feedback inhibition and, 161, 229,319 inflammation and, 228 glucose and, 239 PNMT and, 62,64,259 release, 228 stress and, 202, 206, 209, 228, 229,319,321 sympathoinhibition by, 230 Glucoprivation (see Hypoglycemia) Glucostat,21 2,217,220,238,288, 302,305,321 Glutamate, 144, 153, 156, 175 Growthhormone (CH), 73,181,239, 304,322 autonomic failure and, 472, 475,479,482 glucose and, 215, 219, 222, 238,304,305,464 release of, 179,216,223,239, 466 ‘Guillain-Barresyndrome,14,15, 485, 502 -H-

Habituation, 174, 204,241,248 HACER (hypothalamic area controlling emotional responses), 157, 16I , 163, 184,316 Harvey, William, 1,2, 309 Heart failure, 15, 337,424,495,496 adrenoceptornumbersin,78, 435 autonomic activation in, 299, 424,434 hyponatremia in, 232 norepinephrine depletion in, 436 plasmanorepinephrinein,433, 435,496 norepinephrine spillover in, 78, 380,432,435 norepinephrine uptake in, 435 positive feedback loops in, 219 prognosis in, 15,435 sympathoneural activation in, 433-435,437,447 treatmentof,18,79,435,437, 438 Hemorrhage,62,84,157,232,301, 304,320,457 epinephrineand,84,206,229, 230,301,302,304,320,381 hyperglycemia and, 302 hyponatremia in, 303 hypotensive, 225, 230, 300304,306,320,322 renal sympathoinhibition in, 303,304 stress and, 207, 21 I , 304, 320, 322 subarachnoid, 495 sympathoneural responses m, 156,301,302,303,304 vagal afferent activation in, 304

599

Index

Hereditary amyloid polyneuropathy, 462

Hippocampus, 152, 154, 159, 160, 162, 164-165, 170, 174, 178, 181, 235 Homeostasis, 5,7, IO, 23,24,25,41, 98, 140, 158, 171, 178, 199, 206,207,208,210,222,226, 227,239,240,246,247,254, 262,289,295,304,320,358, 385,421,422,530,546,580 Homeostat, 220,221, 222, 223,259, 321,357,433,441 definitlon of, IO, 211,212,216 disruption, 224, 225,480 osmolar, 295 principles of operation, 216, 575,577,584 resetting, 225,239,247,262, 308,481,578,584 settings, 2 19

theory of stressanddistress, 208-226

Homovanillic acid (see HVA) Hostility essential hypertension and,541 Type A patternand, 16, 550HPA

551 (see

Hypothalamo-pituitaryadrenocortical)

pressure liquid (high HPLC highchromatography, liquid performance chromatography), 369 5-HT (see Serotonin) Hunger, 208, 210, 236, 243, 259, 295, 304,321 Hunter, John, 429

HVA (homovanillic acid), 36, 45, 394, 395,494,496,497,500

fluorinated, 398 6-Hydroxydopamine (6-OHDA), 46, 87, 149, 154, 179,

Hydroxyephedrine, 396,463 Hypercarbia, 226,294,307 Hyperdynamlc circulation syndrome, 16, 340, 364,489, 525-528, 553 92, 141,151, 224,318, 335-340, 364,367, 422, 438, 460, 462, 480-490, 526,553 A1 cells and, 232 aldosterone and, 233 amygdala and, 164 angiotensin I1 and, 163, 165, 233,235 baroreceptors and, 152, 224, 225,247,360,480, 485, 543544 borderline, 17, 539

Hypertension, 15,16,17,

cardiovascularhypertrophyin, 484,539,545,546,552 “cheese effect” and,38,78,374 clinical evaluation of, 335-340, 539,540 “defense reaction” and,247 ephedrine and, 79

“epinephrine hypothesis” of, 542

familial dysautonomia and,467 glucocorticoids and, 227, 337 hypemoradrenergic, 374, 525, 528,553,555

hyperthyroldismand,

70,343,

44 1

hypothalamus and, 94, 1GO, 162 insulin and, 443,445 intracranial, 49 I , 492 n u huatzg and, 79 neurogenic, 224,235,485-486,

600

Index

502,539,541,544-545 norepinephrine In, 235, 537539,540,545,546 norepinephrine spillover in, 378,539 nucleus of the solitary tract and, 151,232 oral contraceptives and, 337 paniclanxiety and, 438,440 pheochromocytoma and, 339, 360,487-490 plasma catecholamines In, 537539,546 plasma renin activity In, 235 post-operative, 487 “pseudopheochromocytoma”

and, 490 pulmonary, 79 renal, 163 ,343 salt sensitivity in, 204, 542543-543 secondary, 335, 337, 340 Selye and, 200,20 I , 204,208 skeletal muscle sympathetlc activity in, 537 spontaneously hypertensive rats and, 88,99,482-485 stress and, 200, 201, 204, 208, 541,546-549,552 sympathetic function in, 13, 480, 481,482-484,503,536537,555 Syndrome X and, 442,445 treatment of, 8,8 I , 460, 540 tyramme and, 38,78,81,374 yohlmbme challenge test in, 362,363,540 Hypertrophiccardiomyopathy(HCM) (see Cardiomyopathy) Hypoglycemia, 4, 32, 84, 94, 206, 210,

215,222,227,229,238,340, 464 adrenomedullaryactivationin, 228,248,304,305,306,320, 372,379 awareness of,256,464 epinephrine and, 464 glucagon and, 304,305,464 glucoprivation and, 304-306 glucostatand,238,305,308, 32 1 growth hormone and, 238,464 HPA axis and, 464 hunger and, 304 hypothalamus and, 305 insulin dissipation by, 304 norepinephrineand,305,306, 372 pancreatic polypeptide and, 356 parasympathetic system and, 304 sympathetic nervous system and, 304,306 symptoms of, 256 Hypotension hemorrhagic, 230,300-304, 306 orthostatic, 56, 88, 92, 102, 21 I , 257,284,286,290,335, 337,340,360,364,367,368, 399,455,456,458,461, 462, 463,465,461,469,472, 474, 475,477,478,479,487, 493, 502 (see also Autonomic PAF; MSA; failure; Parklnson’s disease; ShyDragersyndrome;Sympathetic neurocirculatory failure) definition of, 526 delayed, 341,526,527 Hypothalamo-pituitary-adrenocortical

60 I

Itzdes

(HPA)system,217,227-230, 299,319 stress and, 228, 236, 299, 3 18, 319,320 glucose and, 238,305 hemorrhage and, 299,301 hypertension and, 480 interactions with catecholamme systems, 228,229, 3 15, 3 19 pain and, 309 Hypothalamo-pituitary-thyroid axis, 440,44 1,445 Hypothalamus, 140, 149, 150, 154, 157-159,162,163,165,166, 259,357,437,485,491 adrenergic innervation of, 175 adrenoceptors in, 177, 278, 180 anterior, 103, 163, 172, 288 arcuate nucleus of, 146, 167 corticotropm-releasing hormone and, 228 “defense area” of, 246 dorsal, 149, 154,484 “fight-or-flight” and, 3 15 glucose sensors in, 215, 305 HACER (see HACER) lateral, 144, 146, 149, 281, 315, 484 noradrenergic Innervation of, 16G,168, 170,172,177,178, 183 osnloreceptors and, 2 12 paraventricularnucleus of, 68, 144,146,149,154,160-162, 183,230,235,28 1 perifornlcal, 156, 163, 28 I , 3 15 periventricular nucleus, 154, 167 posterlor, 103, 172, 292, 3 15 preoptlc nucleus of, 146, 157

supraoptic nucleus of, 149, 154, 230,232 temperature sensors in, 215, 288,292 vasopressin and, 230 ventral, 178,484 -1-

Immersion, head-out water, 296,298 Immobilization,204,232,304,318, 388,391,392,491 Impotence, 338,400,458,463,471 Inositol triphosphate (IP3), 31, 34, 72, 74 Insulin, 211, 216, 218, 223, 238, 238, 242,321,463 adrenoceptors and, 73 epinephrme and, 61, 82, 107, 229,238,304,305,464 euglycemlc insulin clamp, 238 glucostatic system and, 238, 304,305 hypoglycemiainduced by, 50, 103,248,256,305,356,463 leptin and, 443 parasympathetic nervous system and, 25, 38, 85, 238,280-281, 289,356,396 resistance to, 13, 79, 21 8, 442443,445,546 release of, 215,219,223,238, 320,443 sensitivity to, 227,463,464 sympathetic nervous system and, 289,305,306,367 vasodilatoreffectof, 94, 223, 443,445,464 Integrative medicine, 19, 223, 575, 577,582,584

Index

602

Interveningvariable,

208, 209, 210,

243,26 1

Intracranial bleeding, 485,492, 503 Isoproterenol, 75, 89 B-adrenoceptors and, 70, 89, 102,230,349,373

effects of, 349,460 hyperdynamic circulation syndrome and, 528,553 infusion of, 364 mitral valve prolapse and,529 nonneuronal uptake and, 52, 54,

358, 367, 371, 528,

LC (see Locus ceruleus) LCED (liquid chromatography with electrochemicaldetection) (see HPLC) L-Dihydroxyphenylserine (see LDOPS) L-DOPS, 92,46 I , 462,466,475,476 Leptin, 162,443,445 Limblc System, 163-165, 166, 168, 173, 184,315

Locus ceruleus (LC), 40, 60, 145, 146,

89, 106,493

norepinephrine release by, 373 [3H]-labelled, 493 posturaltachycardiasyndrome and, 553 pure autonomiac failure and, 460

tachycardiaresponseto,

460,

528,529,553

tilt-table testing and, 349, 364 -JJob stress (see Stress, job) -K-

Kolliker-Fusenucleus,

49,285, 544

144, 145, 146,

147, 148,149

-L-

L-aromatic-amino-acid decarboxylase (DOPA decarboxylase, DDC, LAAAD), 39,41,43,53,370, 390,495

carbidopa and, 390,476 deficiency of, 497-498 Lateral tegmental system, 168, 170 LBNP (lower body negative pressure),

151, 152, 154-156, 147, 150, 156,161,164,166,168,178, 183,237,281 adrenoceptors in, 154, 176, 1 80 cell firing, 154, 155, 176 functions of, 141, 153, 155, 164, 172-174, 176, 180, 183, 184

noradrenergic projections from, 146,154,154,164,166,168, 169, 170 projectionsto, 153, 154, 164, 183 stress and, 208

sympathetic nervous system and, 155, 174,176, Loewl, Otto, 5, 6, 7,27, 280 Lorenz, Konrad, 244,252 -M-

Magnocellular cells,

149, 159,

160,

170,230,232

MAO (monoamine oxidase),41, 55-56, 394,395,397,398

deficiency of,500-501 MAO-A, 12,55,88,392,393

603

Index

MAO-B, 55,88,92,392,393 inhibitors of, 55, 88, 92,374 metabolism of dopamineand, 55, 57, 370,383,389,392, 393, 494

metabolism of norepinephrine and, 53,5557,59,370, 383, 389,433,494 Medianeminence, 149,160,165,166, 167,232 Medulla, 27,28,36,137,141, 144154, 154,167,170,281,305, 307,357 adrenal, 3, 1 1, 12,37,47,56, 61,62,65,107,141, 200, 215, 230,258,368, 379, 388,400, 463,465,469

ventrolateral caudal (see CVLM) dorsal motor nucleus of the vagus nerve In, 139, 16 1 dorsomedial, 153, 154 nucleus ambiguus in (see nucleus ambiguus) nucleus of thesolitarytractin (see NTS) ventrolateral rostral (see RVLM) Melanocyte-stimulating hormone (MSH, y-MSH), 237 Memory, 83, 141,142, 158, 159,172, 173,174, 183,247,255,471 clinical evaluation of, 343, 344 distress and, 164, 165, 184, 240,247 hippocampus and, 164, 173 norepinephrineand, 173,174, 184

MEN

Multiple endocrine neoplasia) (see

Menkes disease, 16,43,391,393,499 Mesolimbic, 17 1, “Metabolic syndrome,” 14,442-444 Metanephrine(MN), 12,56, 58, 360, 370,394,401

Methyldopa(a-methylDOPA), 43,86, 91, 180,375,486,528

Methylnorepinephrine (aMethylnorepinephrine), 43,86, 91, 180,375

MFB(medialforebrainbundle),

159,

169,316

(methoxyhydroxyphenylMHPG glycol,MOPEG)

, 53,57,59, 370, 389, 394, 434, 439,466, 494,496,536 3H-labelled, 395 sources of in plasma,395

MIBG

(meta-iodobenzylguanidine),

396,401,426,463 Microdialysis, 64, 172,395-396 clinical, 395-396

Milieu intkrieur, I O Mitralvalveprolapse,

16,525,529,

532,554

MN (see Metanephrine) Monitored variable, 19, 211, 212, 213, 214,216,217,219,220, 222,224,233,261,295,306, 357,421,578,579

221,

Monoamine oxidase (see MAO) MSA (multiplesystematrophy,ShyDrager syndrome), 15, 18, 239, 339,341, 344, 355, 365,397, 456, 469,470,472,474,478, 480

parasympathetic faillure and, 477-478

MSNA

(see Skeletal muscle sympathetic activity)

604

plasma cardiac

Index

a-MT (a-methyltyrosme, a-methylpara-tyrosme, a-MPT), 41, 91, 375 Multipleendocrineneoplasla, 15, 99, 339,362,442.489 Muscarlnlc, 35I , 352 inhibition norepmephrlne of release, 32,46. 103, 105 neurotransmisslon, 7 receptors,29, 30, 31, 32, 34, 62,85, 103, 105, 176,352 atropineand,103,105, 365 nitrlc oxide and, 66,443 MyocardialInfarction,423-429, 43 1, 437,548 arrhythmlas and, 426-429 D-adrenoceptors and, 100 cardiac sympathetic actlvlty and, 104,219 coagulatlon necrosls in, 490, 49 1 distress and, 251,427,445 on effects catecholammes, 307,43 I , 444 on effects sympathoneuralfunction,423425,444 morning incidence of, 100 prognosis in, 428 stress and, 548, 549,550

-NNA (see Nucleus ambiguus) Naloxone, 179, 237, 308 Natriuresls, 64, 78,81,84, 107, 296, 297,298,386 NE (see Norepinephrme) Negativefeedback,19, 40, 217,218,

244,261,444,445,578 Neurasthenia,16,141,525,526,528529 Neuroblastoma, 43,390,401 Neurocardiogenic syncope (see Syncope) Neurocardiology, I , 13, 20, 336,341, 373,455,575,584 Neurocirculatory asthenia (see Neurasthenia) Neuroendocrinology, 259 Neurogenetic diseases, 493-501 Neuropeptide Y (see NPY) Neurotrophicfactors, 97, 98, 99, 100, 108,477 NGF (nerve growth factor), 9, 99 angiotensin and, 482 catecholamines and,99 discovery of, 97 dorsalrootganglionand, 98, 308,309 familial dysautonomia and,468 immunosympathectomy and, 97, 108,484 pain and, 534 receptor, 97,98,468 spontaneously hypertensive rats and, 97, 108,482,483,484 sympathetic nervous system and, 108,308 Nicotine, 7, 15, 34, 38, 8 5 , 104, 108 Nicotinic, 13, 546 neurotransmission, 7,44, 105 receptors,29,33-35, 51, 62, 105

adrenomedullary secretion and, 105, 108 catecholamme release and, 44

Index

norepinephrine release and, 46, 85 Nigrostriatal, 92, 167,171,184,384. 469.479 Nitric oxide (NO, EDRF, endotheliumderived relaxing factor), 34, 6670, 142,537 acetylcholineand,29,31,32, 66, 105,282,338,443 autonomic outflows and, 67, 68, 107 cGMP and, 3 1 endothelin and,69 insulin and, 443,445 muscarinicreceptorsand,29, 105,443 neurotransmission and, 66,282 nitroglycerine and, 338 nitroprusside and, 443 norepinephrine release and, 27, 47,66, 85 production of, 48 sexual function and, 282,338 synthase, 3 1,40, 68 tetrahydrobiopterin and, 40 vasodilatoreffectsof,27,31, 66, 105, 107,282,443,445 Nitroprusside,67,68,94, 155, 286, 367,382,443,484,486,544 NMN (see Normetanephrine) NO (see Nitric oxide) Nociception, 154, 156 Norepinephrine (partial listing), 8,370 adrenoceptors and,7,70-78, 86, 106,177-181,229,231,234, 374,400,460, 477, 480,491, 542 aging effects on, 101-103, 377 assays of, 369, 387 “fight-or-flightl’and, 309-316

605

aldehyde reductase and, 55-57 arrhythmias and, 21 8, 307, 428, 438 blood pressure and, 21 1,362 in braln, 83, 141, 144, 156, 167, 169-175,176,177,460,470, 476,487,536,555 lC-labelled, 396, 397 in cerebrospinal fluld, 439,461, 466,496 cholinergic stimulation and, 103 clonidineand,360,374,488, 540 cold and, 293,44 1 COMT and, 12,55,394 corticotropin-releasing hormone and, 228 dopamine-&hydroxylase and, 43,291,352,391,393,466, 499 deficiency of, 466,467 depletion of, 14, 17 depression and, 375,438 DHPG and,12,88,386-387, 401,488 effects of, 8, 32, 50, 64, 67, 69, 80, 81, 82, 101, 106,177,184, 218,231,233,362,429,432, 441,442,443,445,491,527, 540,541,542,547 “epinephrinehypothesis”and, 542 exercise and, 286-289,425 familial dysautonomia and, 468 “fight-or-flight’land, 309-316, 53 l fluorinated, 396, 397 ganglion blockade and, 363, 364,382,465 glucagon and, 361

606

Index

glucoprivation and, 303-305 Guillain-Barre syndrome and, 502 heartfailureand,14,17,35 1, 433-436,445 depletion in, 434-435 post-operative, 487 prognosis in, 435-436, 445 heart, 218, 378, 425, 425, 492, 493 hemorrhage and, 299-303 HPA axis and, 229 hypertension and, 362 essential, 536-546 neurogenic, 485-486, 539,545 spontaneously hypertensive rats and, 482-485 hypothyroidism and, 441,442 L-DOPS and, 461,467,476 locusceruleusand,141,152, 154-156, 176-177, 184, 208, 470 MHPG and, 395 microdialysate levels of, 395 mitral valve prolapse and, 529 monoamine oxidase and, 12, 54, 88-89,92, 374, 392,500 myocardialinfarctionand,307, 423,425,428,429 neurasthenia and, 529 neurovascular compression and, 545 normetanephrineand,12,360, 394,40 1 opioids and, 237-238 orthostasisand,284-286,358, 456,458,463,473 pain and, 308,465, 534

panic and, 439 Parkinson’s disease and, 479 pheochromocytoma and, 374, 391,394,401,487-488 plasma levels of, 12, 17,49, 50, 51, 66,69, 93, 96, 97, 101, 158, 182,228,229,230,238,257, 284,285,293,299,300,305, 306,307,318,351,361,362, 371-379,388,392,394,395, 400,423,429,433,438,439, 441, 458, 462,464,465,468, 473,477,488,493,502,529, 531,536,540,544 essential hypertension and, 537-540 kinetics of, 375-379, 539 PNMT and, 61,63 posturaltachycardiasyndrome and, 527-528 pure autonomic failure and, 459,460,461 recycling of, 17, 58-60,389 release of, 9, 12, 18, 27, 30, 32, 36,44-46,49,50,51,66,70, 78,81,82,85,86,87,94,99, 103,106,152,175,218,237, 238,291,356,362,372,376, 379,385,387,389,391,391, 400, 401, 425,427,433,438, 441,443,456,461,466, 473, 475, 477,480,487,528,531, 532,536,539,542,543,554, 555 renin-angiotensin-aldosterone systemand,17,234-236,285, 362,540,55 1 Shy-Drager syndrome and, 473, 474,475,477

607

Index

spillover of, 17, 18,48,49, 101, 102,218,285,289,351,371, 372,373, 375-379, 387,397, 398, 400, 423, 425, 429, 433, 434,438,459,460,464, 465, 473,474,477, 479, 532,533, 539,542 storageof, 17, 97,374,399, 467,554 stressand, 164,208, 228, 250, 291,294,298,300,377,379, 480,535,536,541,555 saltintakeand, 295-296, 542543

sympathetlcnervetrafficand, 48,257,367,400

sympathetic neurotransmitter, 7, 8, 9, 11, 36, 63, 99, 106, 368

sympathomimetic amines and,

vasopressin and, 23 I , 285 vesicular leakage of, 12,373, 387,425

vesicular translocation of, 9, 60, 87, 106,499

yohimbineand,

337, 361-362, 374,461,475,528,540-541, [3H]-labelled, 50, 376, 395, 433,459,460,465,493 Normetanephrine (NMN), 53,59,370, 389,434,500 acetaminophen and, 394

adrenal chromaffin cells and, 57,394

COMT and, 56,58,304 MHPG and, 57,394 monoamineoxidasedeficiency and, 500 pheochromocytoma and, 360,

89-91,374,460,475

394,40 I , 489,50 1

neurocardiogenicsyncopeand,

plasmalevelsof,12,

531-533,554

489,501

reflex sympathetic dystrophy and, 534-535 synthesis of, 38-44, 62,87,91, 92,106,230,352,388,391, 393, 401, 459, 467,468, 477, 480,495,499 turnoverof, 12,391,395,401, 459,468,499 Type A and, 17,55 1 tyramineand, 363, 365, 374, 375,460,476

extraneuronal uptake,of (Uptake-2), 53-54, 93, 106,394 uptake, neuronal of (Uptake-l), 9, 12, 51-53,63,86,87,88, 101, 106,177,356,372,387, 394,425,433,459 urine, 1 1, 62, 299, 378, 536

394,395,

sulfoconjufation of, 394 Uptake-l and, 52 Uptake-2 and, 57 Norrie disease, 500 Novelty, 248, 293, 294,318-319 NPY (neuropeptide U), 50, 144 co-transmission and, 47, 106 exocytosis and, 45 modulation of norepinephrine release and, 47, 85 NTS (see Nucleus of the solitary tract) Nucleus ambiguus (NA) a2-adrenoceptors in, 183 baroreceptors and, 151, 152, 184

degeneration of, 355,470 pathways to, 142, 148, 149, 150, 152, 182

608

Index

vagal outflow and, 28,29, 182, 184

Nucleus of thesolitarytract(NTS),

179,237

138, 149-152, 167, 172 A 2 cells and, 175, 183 a2-adrenoceptors in, 178 angiotensin and, 235,236 baroreceptors and, 138, 147, 151-152, 160,284 168, 175, 357, C 2 cellsand, 544 “defense reaction” and, 246, 484 lesions of, 152, 163,224,232 nitric oxide and, 68, 69 projections from, 144, 145, 146, 147, 150, 151, 155, 158, 160, 161, 182,281 projections to, 146,147,148, 149,150,152,154,156,160, 162,163,164,165,172,182, 232,281,284,357 salt hunger and,295

stress and,237, 3 18,320, 535 syncopeand, 317,318,321 Orthostasis, 226,256, 283-286, 360, 396,530

adjustments to, 283-286, 345 climbing snakes and,256 in mammals, 256 plasma norepinephrine and, 367,458,468,473,486

posturaltachycardiasyndrome and, 526-527 renin-angiotensin-aldosterone system and,285 sodium excretion and, 286 space flight and,298 stress and, 318, 321, 358 sympathetic nervous system and, 257, 284-285, 320, 345, 367,400

sympathetic neurocirculatory failure and, 340, 358, 400, 455, 458,468,473

-0-

Oliver, George, 3,4 OMeDOPA (O-methyldihydroxyphenylalanine,methoxytyrosine, 3MT), 370,383,390,394,495 Opioid endogenous, 236-238 hemorrhage and, 301,302,303 modulation of norepinephrine releaseand, 47, 8 5 , 179,237,

syncope and, 576 Orthostatic hypotension (see Hypotension, orthostatic) Osler, William, 16,43 I , 528, 535, 549 Osmolality “osmostat”and, 212, 213,218, 231,231

vasopressin release and, water deprivation and, 299 lamina terminalis),

and,

165, 166

23 8

pain and, 236,308, 321

213,

218,230,231

OVLT (organumvasculosum

238

naloxone and, 237 norepinephrine brain in

receptors, 236, 238 1x2-adrenoceptors and,

-P-

of the 149, 163,

609

Index

PAF

autonomic (pure failure, Bradbury-Egglestonsyndrome), 15,458-461 catechol levels in, 459 clinicalfindingsin,338, 456, 457,458

DHPG levels in, 459 L-DOPA levels in, 388,459 norepinephrine and, 18, 397, 459 pancreatic polypeptide and, 356 pathology in, 458,460 PET and, 18,397,399,459 pharmacologicaltestsin, 285, 460 “sympatheticneuralprosthesis” and, 2 1 1 treatment of, 460,461 Valsalva maneuver and, 456, 457,459 vasopressin levels and, 285 Page, I.H.., 490,491 Pain, 307, 321,337, 343, 374,425, 430,431,436, 439, 468,494, 526,528,529, 530, 534,535, 555 Painfuldiabeticneuropathy,15,464465 Panidanxiety, 14,15, 336, 340,344, 364,439-440,527 Parabrachialnucleus,144,146,147, 151, 152, 161 Parasympathetic nervous system (PNS), 25-35,320 acetylcholine and, 26, 28 autonomic nervous system and, 25 baroreflexes and, DBH deficiency and, 466

gastrointestinal function and, 280-281,289 hypertension and, 480,539 insulin and, 281 myocardial infarction and, 428 syncope and, 3 17,322,437 urinary bladder and, 30 vegetative processes and, 25 Paraventricular the nucleus of hypothalamus (PVN), 151, 158, 160-162,235 adrenoceptors in, 178 depression and, 175 leptin and, 162 magnocellular cells in, 149, 160 nitric oxide and, 68,69 parvocellular cells in, 160, 162, 183,232 pathwaysfrom,144,145,146, 147,158,160-162,165,183, 236 pathways to, 148, 149, 159, 160-161, 165, 281 noradrenergic,170, 183 stimulation of, 162, 246, 543 sympathetic outflows and, 232, 543 Parkinson’s disease, 29, 182, 344,472 autonomic failure in, 16, 18, 339, 340, 384,459,460,470, 472,473,474,478-480,503 braindopammeand,167,184, 379 COMT inhibitors and, 93 familial, 339 L-DOPAtreatmentof,43,92, 390,477,479 Lewy bodies in, 459,470 MAO-B inhibition and, 56,93 movement disorder in, 171

610

Index

PETscanningand,399,478, 479 sympathetic denervation in, 396,397 Valsalva maneuver in, 456,457 Parvocellular cells, 159, 232 PC 12cells, 5 I , 480 PET(positronemissiontomography), 158 I3N-ammonia, 532 6-[18F]fluorodopamine, 18, 397-399,459,465 IC-hydroxyephedrine,463 PGi (nucleus paragigantocellularis lateralis), 144, 153, 154, 155 Phenolsulfotransferase (PST), 64, 370, 380,382,383,384,499 Phenylalanine hydroxylase (PAH), 40, 41,495 Phenylethanolamine Nmethyltransferase (see PNMT) Pheochromocytoma, 13, 3 15,353,364, 439,487-490 a-methyltyrosine and, 90,92 cardiomyopathy in, 49 1,492 clinical findings in, 90,487 clonidinesuppressiontestand, 360-362,364,374,400,487488 glucagonstimulationtestand, 362,400,488 hypertensionand,15, 90, 337, 360,361,486,489,503 “lncidentaloma” and, 489 malignant, 43, 390, 391,489 metanephrines and, 13, 57, 360, 394,401,487,489,501 multiple endocrine neoplasia and, 99,442 “pseudopheochromocytoma”

and, 16,384,490 von Hippel-Lindau disease and, 362,489,501 Pituitary-adrenocortical system (PACS) (see also Hypothalamopituitary-adrenocortical (HPA) system) 227-230,480 adrenomedullary system and, 1 I , 24, 62, 208, 228, 246, 248, 249,3 15,320 distress and, 208, 228, 239, 246, 248-249, 262,3 18, 320 exercise and, 289, 322 feedback regulation of, 217, 228 “giving up” and,204,3 18 glucose and,219,238,305,322 hemorrhage and,299,301,322 novelty and,204,3 18,320 pain and, 236,309, 322 post-traumatic stress disorder and, 535 stressand, IO, 1 1, 203,204, 207,208,214,227,261,279, 318,319,322,535 Protein kinase (PK), 9, 33,45, 71,74 Plasma renin activity ( P M ) (see also Renin-angiotensin-aldosterone system), heart failure and, 433 heart transplant and, 286 hemorrhage and, 300 6-hydroxydopamine and,236 hypertension and, 17, 363, 540, 541,551 immersion and, 298 orthostasis and, 285,286,527 salt intake and, 295 sympathetic nervous system and, 367

61 I

Index

(phenylethano1amine-NPNMT methyltransferase), 58, 61-63, 175,370,495 Cl cells and, 175 glucocorticoid and, 229,230 nervous PNS (see Parasympathetic system) POMC (pro-opiomelanocortin), 237 Positive feedback, 42 loop, 19, 99, 218-219, 244, 304,307,317,322,424,427, 436,443,575,576,578 in heart failure, 21 8, 219,436 in diabetes, 2 18,443 in distress, 244 in hemorrhagic hypotension, 304 in myocardial infarction, 2 19,424, 427 in syncope, 3 17,322, 575,576 Positronemissiontomographic(PET) scanning (see PET) Post-prandial state, 289-290, 336 angina pectoris in, 290 hypotension,18,223,337-338, 341,461,462,475,502 plasma norepinephrine and, 290 autonomic pattern in, 290, 320 PRA (see Plasma renin activity) Predictability, 248,318-319, 548 PrH (nucleusprepositushypoglossi), 153, 155 Primitive specificity, 1 I , 259-261, 320, 372 Prognosis, 373,455,478,480 in heart failure, 14,435 in hypertension, 546

inmyocardialinfarction,307, 429,445 Prolactin, 73,304, 25 1 Prostaglandin, 47, 85,298 "Pseudopheochromoctyoma,"

(see

Pheochromocytoma) Purinergic neurotransmission, 47 PVN (see Paraventricular nucleus)

-QQT, 438,492 Quadriplegia, 15, 285, 386, 502

-RRaphenuclei,60,144,146,147, 153, 160,178 RAS (see Renin-angiotensinaldosterone system) Reflexsympatheticdystrophy(RSD) (see Complex regional pain syndrome) Reinforcement, 17 1, 173,242-243,246 Renin, 233, 25 1 (see also Plasma renin Renin(PRA); activity angiotensin-aldosterone system) secretion of, 73, 80,2 19, 234 Renin-angiotensin-aldosterone system (RAS), 233-236,321 activity of, 61, 82, 93, 107, 217, 222,234,257,259,286,289, 296,298,299,300,304,320 baroreceptors and, 213, 236, 286,300 in brain, 235 heart failure and,432,433 hemorrhage and, 300-303 hypertension and, 163, 234, 363,481,537,539,540-541,

612

55 1 orthostasls and, 527, 553 salt intake and, 295-296 sodium and, 214, 217, 222, 233,257,298,320,541 interactions with catecholamine systems, 234-235, 236, 541 orthostasis and, 283-285 water deprwation and, 299 Reserpine,42,60,61, 88, 375, 433, 492 “Reservoirs of power,” 5 Resetting homeostat, IO, 140,158,226, 262,481,578,584 distress and,239,246, 247,262,308 baroreflex,152,257,260, 480, 537,543-544 Reward,171,173,242,552 (see also Reinforcement) RVLM(rostralventrolateralmedulla), 67,144-147, 153 ablation of, 154 adrenoceptors in, 179, 18 1 amygdala and, 164 baroreceptors and, 152 Cl cells in, 168, 175, 183 clonidine and, 180 sympathetic nervous system and, 67, 138, 139, 143-147, 157, 162, 173, 181, 183,484 hypertension and, 105, 545, 486,545 hypotension and, 15I , 180, 18I , 484 nitric oxide and,67, 68, 69 pacemakercellsin,175,183, 216 pathwaysfrom,144,146,147,

Index

153,154,157,162,164,175, 182 pathways to, 145, 149, 150, 152, 162, 182, 183 respiration and, 147 Shy-Drager syndrome and, 469 stress and, 484 -S-

Salivation, 4, 5, 29,35,38,86,242, 280,314,538 Salt intake, 295-296 sensitivity, 542, 543 Schizophrenia, 141, 167, 182, 184, 336 Seizures,14,15,172,485,495, 496, 499,500,502 Self-selection, 552, 555 “Selfish gene,” 254, 255,260,482 Selye,Hans, I O , 200,202,205,206, 208,239 “adaptation energy” and, 202 circularities and, 202-203 “conditioning factors” and 202, 206,547 “diseasesofadaptation”and, 201,202,208,250,421 distress and, 201, 202, 204, 21 6,248,249,250 doctrine ofnonspecificity and, I I , 200,201,204,205,207, 208,216,222,248,26 1 GeneralAdaptationSyndrome and, 200-204,248 pituitary-adrenocortical system and, IO, 203,227,228,261, 279,49 1 Serotonin (5-HT) , 175 a2-adrenoceptors and, 181

Index

5-HIAA and, 41,495,496,498 5-hydroxytryptophan and, 496 LAAAD and, 497,498 MAO and, 41,500,501 reserpine and, 88, 375 sympathoneural outflows and, 153 tetrahydrobiopterin and, 4 I , 495 transporter, 54 Sexual activity, 141, 158, 239, 282 S F 0 (subfornical organ), 159, 160, 165-166, 183, 232, 235 “Sham rage,” 3 15 Shock, 81 anaphylactic, 307 circulatory, 81,307,422 defibrillatory, 212,307 electric,160,172,242,31 8, 49 1 endotoxic, 307 General Adaptatlon Syndrome and, 200 glucocorticoid and, 227 naloxone and, 237 SHRs (spontaneously hypertensive rats), 482-485, 537 dopaminereceptorsand, 484, 543 NGF and, 98,482,485 plasma catechol levels, stress responses in, 483-484, 54 1 sympathetic nervous system and, 482-485 cardiovascularhypertrophyin, 485 SIF (smallintenselyfluorescent)cells, 258 Silent ischemia, 430 Simulation,141,142,183,240,255,

613

582 Skeletal muscle sympathetic activity (SMSA, MSNA),366 adiposity and, 444,445 aging and, 377 baroreceptors and, 365, 543 heritability of, 254 hypertension and, 17, 222, 537, 543 insulin and, 238 leptin and, 444,445 LMMA and, 66,70 orthostasis and, 527 plasma norepinephrine and, 86 salt intake and,542 in Shy-Drager syndrome, 475 vasopressin and, 233 weightlessness and, 299 yohimbine and, 86 Smith, Orville, 3 15 (see Skeletal muscle SMSA sympathetic activity) SNS (see Sympathetic nervous system) SON (see Supraoptic nucleus) Spectral analysis heart rate of variability, 280, 350-351,396, 463,53 1 Spillover, norepinephrine (see Norepinephrine, spillover of) SPN (see Sympathetic preganglionic neuron) Starling’s law of the heart, 21 8 Stress, 5 autonomic systems in, 279-322 Cannon and, 83, 199,200, 205206 definition of, 210 distress and, 239-251 emotional, 8 I , 104 homeostatictheoryof,10-11,

614

208-226 in evolutionary perspective, 251-259 insulin and, 238-239 job, 551-553 locus ceruleus and, 172, 174 hypothalamo-pituitaryadrenocortical system and, 227230 opioids and, 236-238 system; post-traumatic, 16, 174 primitive specificity of, 259-261 renin-angiotensin-aldosterone system and, 233-236 Selye and, 200-205 theories of, 199-208 vasopressin and, 230-233 Stroke, 15,91, 335,491,492,503,583 Substantianigra (SN), GO, 167,178, 184,459 Sudden death, 14, 237, 251, 424, 428, 436-437,474,491,493, 549 Sulfoconjugation, 12, 13, 66, 380, 38 I , 383 Supersensitivity,denervation,78,356, 365, 426, 429,460,462,493, 527,534 Supraopticnucleus (SON), 141,149, 151, 161, 170, 178 Sweating, 5, 8, 21 5, 247,288,339, 352,353,471 emotional, 8 exercise and, 288 hypothalamus and, 292 pheochromcytoma and, 353 QSART and, 354,400 thermoregulatory, 291, 352, 353,400 Sympathetic microneurography (see Skeletal muscle sympathetic

Index

activity) Sympathetic neuroimaging, 396-399 Sympathetic preganglionic neuron (SPN), 36,37,38,67,94,99, 106,138,141,143,144,147, 149,151,153,154,157,158, 161, 162, 167, 170, 175, 183 Sympathico-adrenalsystem,206,260, 371, 536 (see also Sympathetic nervous Adrenomedullary system) Cannonand,24,35,199,200, 304,308 pain and, 308 Sympathetic nervous system (SNS, sympathoneural system), 24-25, 35-63, 64 aging and, 101-103 Bernard and, 2 central neural regulation of, 137-166 cholinergicinhibition of, 103104 clinical evaluation of, 335-401 medical history and, 335-340 neurochemical tests and, 368-396 neuropharmacological tests and, 357-365 neurophysiological tests and, 365-368 physical examination and, 340-344 physiological tests and, 345-356 sympathetic neuroimaging and, 396-401 co-transmission in, 47-52 embryology and development

615

Index

Of, 96-100 Galen and, 1 heart failure and,433-436 myocardial infarction and, 423429

mysterious controversial or entities and, 525-555 chronic fatigue syndrome and, 530533

essential hypertension and, 536-546 postural tachycardia syndrome and, 5265 29 mitral valva prolapse and, 529-530 neurocardiogenic syncope and, 530-533 post-traumatic stress disorder and, 535-536 reflex sympathetic dystrophy and, 533-

carotid sinus, 15, 533 “collapse firing” hypothesis of, 53 1 distress and, 183, 318 “giving up” and, 318 isoproterenol and, 364 neurocardiogenic (vasodepressor,vasovagal),14, 19,317,437 adrenomedullary stimulation in, 531-532

chronicfatiguesyndromeand, 16 precipitants of, 317,531 sympatheticinhibitionin, 526, 530-533

treatment of, 532-533 post-prandial, 336 tilt-table testing and, 349, 400 “Syndrome X,” (see Metabolic syndrome) “Syntoxic,” 20 1 -T-

535

neurocardiologic disorders and, 421-445,455-503

noradrenergic neurotransmission in, 36-38 norepinephrineinactivationin, 52-61

norepinephrine synthesis in, 38-

Temperature (see also Thermoregulation), body, 158,342,353,355 birth and, 245 exercise and, 288 regulation of, 21 5, 247,

44

norepinephrinereleasein, 41

stress and, 279-322 urinary bladder and, 30 Sympathin, 6, 7, 8,368 Syncope aortic stenosis and,344 baroreflex failure and, 486

255-256,441,498

44-

environmental, 82, 343, 377, 47 l cold, 97, 206, 260,292294

heat, 290-292, 3 17, 353 reef corals and, 255 feedback about, 21 1 house, 220,222

616

sensors,215,288,440,464, 468 skin,3,313, 341, 342,344, 533,534,554 Tetrahydrobiopterin,41,370, 500 DHPR deficiency and,393,495 nitric oxidesynthaseand,32, 40 synthesis and recycling, 40 tyrosinehydroxylaseand,40, 42,370,391,499 Tetrodotoxin, 87 TH (see Tyrosine hydroxylase) Thirst,259,299,321 (see also Water deprvation) angiotensm I1 and, 165, 236 Thyrotropin-releasing hormone (TRH), 161, 172, 181 Tilt-tabletesting, 349, 364, 400, 532, 554 Transfusion, 296,298 Transplant heart, 286,352,393,435,53 1 pancreas, 463 Trembling, 321 epinephrine and,83,3 12, 3 14 fear and, 310-312,314, 321 neurasthenia and, 528 sympathetic stlmulation and, 35 yohimbine and, 3 12 TRH (see Thyrotropin-releasing hormone (TRH also is an abbreviation tryptophan for hydroxylase) Tricyclicantldepressants,54, 88, 107, 176,338,439 Trimethaphan, 34,38, 85,94,348,364, 382,465,474 Shy-Drager syndrome and, 475, 479

Index

Type A behaviorpattern,13,16-17, 429,541,546,548,549-551, 552 Tyramine, 15,384 C l region and, 172, 173 “cheese effect” and, 374 in food, 56, 337, 374 MAO inhibitorsand,56,89, 337,374 mydriasis and, 356 myocardial hypertrophy and, 485 pheochromocytoma and, 488 plasma norepinephrine and, 363,374 pressor responses and, 363 pure autonomic failure and, 460 Shy-Drager syndrome and,460, 476 stimulation test,365 sympathomimeticaminesand, 89,90,337,374 Tyrosine hydroxylase (TH), 38-42, 53, 106, 151, 171,370,383 cc-methyltyrosine and, 90 in brain, 180,469,470 deficiency of, 16,500 DHPR deficiency and, 495 diet and, 384 L-DOPAlevelsand, 12, 388392 DOPAC levels and, 392-393 gastrointestinaltractand,66, 382 hypertension and, 546 knockout of, 494 modulation of,5 1 norepinephrine stores and,60 reserpine and, 88 sympathetic ganglia and, 458

61 7

Index

tissue localization of, 43,483

-uUCR (see Unconditloned response) UCS (see Unconditioned stimulus) Unconditioned response (UCR), 242 Unconditionedstlmulus(UCS),173, 242 Uptake-l (see Norepinephrine,uptake, neuronal) Uptake-2 (see Norepinephrine, uptake, extraneuronal)

-vVagus nerve, 6.321 afferents in, 150 baroreflex and, 2 13 blockade of, 486 dorsalmotornucleusof,150, 167 glucose regulation and, 238, 305 heart failure and, 432 hemorrhage and, 301 meal ingestion and, 28 1 orthostasis and, 283 parasympathetic neurotransmission and, 27 syncope and, 576 "Vagusstoff," 6, 27, 280 Vasalvamaneuver,18, 101, 226,345341,349,350,358,364,366, 400,456, 451, 459, 462, 466, 473,477,478,502,526 Vanillylmandelicacid(VMA),53,57, 370,394,395,496,500 Vasodepressor reactions (see Syncope) Vasopressin (AVP), 230-233, 259,

319,320,321,481 AI cells and, 170, 183,232 ACTH release and, 232 adrenoceptors and, 73, 178, 181,230,231,232 angiotensin I1 and, 165, 236 baroreflexes and, 213, 231, 232, 286 Brattleboro rats and, 254 cardiopulmonary filling and, 217,284,286,295,296,298, 299 cardiovascular collapse and, 307 CVLM and, 149 effector sharing and, 214, 222 exercise and, 289, 319 exogenous, 23 1 glucose and, 304 heart failure and,432,433 heart transplant and, 286 hemorrhage and, 300-302 hyponatremia and, 303 in vasodepressor reactions, NTS and, 232 orthostasis and, 283,285,286 osmolality and, 165, 213, 295 OVLT and, 165 platelet activation and, 83 PVN and, 160-161 renin-angiotensin-aldosterone system and, 234,299 salt intake and, 295, 296 sympathectomy and, 233 syncope and, 317,318,322 water deprlvation and, 230. 295,299 weightlessness and, 257 Velo-cardio-facial syndrome, 501 Ventricularfibrillation, 86, 212,237,

618

medullary

Index

307,427,428,429 Vesicular monoamine transporter (VMAT), 46, 60-61,66, 370 Vigilance, 73, 153, 155, 172, 174, 176, 184,207,224,240,535,554 VIP (vasoactive intestinal peptide), 47, 85 Vitalism, 1, 2, 203 VMA (see Vanillylmandelic acid) VMAT (see Vesicular monoamine transpoter) VNB (ventral noradrenergic bundle, ventral catecholamine bundle), 170 von Hippel-Lindau disese, 15, 339, 362,489,501 Volustat, 213, 214, 222, 230, 236, 283, 295,321,357 “Voodoo death.” 3 18 -W-

Water deprivatlon, 212-213, 216, 230, 299 Weightlessness, 257,296, 298,299

- XYZ Yohimbine, adrenoceptors and, 72, 176 anesthesia and, 179 challenge test, 17, 361-363, 374,400,540-541 in brain, 180, 374 effects of in SHRs, impotence and, 340 panidanxiety and, 439 post-traumatic stress disorder and, 536,554 posturaltachycardiasyndrome and, 528 salivation and, 280 Shy-Drager syndrome and, 363, 460,461,475,476,477,479 sympathetic nervous system and, 47,86 syncope and, 53 I , 532 trembling and, 3I2