Color Atlas of Physiology [7 ed.]

Table of contents :
Cover
At a Glance
Title Page
Copyright Page
Contents
Preface to the Seventh Edition
Preface to the First Edition
From the Preface to the Third Edition
1. Fundamentals and Cell Physiology
2. Nerve and Muscle, Physical Work
3. Autonomic Nervous System (ANS)
4. Blood
5. Respiration
6. Acid-Base Homeostasis
7. Kldneys, Salt, and Water Balance
8. Cardiovascular System
9. Thennal Balance and Thermoregulation
10. Nutrition and Digestion
11. Hormones and Reproduction
12. Central Nervous System and Senses
13. Appendix
Further Reading
Index

Citation preview

Stefan Silbernagl Agamemnon Despopoulos 7th Edition

basic sciences

~Thieme

At a Glance 1

Fundamentals and Cell Physiology

2

2

Nerve and Muscle, Physical Work

46

3

Autonomic Nervous System (ANS)

82

4

Blood

92

5

Respiration

112

6

Acid-Base Homeostasis

146

7

Kldneys, Salt, and Water Balance

156

8

Cardiovascular System

198

9

Thennal Balance and Thermoregulation

234

10

Nutrition and Digestion

238

11

Hormones and Reproduction

280

12

Central Nervous System and Senses

328

13

Appendix

394

Further Reading

413

Index

415

Color Atlas of Physiology 7th edition Stefan Silbemagl, MD Professor Institute of Physiology University of Wiirzburg Wiirzburg, Gennany

Agamemnon Despopoulos, MD Professor Formerly: Ciba Geigy

Basel, Switzerland 201 Color Plates by Ruediger Gay and Astrled Rothenburger

Thieme Stuttgart · New York

Delhi · Rio de janeiro

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Plate 1.1 Internal and External Environment A. Unla!llulilr organl110 In the mnlitilnt externill environment of the prfmonllill 5eil Primordial

~

Slgnll reception

Hm

.(-~~

/

B. Mainbenilnce of a litilble internal environment in humans - - - - - - - - - - - , ..._.,on through neNOtJs system

and hormones

Emf"'onof heilt

(wab!r, s.alt)

Blood}~ cel/uklr

- - - lntmtlce /

spoce

lntrrJrellular spcce

Elll:rellon

ofexas:s - wab!r

Wilsie ilnd

- s.alts -adds

taxlns

ElKn!llonof waste ilnd taxlns

3

4

.....

The Body: an Open System with an Internal Environment (continued) II> sponsible for the exchange of gases (02 in- are disciplines that border on physiology, true take, col elimination), the liver and kidney for bridges between them and physiology have the excretion or waste and foreign substances, been established only in exceptional cases. and the skin for the release of heat The kidney and lungs also play an important role in regulating the internal environment. e.g., water Control and Regulation content, osmolality, ion concentrations, pH In order to have useful cooperation between (kidneys, lungs) and ~ and COz pressure the specialized organs of the body, their functions must be adjusted to meet specific needs. (lungs)(-+ B). The specialization of cells and organs for In other words, the organs must be subject to specific tasks naturally requires lntegl'iltlon, control and regulation. Control implies that a which is achieved by convective transport over controUed variable such as the blood pressure long distances (circulation, respiratory tract). is subject to selective external modification, humoral transfer of information (hormones), for example, through alteration of the heart and transmission of electrical signals in the rate (..... p.228). Because many other factors nervous system, to name a few examples. also affect the blood pressure and heart rate, These mechanisms are responsible for supply the controlled variable can only be kept conand disposal and thereby maintain a stable in- stant by continuously measuring the current ternal environment, even under conditions of blood pressure, comparing it with the referextremely high demand and stress. Moreover, ence signal (set point), and continuously corthey control and regulate functions that en- recting any deviations. lf the blood pressure sure survival in the sense of preservation of the drops-due, for example, to rapidly standing species. Important factors in this process in- up from a recumbent position-the heart rate clude not only the timely development of re- will increase until the blood pressure has been productive organs and the availability of fertil- reasonably adjusted. Once the blood pressure izable gametes at sexual maturity, but also the has risen above a certain limit, the heart rate control of erection, ejaculation, fertilization, will decrease again and the blood pressure will and nidation. Others include the coordination normalize. This type of closed-loop control is of functions in the mother and fetus during called a negadft fHdbKk mntrol system or a pregnancy and regulation of the birth process mntrol drcult (-+ Cl ). It consists of a controller with a programmed set-point value (target and the lactation period. The atntl'ill n•rvous syst.m (CNS) processes value) and control elements (effectars) that can signals from peripheral sensors (single adjust the controlled variable to the set point sensory cells or sensory organs), activates out- The system also includes sensors that continuwardly directed effectors (e.g., skeletal ously measure the actual value of the conmuscles), and Influences the endocrine glands. trolled variable of interest and report it (feedThe CNS is the focus of attention when study- back) to the controller, which compares the acing human or animal behavior. It helps us to lo- tual value of the controlled variable with the cate food and water and protects us from heat set-point value and makes the necessary ador cold. The CNS also plays a role in partner justments if disturbance-related discrepancies selection, concern for offspring even long after have occurred. The control system operates their birth, and integration into social systems. either from within the organ itself(aumregulaThe CNS is also involved in the development. tion) or via a superordirulte organ such as the expression, and processing of emotions such central nervous system or hormone glands. as desire, listlessness, curiosity, wishfulness, Unlike simple control, the elements of a conhappiness, anger, wrath, and envy and of traits trol circuit can work rather imprecisely such as creativeness, inquisitiveness, self- without causing a deviation from the set point awareness, and responsibility. This goes far be- (atleast on average). Moreover, control circuits yond the scope of physiology-which in the are capable of responding ID unexpected disnarrower sense is the study of the functions of turbances. In the case of blood pressure reguthe body- and, hence, of this book. Although lation (..... C2), for example. the system can re- II> behavioral science, sociology, and psychology Urinary substances, add-base disturbances, hypertension

Plate 1.2 Control and Regulation I

5

C.CDnt~d~~----------------------------------------~

Set point value •

Actual value

-

Control element 1

Senlar

It'/ Control 2 Control /

._,___=. .

.........._

1 Control circuit prindple

2

Control circuit: blood pressure

element

/

elementn

~ Disturbance

6

.....

The Body: an Open System with an Internal Environment (continued) II> spond to events such as orthostasis (-+ p. 216) or sudden blood loss. The type of control circuits described above keep the controlled variables constant when dtstu!Wnal nrtables cause the controlled variable to deviate from the set point (-+ 02). Within the body, the set point is rarely invariable, but can be "shifted" when requirements of higher priority make such a change necessary. In this case, it is the variation of the set point that creates the discrepancy between the nominal and actual values, thus leading to the activation of regulatory elements (-+ 03 ). Since the regulatory process is then triggered by variation of the set point (and not by disturbance variables), this is called servocontrol or servomechanism. Fever (-+ p. 236) and the adjustment of muscle length by muscle spindles andy-motor neurons (-+p. 334) are examples of servocontrol. In addition to relatively simple variables such as blood pressure, cellular pH, muscle length, body weight and the plasma glucose concentration, the body also regulates complex sequences of events such as fertilization, pregnancy, growth and organ differentiation, as well as sensory stimulus processing and the motor activity of skeletal muscles, e.g., to maintain equilibrium while running. The regulatory process may take parts of a second {e.g., purposeful movement) to several years {e.g., the growth process). In the control circuits described above, the controlled variables are kept constant on average, with variably large, wavelike deviations. The sudden emergence of a disturbance variable causes larger deviations that quickly normalize in a stable control circuit (-+ E, test subject no. 1 ). The deg.-.e of deviation may be slight in some cases but substantial in others. The latter is true, for example, for the blood glucose concentration, which nearly doubles after meals. This type of regulation obviously functions only to prevent extreme rises and falls (e.g., hyper- or hypoglycemia) or chronic deviation of the controlled variable. More pre-cise maintenance of the controlled variable re-quires a higher level of regulatory sensitivity (high amplification foetor). However, this extends the settling time(-+ E. subject no. 3) and can lead to regulatory instability, Le~ a situa-

tion where the actual value oscillates back and forth between extremes (unstable oscillation, -+E. subject no. 4). Osdlatlon of a controlled variable in response to a disturbance variable can be attenuated by either of two mechanisms. First, sensors with dit!erential characteristics (D sensors) ensure that the Intensity of the sensor signal increases in proportion with the rate of deviation of the controlled variable from the set point (-+ p. 3301f.). Second, feedforward control ensures that information regarding the expected intensity of disturbance is reported to the controller before the value of the controlled variable has changed at all. Feedforward control can be explained by example of physiological thermoregulation, a process in which cold receptors on the skin trigger counterregulation before a change in the controlled value (core temperature of the body) has actually occurred (-+p.236). The disadvantage of having only D sensors in the control circuit can be demonstrated by example of arterial pressosensors (• pressoreceptors) in acute blood pressure regulation. VerY slow but steady changes, as observed in the development of arterial hypertension. then escape regulation. In fact. a rapid drop in the blood pressure of a hypertensive patient will potentially cause a counterregulatory increase in blood pressure. Therefore, other control systems are needed to ensure proper long-term blood pressure regulation.

Control circuit disturbance, orthostatic dysregulation, hypotension

Plate 1.3 Control and Regulation II D. Control drwlt respon~e to dllilurbiii"Kll!! or let point (SP) deviation - - - - - - - ,

? :n~ntrnl~r) ~?~l~r)

~

~

It(_;

COntrolled ~

Dbturil-

~

~IICII!

COntrolled

m

Dlsturb-

~nee

± t:ic

Set point

Time

Time

1 Stable mntrol

2 Strong disturbanCI!

Time

3 Large set point shift

E. Blood preuure cantRil afb!r suddenly standing ei'Kt - - - - - - - - - - , Subject:1

Qlti and mmplab! NCum tD baseline

Subject:2 Slawiinlllnmmpln! adfllltnwnt (...,an from m paint)

90

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...~

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ill

::!!

10

20

~

70

80$

~Iter A. Dltlmor &.l. MechefR)

7

8

.....

TheCell The cell is the smallest functional unit of a living organism. In other words, a cell (and no smaller unit) is able to perform essential vital functions such as metabolism, growth. movement, reproduction. and hereditary transmission (W. Roux) (..... p. 4). Growth, reproduction, and hereditary transmission can be achieved by ceU division. Cel compoMRts: All cells consist of a cell membrane, cytosol or cytoplasm (ca. 50 vol.%), and membrane-bound subcellular structures known as o~pnelles (--+A. B). The organelles of eukaryotic cells are highly specialized. For instance, most of the genetic material of the cell is concentrated in the cell nucleus, whereas "digestive" enzymes are located in the lysosomes. OXidative ATP production takes place in the mitochondria. The cell nucleus contains a liquid known as karyolymph, a nucleolus, and chromatin. Ouomatin contains deoxyribonucleic acids (DNA), the carriers of geneticinformation. Two strands of DNA forming a double helbc (up to 7 em in length) are twisted and folded to form chromosomes 10 ~m in length. Humans normally have 46 chromosomes, consisting of 22 autosomal pairs and the chromosomes that determine the sex (XX in females, XY in males). DNA is made up of a strand of three-part molecules called nucleotfdes, each of which consists of a pentose (deoxyribose) molecule, a phosphate group, and a base. Each sugar molecule of the monotonic sugar-phosphate backbone of the strands ( ...deoxyribose phosphate-deoxyribose...) is attached to one of four different bases. The sequence of bases represents the genetic code for each of the more than 30 000 different proteins that a cell produces during its lifetime (gene expression). In a DNA double helix, each base in one strand ofDNAis bonded to its complementary base in the other strand according to the rule: adenine (A) with thymine (T) and guanine {G) with cytosine (C). The base sequence of one strand of the double helix (-+E) is always a "mirtor image• of the opposite strand Therefore, one strand can be used as a template for malting a new complementary strand, the information content of which is identical to that of the original. In cell division, this process is the means by which duplication of genetic information (replication) is achieved. Genetic dlsorden, tnlnscrlptlon dlsorden

Messenger RNA (mRNA) is responsible for code transmission, that is, passage of coding sequences from DNA in the nucleus (base sequence) for protein synthesis in the cytosol (amino acid sequence) (-+C1). mRNA is formed in the nucleus and differs from DNA in that it consists of only a single strand and that it contains ribose instead of deoxyribose, and uracil (U) instead of thymine. In DNA. each amino acid (e.g., glutamate, -+E) needed for synthesis ofa given protein is coded by a set of three adjacent bases called a codon or triplet (C-T-C in the case of glutamate). In order to transcribe the DNA triplet, mRNA must fortn a complementary codon (e.g., C-A-C for glutamat:l!). The relatively small transfer RNA (tRNA) molecule is responsible for reading the codon in the ribosomes ( ..... C2). tRNA contains a complementary codon called the anticodon for this purpose. The anticodon for glutamate is C-U-C(-+ E). RNA synthesiS in the nucleus is controlled by RNA polymemses (types 1-Ill). Their effect on DNA is normally blocked by a rrpmsor protein. Phosphorylation of the polymerase occurs if the repressor is e.liminated ( de-repression) and the genmll tnlnscription factDrs attach to the so-called promoter sequence of the DNA molecule (T-A-T-A in the case of polymerase II). Once activated, it separates the two strands of DNA at a particular site so that the code on one of the strands can be read and transcribed to form mRNA (tr1nsatptlon, -...Cla, D). The heterogeneous nudear RNA (hnRNA) molecules synthesized by the polymerase have a characteristic "cap" at their 5' end and a polyadenine "tall- (A-A-A-...) at the 3' end (->D). Once synthesized, they are immediately "enveloped" In a protein coat, yielding heterogeneous nuclear ribonudeoprotein (hnRNP) particles. The primary RNA or prrmRNA of hnRNA contains both coding sequences (exons) and noncoding sequences ( introns). The exons code for amino acid sequences of the proteins to be synthesized, whereas the introns are not involved in the coding process. tntrons may contain 100 to 10 OOD nudeotides; they are removed from the primary mRNA strand by splicing (--+Clb, D) and then degraded. The introns, themselves, contain the information on the exact splicing site. Splicing is AlP-dependent and requires ...

Plate 1.4 lhe Celli

9

T,glttftttldion -~~~~~~~~,.._ ~~ ~~~~~~~~--~~~~

Cytnsol ~~~:lr'd~~:....--­ C~ ~~J....Z..,..7 L~~ -n~~~--~

~a ~~~--~~~=i~~~~ ~~ ---~~----~~

~R --~~~~~~~~~~~~

Mittx:htJndrion -1;~~ ~~~ -F~~~~~~ ~ ~~~~~~~~~ ~ ~~~-+~~~~­

Nuckollls

B. Cell struc:tlJre (eplthell1l all) In IIKtran micrograph ----------------.....,

l the inll!raction of a number of proll!ins

.....

The nuclear envelope consists of two memwithinaribonucleoproteincomplexcalledthe branes (• two phospholipid bilayers) that spliceosomr.lntrons usually make up the lion's merge at the nuclear pores. The two memshare of pre-mRNA molecules. For example, branes consist of different mall!rials. The exthey make up 95% of the nucleotidl! chain of ternal membrane is continuous with the ml!mcoagulation factor VllL which contains 25 in- brane of the endoplasmic reticulum (ER), trons. mRNA can also be modified (e.g~ which is di!SCribed below (-+F). through methylation) during the course of Thl! mRNA exporll!d from the nucleus posltnlnscrtpdonal rnoclflatlon. tra~ls to thl! ribosomes (-+ Cl ), which either RNA now exits the nucleus through nuc- float freely in the cytosol or are bound to the lear pores (around 4000 per nucleus) and en- cytosolic side of the endoplasmic reticulum, as ters the cytosol (-+ Clc). Nucll!ar pores are described below. Each ribosome is made up of high-molecular-weight protein complexes dozens of proteins associated with a number (12SMDa) located within the nuclear en- of structural RNA molecules called ribosomal velope. They allow large molecules such as RNA (rtlNA). The two subunits of the ribosome transcription factors, RNA polymerases or cy- are frrst transcribed from numerous rRNA toplasmic sll!rold hormone receptors to pass genes in the nudeolus, then separately exit the into the nucleus, nuclear molecules such as cell nucleus through the nuclear pores. AsmRNAandtRNAtopassoutofthenucleus,and sembled togethl!r to form a ribosome, they other molecules such as ribosomal proteins to now comprise the biochemical "machinery" travel both ways. The (ATP-dependent) pas- for protein synthesh (tn~nsl.tlon)(-+ C2). Synsage of a molecule in either direction cannot thesis of a peptide chain also requires the presoccur without the help of a specific signal that ence of specific tRNA molecules (at least one guides the molecule into the pore. The above- for each of the 21 proteinogenous amino mentioned S' cap is responsible for the exit of acids). In this case. the target amino add is mRNAfrom the nucleus, and one or two specific bound to the C-C-A end of the tRNA molecull! sequences of a few (mostly cationic) amino (same in all tRNAs). and the corresponding acids are required as the signal for the entry of anticodon that recognizes the mRNA codon is proll!insintothenucleus. These sequences form located at the othl!r end (-+E). Each ribosoml! partofthepeptldechainofsuchnudearproteins has two tRNA binding sites: one for the last inand probably creall! a peptide loop on the pro- corporated amino acid and another for the one ll!in's surface. ln the case of the cytoplasmic re- beside it (not shown In E). Protein synthesis ceptor for glucocorticoids (-+ p. 292), the nu- begins when the start codon is read and ends dear localization signal is masked by a once the srop codon has been reached. The chaperon!! protein (hl!at shock protein 90, ribosome then breaks down into its two hsp90)in thl! absence ofthe glucocorticoid, and subunits and releases the mRNA (-+ C2). Ribois released only after the hormone binds, somes can add approximately 10-20 amino thereby freeing hsp90 from the receptor. The acids per second. However, since an mRNA "activated" receptor then reaches the cell nu- strand is usually translated simultaneously by deus, where it binds to specific DNA sequences many ribosomes (polyrlbosomts or po/ysomts) and controls specific genes. at different sites, a protein is synthesized much MltadJondrt.l DNA (mtDNA). In the 1960s, fastl!r than its mRNA. In the bone marrow, for DNA was aiso found in the nucleoids of the mi- example, a total ofaround 5 x 1014 hemoglobin tochondrial matrix. long afll!r the discovery copies containing 574 amino acids each are and characll!rization of nuclear DNA. mtDNA produced per second. consists ofa double strand thatforms a ring on IWcroRNA (• miRNA or miR) was frrst dewhich some of the genes for the enzymes of scribed about 20 years ago. These are short, the respiratory chain are locall!d. However, noncoding RNAs, consisting of about 22 numost of the mitochondrial proteins are synthe- cleotides in a hairpin shape, which play an imsized in the cytoplasm (see above). mtDNA is portant part in posttranscription gene regulainherill!d only from the mother as paternal mi- tion, especially gene silencing. They work tochondria are not passed on at fertilization. by binding specifically to mRNA, making II> Translation disorders, virus pathogenicity, tumorigenesis

Plate 1.5 The Cell II C. Transcription •nd tr•nslldlon - - - - - - - - - - - - - - - - - - - ,

J~~.f,{ CienomlcDNA \,

¥

l;i Cl

Nudeus

Ia

,-RNA polymerase

~---

11

Transa1ptlon factors and signal

1

RNA

~Transa1 -ptf-on----.I \ { ~rrwl'/

2 Translation in ribosomes

" Ill

]

c

1111

E

~ ~~,, IJ\/1

1" ~

-

~n«NA

o cantnJI E. Pnlb!ln axllng In DNA ilnd RNA c;.omlc DNA

1-15

16-44

~

45-67

DNA !r!A!A!A!A!r! translation diffiCult or impossible, but sometimes facilitating it. The endoplliSmk reticulum (ER. --> C, F) plays a central role In the synthesis of pnl(eins and lipids; it also serves as an intracellular Co2+ store (--> p. 17 A~ The ER consists of a netlike system of Interconnected branched channels and flat cavities bounded by a membrane. The enclosed spaces (dsttms) make up around 10% of the cell volume, and the membrane comprises up to 70% of the membrane mass of a cell Ribosomes can attach to thl! cytosolic surface of parts of the ER. forming a rough endoplasmic reticulum (RER). These ribosomes synthesize export proteins as Wl!ll as transmembrane proteins (->G) for the plasma membrane, endoplasmic reticulum, Golgi apparatus,lysosomes, etc. The start of protein synthesis (at the amino end) by such ribosomes (still unattached) induces a signal sequence to which a signal recognition particle (SRP) in the cytosol attaches. As a result, (a) synthesis is temporarily halted and (b) the ribosome (mediated by the SRP and a SRP receptor) attaches to a ribosome receptor on the ER membrane. After that, synthesis continues. In export promn synthesis, a transloc.ator protein conveys the peptide chain to the cisternal space once synthesis is completed. Synthesis ofmembrane proteins is interrupted several times (dependIng on the number of membrane-spanning domains (..... C2) by translocator protein closure, and the corresponding (hydrophobic) peptide sequence Is pushed Into the phospholipid membrane. The smooth endoplasmic reticulum (SER) contains no ribosomes and is the production site of lipids (e.g., for lipoproteins, ..... p. 268ff.) and other substances. Thl! ER membrane containing the synthesized membrane proteins or export proteins forms ~sides which are transported to the Golgi apparatus. The Golgi complex or Colgl apparatus ( ..... F) has sequentially linked functional compartments fur further processing of products from the endoplasmic reticulum. It consists of a dsGolgi network (entry side facing the ER), stacked flattened cisternae (Golgi stacks), and a trons-Golgi network (sorting and distribution). Functions of the Golgi complex:

Bacterial defense, acute pancreatitis, cystinosis

+ polysaccharide synthesis;

+

protein processing (posttnnslaUonal modlflcaUon), e.g., glycosylation of membrane proteins on certain amino acids (In part in the ER) that are later borne as glycocalyces on the external cell surface (see beiow) andy-carboxylation of glutamate residues (..... p. 108); + phosphorylation of sugars of glycoproteins (e.g., to mannose-6-phosphate, as d~scribed below); + "packaging" of proteins meant for export into secretory vesicles (secretory granules), the contents of which are exocytosed into the extracellular space (see p.260, for example). Hence, the Golgl apparatus represents a central modification, sorting and distribution center for proteins and lipids received from the endoplasmic reticulum. Regul1tlon of gen• upreulon takes piace on the level of transcription (..... Cll). RNA modification (-->C1b), mRNA export (-->C1c), RNA inhibition (see above), RNA degradation (..... C1 d), translation (-+ C1e), modification and sorting(--> F, f), ;md protein degradation(--> F, g~

The mltochondrlll (-+A, B; p. 17 B) ar~ the site of oxidation of carbohydrates and lipids to C02 and HaO and associated 02 expenditure. The Krebs cycle (citric acid cycie), respiratory chain. and related ATP synthesis also occur in mitochondria. Cells intensely active In metabolic and transport activities are rich in mitochondria-e.g., hepatocytes, intestinal cells, and renai epithelial cells. Mitochondria are enclosed in a double membrane consisting of a smooth out~r membrane and an inner membrane. The latter is deeply infolded, forming a series of projections (cristae) and enclosing the matrix; it also has important transport functions (--> p.17 B). Mitochondria probably evol~ as a result of symbiosis between aerobic bacteria and anaerobic cells (symbiosis hypothesis). The mtDNA, which resembles bacterial DNA. and the double membrane of mitochondria are relicts of their ancient history. Mitochondria aiso contain ribosomes which synthesize some of the proteins encoded by mtDNA. t..ysosomes are ~sides (--> F, g) that arise from the ER (via the Golgi apparatus) and are invol~d in the intracellular digestion of macromolecules. These are taken up into the

11>

Plate 1.6 The Cell Ill F. Protein synthelii, 501'tfng, recydlng, and breakdown - - - - - - - - - ,

Transcription

~

'-....._

13 >o

EJI Cl

NIKkus

Q

J.a..

m~

~·'.. ~

~

-a

1: Ill Ill

~II

..E

-a

= .f

-

0

Control

14

......

The Cell (continued) II> cell either by endocytosis (e.g., uptake of al- that may be either smooth or deeply infolded, bumin into the renal tubules; ..... p. 166) or by like the brush border or the basal labyrinth phagocytosis (e.g., uptake ofbacteria by macro- (-->B). Depending on the cell type, the cell phages; -->p.98ff.). They may also originate membrane contains variable amounts of phosfrom the degradation ofa cell's own organelles pholipids, cholesterol, and glycolipids (e.g., cere(autophagia. e.g~ of mitochondria) delivered brosides). The phospholipids mainly consist of inside autophagosomes (-->a, F). A portion of phosphatidylcholine (-->Cl), phosphatidylthe endocytosed membrane material is re- serine, phosphatidylethanolamine, and sphincycled (e.g., receptor recycling in receptor-me- gomyelin. The hydrophobic components of the diated endocytosis;--> p. 28). Early and late en- membrane face each other, whereas the hydosomes are intermediate stages in this vesic- drophilic components face the watery surular tnmsport. Late endosomes and lysosomes roundings, that is, the extracellular fluid or cycontain addic hydrolases (proteases, nu- tosol (--+ C4). The lipid composition of the two cleases, lipases, glycosidases, phosphatases, layers of the membrane differs greatly. Clyetc., that are active only under addle condi- colipids are present only In the external layer, tions). The membrane contains an I:r-ATPase as described below. Cholesterol (present in that creates an addle (pH 5) interior environ- both layers) reduces both the fluidity of the ment within the lysosomes and assorted tnms- membrane and its permeability to polar subport proteins that (a) release the products of stances. Within the two-dimensionally fluid digestion (e.g., amino adds) into the cyto- phospholipid membrane are proteins that plasm and (b) ensure charge compensation make up 25% (myelin membrane) to 75% during H• uptake (a- channels). These (inner mitochondrial membrane) of the memenzymes and transport proteins are delivered brane mass, depending on the membrane type. in primary lysosomes from the Colgi apparatus. Many of them span the entire lipid bilayer once Mannose-6-phosphate (M6P) serves as the (-->Cl) or several times (-->G2) (transmem"label" for this process; it binds to M6P recep- brane proreins), thereby serving as ion chantors in the Colgi membrane which, as in the nels, carrier proteins, hormone receptors, etc. case of recepiDr-mediated endocytosis The proteins are anchored by their lipophilic (-->p.28), cluster in the membrane with the amino acid residues, or attached to already anhelp of a dathrin framework. In the acidic en- chored proteins. Some proteins can move vironment of the lysosomes, the enzymes and about freely within the membrane, whereas transport proteins are separated from the re- others, like the anion exchanger of red cells, ceptor, and M6P is dephosphorylated. The M6P are anchored to the cytoskeleton. The cell surreceptor returns to the Colgi apparatus (recy- face is largely covered by the glycocalyx. which cling, ..... F). The M6P receptor no longer recog- consists of sugar moieties ofglycoproteins and nizes the dephosphorylated proteins, which glycolipids in the cell membrane (-+ Cl, 4) and prevents them from returning to the Golgi ap- of the extracellular matrix. The glycocalyx mediates cell- cell interactions (surface recogniparatus. Peroxlsomn are microbodies containing tion, cell docking, etc.). For example, comenzymes (imported via a signal sequence) that ponents of the glycocalyx of neutrophils dock permit the oxidation of certain organic onto endothelial membrane proteins. called molecules (R-H2). such as purines, amino sel«rins R+ lh02. The peroxisomes also contain catalase, which and change its shape (during cell division, etc.), transforms 2 H~ into 02 + 2 H20 and oxidizes make selective movements (migration, dlia), and conduct intraceUular transport activities toxins, such as alcohol and other substances. Cel membrane. Whereas the membrane of (vesicle, mitosis). Jt contains actin filaments as organelles is responsible for intracellular com- well as microtubules and intmnediate filapartmentalization, the main job of the cell ments (e.g., vimentin and desmin filaments, membrliM (-->C) is to separate the cell interior neumfilaments, keratin filaments) that extend from the extracellular space ( ..... p. 2). The cell from the centrosome. membrane is a phospholipid bllqer (--> Cl) Tubular protelnurtll, mxlclty of lipophilic substances, Immune deficiency

Plate 1.7 The Cell IV C. Cell memb111ne

>o

: .•. ....1. l . c:::;; -. 'if:j, ... . ~

Upld molecule

•'!,..._:• .:

•~_.

.. ~ v

15

o;

--EldJBC21rll...

lnteg111l membrane protein Glycopl"lnin

~

~

•>1 : ::

~ ,~·

~~

:

..

• ~

Q

Glycolipid

~

:

Clyooc:.;llyx

~!'

-a 1:

Ill Ill

Upld bilayer

(Ci1.5nm)

IYthf~~U

1- Upaphilic amioo

acid residues

2 Multiple membrane-

spanning Integral protein

3 Phospholipid (phosphaticlylcholrne)

~II

..E

-a

= .f

Membrane constituents

J ' l --

J.a.. ~

~

l.

f*~J

EJI Cl

Phosphatlclytsellne

4 Membrane lipids

16

.....

Transport In, Through and Between Cells The lipophilic cell membrane protects the cell interior from the extrilcellular fluid, which has a completely different composition (--+ p.2). This is imperative for the creation and maintenance of a celrs internal environment ~ means of metabolic energy expenditure. Channels (pores), carriers, ion pumps (--+ p. 261f.) and the process of cytosis (-+ p. 28) allow transmembr- tnlnspol't of selected substances. This includes the import and export of metabolic substrates and metabolites and the selective transport of ions used to create or modify the cell potential (--+ p. 32), which plays an essential role In the excitability of nerve and muscle cells. In addition, the effects of substances that readily penetrate the cell membrane in most cases (e.g., water and C02) can be mitigated ~ selectively transporting certain other substances. This allows the cell to compensate for undesirable changes in the cell volume(-+ p.178) or pH of the cell interior. lntracelhAr Tnmsport

The cell interior is divided into different compartments by the organelle membranes. In some cases, very broad intracellular spaces must be crossed during transport. For this purpose, a variety of specifiC intracellular transport mechanisms exists, for example: + Nuclear pores in the nuclear envelope provide the channels for RNA export out of the nucleus and protein import into it (..... p. 11 C); + Protein transport from the rough endoplasmic reticulum to the Golgi complex (-+p.13F); + Axonal transport in the nerve fibers, in which distances of up to 1 meter can be crossed ( ..... p.46). These transport processes mainly take place along the filaments of the cytoskeleton. Example: while expending ATP, the microtubules set dynein-bound vesicles in motion in the one direction, and kinesinbound vesicles in the other (-+ p. 13 F; p.37A4). The main sites of lntrac:elkAr transmembrane transport are: + Lysosomes: Uptake ofW ions from the cytosol and release of metabolites such as amino adds into the cytosol (-+ p.12); + Endoplasmic reticulum (ER): In addition to a translocator protein (-+ p. 10), the ER has two other proteins that transport Ca1 • ( ..... A). Ca2• lsd'lemla, storage diseases, neural regeneration

can be pumped from the cytosol into the ER by a Ca2 •-ATPase called SE~ (sarcoplasmic endoplasmic reticulum Cal+-transporting ATPase). The resulting Cal+ stores can be released into the cytosol via a Cal+ channel (ryanodine receptor, RyR) in response to a triggering signal(-+ p.38). + Mi!Ochondria: The outer membrane contains large pores called porins that render it permeable to small molecules (< 5 kDa), and the inner membrane has high concentrations of specific carriers and enzymes (-+B). Enzyme complexes of the resplmtory chain transfer electrons (e-) from high to low energy levels, thereby pumping W Ions from the matrix space into the lntermembrane space (..... Bl ), resulting in the formation of an H' ion gradient directed into the matrix. This not only drives ATP synthase (ATP production; --+ B2), but also promotes the influx of pyruvate- and inorganic phosphate, Pc (symport; --+ B:Zb, c and p. 26). cal· ions that regulate ea1•-sensitive mitochondrial enzymes in muscle tissue can be pumped into the matrix space with ATP expenditure(-+ B2), thereby allowing the mitochondria to form a sort of ca1• buffer space for protection against dangerously high concentrations of Ca2• in the cytoSOL The insidenegative membmne potential (caused by W release) drives the uptalce of ADJil- in exchange for ATJ>4- (potential-driven transport; ..... B:Za and p.22). Transport between Ad)•cent Cells In the body, transport between adjacent cells occurs either via diffusion through the extracellular space (e.g., paraaine hormone effects) or through channel-like connecting structures (connexons) located within a so-called gap junction or nexus (..... C). A connexon is a hemichannel formed by six connexin molecules (~ C2). One connexon docks with another connexon on an adjacent cell, thereby forming a common channel through which substances with molecular masses of up to around 1 kDa can pass. Since this applies not only for ions such as Ca2• , but also for a number of organic substances such as ATP. these typeS of cells are united to form a close electrical and metabolic unit. as is present in the epithelium, many smooth muscles (single-unit type, ..... p. 74), the ,..

Plate 1.8 Transport I

17

l;i Cl

Ia 1

" Ill

] Dlschp. 26~

1" ~

-

24

.....

Osmosis, Filtration and Convection In flltnltlon (-+8), Water flow or volume flow (Jv) across a wall or partition (membrane or cell layer), in living orJv = K! · (6P-6x) • K!· Po~~ (1.131 ganisms is achieved through osmo.ris ( diffu- Filtration occurs mainly through capillary sion ofwater) or filtrotion. They can occur only walls, which allow the passage of small ions if the wall is water-permeable. This allows and molecules (o • 0; see below). but not of osmotic and hydrostatic pressure differences plasma proteins (~ 8, molecule X). Their con(dn and AI') across the wall to drive the fluids centration difference leads to an oncotic pressure difference (M) that opposes 6P. Therethrough it. Osmotk flow (Jv) equals the hydraulic con- fore, filtration can occur only if 6P > dn (-+ 8, ductivity (~) times the osmotic pressure pp.I60 and 220). Solvent drag occurs when solute particles difference (6n) (-+A): Jv - Kr· dn [1.11) are carried along with the water flow of osmoThe osmotic pn~~sure dllhn!nce (6x) can be sis or filtration. The amount of solvent drag for calculated using wm't Hoffs law, as modified solute X Ox) depends mainly on osmotic flow Ov) and the mean solute aclivily lix (-+ p. 398) by Staverman: dn - o · R · T · 6C..,.,, (1.12) at the site of penetration, but also on the where o is the reftection coeffident of the par- degree of particle reflection from the memticles (see below), R is the universal gas con- brane, which is described using the reflection stant (-+ p. 20), T is the absolute temperature, coefllclent (o). Solvent drag for solute X Ox) is and 6Cosm [osm -lcgHl0-1 ] is the difference be- therefore calculated as tween the lower and higher particle concen.J. = Jv (1 - o) if. [mol· s-1] [1.14] trations, Gsm-~sm (-+A). Since 6c_,, the Larger molecules such as proteins are entirely drlvingforct for osmosis, is a negative value, Jv reflected and o • 1 (-+ 8, molecule X). Reflecis also negative (Eq. 1.11). lbe water therefore tion of smaller molecules is lower and o < 1. flows against the concentration gradient of the When urea passes through the wall of the solute particles. In other words, the higher proximal renal tubule, for example, a = concentration, c&m. attracts the water. When 0.68. The value (I -a) Is also called the sieving the concentrution ofwater is considered in os- coefficient(-+ p. 162). Plasma prcaln binding occurs when smallmosis, the H10 concentration in A, a, Gt.o. is greater than that in A, b, lt,o. ~H1o-C~ is molecular substances in plasma bind to protherefore the driving force for H~ diffusion teins (-+ C). This hinders the free penetration ofthe substances through the endothelium or (~A). Osmosis also cannot occur unless the reflection coeffident is greater than zero the glomerular filter(-+ p. 162ff.). At a glomer(o>O), that Is, unless the wall of partition is ular filtration fraction of20%, 20% of a freely filterable substance is filtered out. If, however, less permeable to the solutes than to water. Aquaporlns (AQJ') are water channels that 9/10 of the substance is bound to plasma propermit the passage of water in most cell mem- teins. only 2% will be filtered during each renal branes. A chief cell in the renal collecting duct pass. Convection functions to transport solutes contains a total of ca. 107 water channels, comprising AQJ'2 (regulated) in the luminal mem- over long distances-e.g., in the circulation or brane, and AQJ'3 and 4 (permanent) in the ba- urinary tract. The solute is then carried along solateral membrane. The permeability of the like a piece ofdriftwood. The quantity ofsolute epithelium of the renal collecting duct to transported over time Uc-) is the product of water (..... A. right panel) is controlled by the in- volume flow Jv (in ml. s-1) and the solute consertion and mnoval ofAQp2, which is stored in centration C (mol . m-3 ): the membrane of intracellular vesicles. In the Jc- - Jv · C [mol · s-1). (1.15] presence of the antidiuretic hormone ADH (V1 The flow of gases in the respiratory tract. the receptors, cAMP; ..... p.288), water channels transmission of heat in the blood and the reare inserted in the luminal membrane within lease of heat in the form of warmed air occurs minutes, thereby increasing the water perme- through convection (-+ p. 234). ability of the membrane to around 1.5 x to-t7 L·s- 1 per channel. Edema, diabetes mellitus and Insipidus, electrolyte disturbance, Infusion solutions

Plate 1.12 Osmosis and Filtration

25

l;i

a

H~ A driving force for electroneutral transport (e.g., ~·/H' antiport), whereas the negative membrane potential (--+ p.321f.) provides an additional driving force for rheogenk Na' cotransport into the cell When secondary active transport (e.g., of glucose) is coupled with the influx of not one but two Na' ions (e.g~ SGLTI symporter), the driving force is doubled. The aid ofATPases is necessary, however, if the required "uphill" concentration ratio is several decimal powers large, e.g., to& in the extreme case ofW ions across the luminal membrane of parietal cells in the stomach. ATPase-mediated transport can also be electrogenic or electroneutral, e.g., Na'-IC'"-ATPase (3 Na'/2 IC'"; cf. p.SO) or W-K·-ATPase (1 H'/11C'"), respectively. Characteristics of active transport: • It can be saturated, i.e., it has a limited maximum capadty • It is more or less sptdjic, i.e., a carrier molecule will transport only certain chemically similar substances which inhibit the transport of each other (campetilfve inhibi-

u,..J.

tion). • Va.riable quantities of the similar substances are transported at a given concentration, i.e~ each has a dilferent aJJinity (-1/Kw:. see below) to the transport system. • Active transport is inhibited when the enerxY supply to the cell is disrupted. All of these characteristics except the last apply to passive carriers, that is, to uniportermediated (fadlitated) dilfusion (-+ p. 22 ). The transport rate of saturable transport Usatl is usually calculated according to Michaelis- Menten kinetics:

c

Jsot = J.,.. · leu+ C (mol · m~ · s-1] .

[1.16]

where Cis the concentration ofthe substrate in question, j_,. is its maximum transport rate, and K,..,. (Michaelis constant) is the substrate concentration that produces one-half J.,.. (..... p. 405ff.). Cytosls is a completely different type of active transport involving the formation of membrane-bound vesicles with a diameter of 5Q-400 nm. Vesldas are either pinched off from the plasma membrane (exocytosis) or incorporated into it by invagination (endocytosis) in conjunction with the expenditure of ATP. In cytosis, the uptake and release of mac-

romolecules such as proteins, lipoproteins, polynucleotides, and polysaccharides into and out of a cell occurs by specific mechanisms similar to those inwlved in intracellular transport(-+ p.12ff.). Endocytosis (-+P!.t.1.6F, p. 13) can be broken down into different types, including pinocytosis, receptor-mediated endocytosis, and phagocytosis. Pinocytosis is characterized by the continuous unspecific uptalce of extracellular fluid and molecules dissolved in it through relatively small vesicles. Receptormedliltecl endocytosis (-+C) involves the selective uptake of spedfic macromolecules with the aid of receptors. This usually begins at small depressions (pits) on the plasma membrane surface. Since the insides of the pits are often densely coated with the protein clathrin, they are called clathrin-coa!M pits. The re~p­ tors involved are integral cell membrane proteins (e. g., those for low-density lipoprotein (IDL) in hepatocytes) or intrinsic factor-bound cobalamin (e.g., in ileal epithelial cells). Thousands of the same receptor type or of dilferent receptors can converge at coated pits (..... C}. yielding a tremendous increase in the eff'JCilCY ofligand uptake. The endocytosed vesicles are initially coated with clathrin, which is later released. The vesicles then transform into early endosomes, and most of the assodated receptors drculate back to the cell membrane (-+ C and p. 13). The endocytosed ligand is either exocytosed on the opposite side of the cell (transcytosis, see below), or is digested by lysosomes p.13F). The liquid contents of the vesicle then are automatically emptied in a process called mnstltutlve eJUJcytosls (-+ D)• In constitutive exocytosls. the protein complex coatoml!r(cmlt assembly protomer) takes on the role of dathrtn (see above). Within t he Golgl membrane. GNRP (guanine nucleotide-releasing protein) phosphorylates the GOP of the ADP·ribosylation factor (ARF) to GTP (-+ 01 ), resulting In the dispatch of vesicles from the trans-Golgi network. ARF-GTP CDmplexes then anchor on the membrane and bind wtth coatomer (-+ D2), thereby producing COIIIDmel'-c:OIIted Wildes(-+ 03). The membranes of the vesicles CDOtain v-SNAREs (vesicle synaptosome-associated protein receptors). which recognize t-SNAREs (target-SNAREs) in the target membrane (the plasma membrane, in this case). This results in cleavage of ARF 4 ·2 · 1o- , .oiG will be > 0, the net reaction will proceed backward, and A will arise from B and C• .oiG is therefore a measure of the direction of

• re1dlon and of its distance from equilibrium. Considering the concentration-dependency of AG and assuming the reaction took place in an open system (see below) where reaction prod-

~~~ea:~:::~~ ~:~~~~:.~:~11:!;

:a::

would be a large negative value, and that the ~b~~~~ would p~rsist without reaching equi-

The magnitude of aG0, which represents the difference between the en~rgy l~vels (ch~mical potentials) of the product Pp and educt P. (..... A), does not tell us anything about the fit. of the reldton. A reaction may be very slow, even ifaCO < 0, because the reaction rate also depends on the energy level (P.) needed nnnsiendy to create the necessary transitional state. P. is than (-+ A). The additional amount of energy required (P. - P.) to reach

high~r

P~

this level is called the utlntlon energy Eo. It is usually so large (- 50 kJ · mol- 1 ) that only a tiny fraction (F - 1o- 9) of the educt molecules are able to provide it (-+A, B). The energy levels of these individual educt molecules are incidentally higher than P., which represents the mean value for all educt molecules. The size of fraction F is temperature-dependent (-+B). A to"C decrease or rise in temperature lowers or raises F (and usually the reaction rate) by a factor of 2 to 4, i.e., the Q1a value of the reaction is 2 to 4. Considering the high E. values of many noncatalyzed reactions. the development of enzymes as biological catalysts was a very important step in evolution. Enzymes enormously accelerate reaction rates by lowering the activation energy E. (-+A). According to the Arrhenius equation, the r1t. constlnt k (s- 1)of a unimolecular reaction is proportional to e-Ma.r>. For example, If a given enzyme reduces the E1 of a unimolecular reaction from 126 to 63 kJ · mol- 1, the rate constant at 310"K (37"C) will rise by e-63000~U1 · 3IOlfe-12iOOO/ (a:n · 310> , i.e., by a factor of 4 -tote. The enzyme would therefore reduce the time required to metabolize 50% of the starting materials(~/>) from, say, tO years to7msecl The forward rate of a reaction (mol · L- 1 • s- 1 ) is related to the product of the rate constant (s- 1) and the starting substrate concentration (mol · L-I). The second law of thermodynamics also implies that a continuous loss of free energy occurs as the total disorder or entropy (S) of a dosed system increases. A living organism represents an open syst.m which, by definition, can absorb energy-rich nutrients and dis-

~=::~~ ~":~~~ ~~~~=b~~~.ri=i~ !~

vironment) increases in the process, an open system (organism) can eith~r maintain its entropy level or reduce it using free enthalpy. This occurs, for exampl~. when ion gradi~nts or hydraulic pressure differences are created within the body. A closed system therefore has a maximum entropy, is in a true state ofchemical equilibrium, and can perform work only once. An open system such as the body can continuously perform work while producing

~::li~::~u~~~:::':~~~yt~e~~tere'! processes within the body, e.g., in the reaction II>

Nub1tlon disorders, sport training, hyperthyroidism 1nd hypothyroidism

Energy Turnover (continued) ~ C02+H20'"""' HC03-+ W.ln mostcases(e.g., metabolic pathways, ion gradients), only a steady state is reached. Such metabolic pathways are usually irTI!'JI?TSible due, for example, to excretion of the end products. The thought of reversing the "reaction· germ cell-+ adult illustrates just how impossible this is. At steady state, the rate of a reaction is more important than its equilibrium. The regulation of body functions is achieved by controlling reaction rates. Some reactions are so slow that it is impossible to achieve a sufficient reaction rate with enzymes or by reducing the concentration of the reaction products. These are therefore endergonic reactions that require the input of outside energy. This can involve "activation• of the educt by attachment of a high-energy phosphate group to raise the P•. AlP (adenosine triphosphate) is the universal carrier and transformer of free enthalpy within the body. ATP is a nucleotide that derives its chemical energy from energy-rich nutrients (--+ C). Most ATP is produced by oxidation of energy-rich biological molecules such as glucose. In this case, oxidation means the removal of electrons from an electron-rich (reduced) donor which, in this case, is a carbohydrate. C~ and H20 are the end products of the reaction. In the body, oxidation (or electron transfer) occurs in several stages, and a portion of the liberated energy can be simultaneously used for ATP synthesis. This is therefore a mupled re11ctlon (--+Cand p.17B). The standard free enthalpy AGo of AlP hydrolysis, ATP'"""' ADP + Pt [1.31] is - 30.5 kj · mol- 1 • According to Eq. 1.27, the AG of reaction 1.31 should increase when the ratio ([ADP]· [Pt)l/[ATP] falls below the equilibrium constant K.q of ATP hydrolysis. The fact that a high cellular ATP concentration does indeed yield a AG of approximately - 46 to - 54 kj. mol- 1 shows that this also applies in practice. Some substances have a much higher AG0 of hydrolysis than ATP, e.g., creatine phosphate (- 43 kj. moJ- 1). These compounds react with ADP and P; to form ATP. On the other hand, the energy of ATP can be used to synthesize other compounds such as liTP, GTP and glucose-6phosphate. The energy content of these sub-

43

stances is lower than that of ATP, but still relatively high. The free energy liberated upon hydrolysis of ATP is used to drive hundreds of reactions within the body, including the active transmembrane transport of various substances, protein synthesis, and muscle contraction. According to the laws of thermodynamics, the expenditure of energy in all of these reactions leads to increased order in living cells and, thus, in the organism as a whole. Ufe is therefore characterized by the continuous reduction of entropy associated with a corresponding increase in entropy in the immediate environment and, ultimately, in the universe.

....

44

Aging Aging is a normal and unavoidable process that ends with death. There is great global variation in the aver;l!lll! nre expectancy of newborn babies (-+A); in Germany in 2009 it was 76.3 years for boys and 82.4 years for girls. Average life expectancy lncre.-~ses with age as those who died at a young age are no longer counted. Reduced Infant mortality and control of most infectious diseases have alowed life expectancy to increase considerably over the past Cl!fltury In Industrialized nations. The leading causes of dNth in these nations are now diseases of advanced age, with cardiovascular disease accounting for ca. SO% (men > women) and tumors for 25%.

Diseases are what usually prevent people from achieving their maximum life span, which, as in the past, is still about 100 years. After 10 years, only 0.005% of 98-year-olds are still alive. Aging produces a reduction In many boclly toocttons. For most very old people who are otherwise healthy,ftuilty becomes the limiting factor. This "age-related wealrness" is characterized by diminished muscle strength, slower reflexes, impaired mobility and balance, and a lack of stamina. This results in falls, fractures, and loss of independence. Muscle weakness is caused not only by aging and wear processes (as in the joints) but also by lack of exercise. The Immune sysmm also ages (immunosenescen.ce).ln old age, activation of the immune response is slower, vaccination is less effective, and susceptibility to infectious diseases, tumors, and autoimmune diseases is greater. Ufe span and aging are partially genetically det•rmlned:

Certain mutations result in premature aging (progeN). Conversely, there are genetic mutations (lnduding age-l) that can significantly Increase a nematode's life span. The ~1 mutation confers Increased resistance to oxygen free radicals (reactive Ol(ygen species, ROS). The finding that molecules damaged by ROS accumulate with age (-+C) while the activity of enzymes that protect against oxlda· tion decreases suggests thatoxldatlw damage may also be Involved In human aging. The Klotho gene (named after one of the Fates of Greek mythology) inhibits aging. When expression of this gene is increased, ~fe is prolonged, whereas life span is shortened when it is absent. Klotho codes for a membrane protein that binds to ~reaptorfor fibroblast growth factor (FCif23) and regulates

Senility, senile diseases. e.g. heart, brain

phosphatP/c:alcWm homeostasis. Homozygous absence of either the Klotho or FGF23 gene causes hy· perphosphatemla and hypercalcemia, followed by accelerated aging.

Energy metabolism is no longer optimally regulated in old age (for causes, -+ B; CCK • cholecystokinin). However, energy consumption also falls, not least because of a reduction in physical activity. The cauMt of aging are unclear. Even cultured cells "age," that is, they stop dividing after a certain number of cycles. Only a few cells are "immortal"; these include germ cells, hematopoietic stem cells, and also cancer cells. A low-alone diet in younger years increases life expectancy as it reduces the fasting plasma glucose level, blood cholesterol level, insulin resistance, visceral fat, and the consequent release of inflammatory mediators. These positive ftfects can be stimulated with reswratrol, a polyphenol found in wine. It activates ~ genes that code for sirtuins (Sirtl-7, NAD-dependent deacetylast!s). In many species, Sirtl Increases resistance to Olddatlve stress along with life expectancy; some of these sirtuin effects are mediated by forkhead box 0 (FOXO) transcription factors. Whether this also occurs In humans ls still unclear.

Chromosomes are increasingly damaged over the course of lifetime (..... C). This is normally prevented by the telomere, a specialized nucleoprotein complex that sits on the chromosomes as a protective cap. In somatic cells, the telomere becomes a bit shorter with each cell dMsion. When this happens over many cell generations, telomere protection cf!ases and the DNA repair mechanism comes Into play automatically, with activation ofthe p53 reoction pathway, and fu rther cell division is halted. This is known as nplicatiw when it is due to aging (-+C). If DNA repair falls, cell death by apoptosls takes place, also via p5l. Mlochonclrta also age, especially In nonproMferatlve cens like those of the heart and brain. Mutations in the mtDNA occur increasingly, endangering the cell's energy supply. In mice with telomere dysfunction, mitochondrial dysfunction also develops, because the activity of the main mitochondrial regu· lators (PGC-1a and 111) Is reduced. Again, p53, which suppresses the PGC-1 genes, Is responsible (-+ C).

-.nee

Plate 1.21 Aging

45

A. Averagl! liM opecblncy of newborns In the UN llll!mbl!r stdl!s (2006) - - - . . . , -

82 years ilnd older

-

74-81 years 72-73years 65-71 years 55-65years

-

'10- 54 years

-

35- 39 years Wider 35 ye01rs

-

Plasma: -Cilucose t - R-ee fatty adds t -Insulin

-Glucagon

tt

DNA dilmilge response

~ p5JdWaon

DMdon of prollferilllve _/ PreYentlon of cells stopped: /' repllcathe •-nee spontaneous tumon Mltlld!andrf!ll

1

ED PCiC-1 -f

1n . f' dJsfgnctlon non-prollfarauw cells

XXlOOOOOC:

e.g. In:

Heott

ROSt

1

---+ CCK tt

-

46

Neuron Structure and Function An excitable cell reacts to stimuli by altering its membr.me characteristics (-+p.32). There are two types of exciuble cells: nmoe cells, which transmit and modify impulses within the nervous system, and muscle cells, which contract either in response to nerve stimuli or autonomously (-+ p. 63). The human nervous system consists of more than 1010 nerve cells or neurons. The neuron is the slnlctural and functional unit of the nervous system. A typical neuron (motor neuron, -+Al) consists of the soma or cell body and two types of processes: the axon and dendrites. Apart from the usual intracellular organelles (-+ p. 8ff.), such as a nucleus and mitochondria (-+ A2), the neuron contains neurojibrils and neurorubulu. The neuron receives afferent signals (excitatory and inhibitory) from a few to sometimes several thousands of other neurons via its dendrttes (usually arborescent) and sums the signals along the cell membrane of the soma (summation). The axon (Neurit) arises from the i!XIln hillock of the soma and is responsible for the transmission of efferent neural signals to nearby or distant ef!er:tors (muscle and glandular cells) and adjacent neurons. Amns often have br.mches (co/Jaterals) that further divide and terminate in swellings called synaptic knobs or terminal buttons.lf the summed value of potentials at the i!XIln hillock exceeds a certain threshold, an ac:tion potential (-+ p. 50) is generated and sent down the i!XIln, where it reaches the next synapse via the terminal buttons (-+ Al, 3) described below. Vesicles containing materials such as proteins, lipids, sugars, and transmitter substances are conveyed from the Golgi complex of the soma (-+ p. 13 F) to the terminal buttons and the tips of the dendrites by rupid axonBl). The potential therefore reverses, and restoration ofthe resting potential, the repolartzatlon phase of the action potential, begins. Depolarization has increased (relatively slowly) the open probability of voltagegated J-C) g1-l

~Y(NPY)

Yl-2

Oplold peptldes

~6,K

Oxytodn

PUr1nes:

AMP, Adenosln

AlP AlP, ADP, UTP, UDP

s.rotonln (~111!)

PlA1.3 PlA2..2b P2X1-7

+ +

P2Y1-14

s-tn1 S-HT2 5-HTl S·HT-t-7

SomiiiDSI:iltln (• SIH)

SRIF

Tilchylclnln

NKl-3

Inhibits or promotes

Amino acids

!

Call!cholamines Peptldes

Others

lonotropic receptor (ligand-gated

ion channel)

Metabotropic receptor (G protein-mediated effect)

~r~ fJ~'~ (Modified from F. E. Bloom)

59

60

N

Motor End-plate The transmission of stimuli from a motor axon to a skeletal muscle fiber occurs at the motor end-plate, MEP (->A), a type of chemical synapse (-+p.54ff.). The transmitter involved is •~tylchollne (ACh,-+ d. p. 86), which binds to the N(nicotinergic )-cholinoceptors of the subsynaptic muscle membrane (-> AJ). N-cholino~ptors are ionotropic, that is, they also function as ion channels (-> A4). The N-cholinoceptor of the MEP (type N:w) has ftve subunits (2a. 1~. 1y, 111). each of which contains four membrane-spanning a-helices(-+ p. 14). The channel opens briefly (-> 81) (for approximately 1 ms) when an ACh molecule binds to the two a-subunits of an N-cholinoceptor (-+ A4). Unlike voltage-gated Na•-channels, the open-probability Po of the N-cholinoceptor is not increased by depolarization, but is determined by the ACh concentration in the synaptic cleft(-> p. S4ff.). The channel isspedjictocations such as Na•, IC', and Ca1 • . Opening of the channel at a resting potential of ca. -90 mV leads mainly to an influx of Na• ions (and a much lower efflux of IC'; -+ pp.32ff. and 48). Depolarization of the subsynaptic membrane therefore occurs: endpl.te potential (EPP). Single-channel anTents of2.7pA (-+81) are summall!d to yield a mln-.ture end-plate current of a few nA when spontaneous exocytosis occurs and a veskle releases a quantum of ACh activating thousands ofNt~~-cholinoceptors (-+ 82). Stil~ this is not enough for generation ofa postsynaptic action potential unless an action potential transmitted by the motor neuron triggers exocytDsis of around a hundred vesicles. This opens around 200000 channels at the same time. yielding a neumlly induced end-plate current (IEP) of ca. 400 nA (-+ 83). Encl-plnJI current. IEP, is therefore dependent on: + the number of open channels, which is equal to the total number ofchannels (n) times the open probability (Po) and P• is determined by the concentration of ACh in the synaptic deft (up to 1 mmoi/L); + the single-channel conductance y (ca. 30 pS); + and, to a slight extent, the membrane potential, E.. since the electrical driving "force• (=Em-Et.._x; ->p.32ff.) becomes smaller when E. is less negative.

E....• is the common equMibrium potential fo r Na• and K• and amounts to approximately o mv. It Is also called the reverul potential because the direction of 1,. (· 1., +I.), which entl!rs the cell when Em Is negative (Na• influx > K' outflow), reversts whtn Em is positive (K' outflow > Na• Influx). As a result, [2.1] 1,. - n · Po · y · (Em- E..,.) [A] Because neurelly Induced EPPs in skeletal muscle are much larger (depolarization by ca. 70mV) than neuronal EPSPs (only a few mV; -> p. 56ff.). a single motor axon action potential is above threshold. The EPP is transmitted electrotonically to the adjacent sarcolemma, where muscle action potentials are generated by means of voltage-gated Na• channels, resulting in muscle contraction. Termln•tlon of synaptic transmission to skeletal muscle occurs ( 1) by rapid degradation of ACh in the synaptic cleft by acet:ykholinestmrse localized at the subsynaptic basal membrane, and (2) by diffusion of ACh out of the synaptic deft(-+ p.86). Amotor end-plat!! can be blocla!d by certain polsons and drugs, rtsulting in muscularweakntss and, In some cases, parulysls. Botulinum neurotoxin, for example, inhibits the discharge of neurotransmitters from the vesicles, and a-bungarotoxln In cobra venom blocks the opening of lon channels. Curarelike substances such as (+)-tubocurarine are used as muscle relullnts In surgical operations. They displace ACh from its binding site (~itiw inhibition) but do not have a depolarizing effect of their own. Their Inhibitory effect can be reversed by cholinesll!rcM inhibitors such as neostigmine (decurarinization). These agents increase the concentration of ACh In the synaptic cleft, thereby displacing curare. Entry of arrticholinesterase agents into Intact synapses leads to an increase in the ACh concentration and, thus, to parulysls due Ill pmnonent depolarization. ACh-llke substances such as suxamethonlum have a similar depolarizing effect, but decay more slowly than ACh. In this case, paralysis occurs because permanent depolarization also permanently inactivatl!s Na• channels near the motor end-plate on the sarcolemma (--+ p. SO).

MuKie relaxants and denervatlon, myasthenia gravis, Lambert-Eaton myasthenic syndrome

Plate 2.9 Motor End-plate

61

N

ruru I I I I

0

1

2

3

nme ms

1 Single-channel aurent

2 Miniawre end-plate CUITent

3 Nerve-induced end-plate CUITent

~-•odS.IImlnn(1)ar•hftK._.ltll(2)}

62

N

Motility and Muscle Types Active motility (ability to move) is due to either the lnt.ractlon of energy-consuming 1110tor prob!l111 (fueled by AJPase) such as myosin, kinesin, and dynein with other proteins such as actin or the polymertutlon and depolymerization of actin and tubulin. Cell division (cytokinesis~ cell migration (-->p.30), intracellular vesicular transport and cytosis (-->p.12f.), sperm motility (-->p.326f.), ovum transport (--> p. 326), axonal transport (--> p.46), electromotility of outer hair cells (--.p.388), and ciliary motility (--.pp.36 and 116) are examples of cell and organelle motility. The muscles consist of cells (fibers) that contract when stimulated. Skelml musde is responsible for locomotion, positional change, and the convection of respiratory gases. car· dlac muscl• (-->p.202ff.) is responsible fur pumping the blood, and smooth muscle (-> p. 74) serves as the motor of internal organs and blood vessels. The different muscle types are distinguished by several functional characteristics (->A ~

Motor Unit of Sblebll Muscle Unlike some types of smooth muscle (singleunit type; --.p. 74) and cardiac muscle fibers, which pass electric stimuli to each other through gap junctions or nexus (--.A; p. 16f.), skeletal musde fibers are not stimulated by adjacent muscle fibers, but by motor neurons. In fact, muscle paralysis occurs if the nerve is severed. One motor neuron together with all muscle fibers Innervated by it is called a motor unit. Muscle fibers belonging to a single motor unit can be distributed over large portions (1 cm2 ) of the muscle cross-sectional area. To supply its muscle fibers, a motor neuron splits into coUaterals with terminal branches (-> p. 46). A given motor neuron may supply only 25 muscle fibers (mimetic muscle) or well over 1000 (temporal muscle). Two types of sbleUI muscle fibers can be distinguished: S - slow-twitch fibers (type 1) and F - fast-twitch fibers (type 2), including two subtypes, FR (2A) and FF (2 B). Since each motor unit contains only one type of fiber, this classification also applies to the motor unit

Slow-twltdl fibers are the least fatigable and are therefore equipped fur sustained ptr[ormana. They have high densities of capillaries and mitochondria and high concentrations of fat droplets (high-energy substrate reserves) and the red pigment myoglobin (short-term~ storage). They are also rich in oxidative enzymes. Fest-twltdl ftblrs are mainly responsible fur brief and rapid contractions. They are quickly fatigued (FF > FR) and are rich in glycogen (FF > FR) but contain little myoglobin (FF- p. 71 A).

Palsy, cramps, tet•ny, spastldty, contracture, myopathies

---------

A. stnKture and fundion of heart. skeletal and RTmOth l1lll5de - - - - - - - - - - - - - - - - - - - - - - - - ,

Strucb.Jre and function

~

Skeletal musde {stllatll'!d)

Motor

end-91atm Fibers Mltlxhonch1a Nucleusper fiber sarcomere$

Few None

Yes, length ~ 2.6 l1fT'I

Yes 4'llndrfcal, long (~ 15 em) Few (depending on muscle type) Multiple Yes. length ~ 3.65 ,.m

~.coupling

Some (slngiHinlt type)

Yes (functional syncytium)

No

sarcoplasmic reticulum

utile diM!Ioped

Modl!l"iilteeydewloped

Highly developed

~"swltd!"

Cllmoclulln/Cilldesmon

Troponln

Troponln

Some spontllnecJus rhythmic ictlvlty (lr'-11r'1 Change In IDne or rhythm frequency

Yes(slnus nodesca.1s"1)

No (reQuires nerw sUmulusl

Allornol'll!

Graded

Yes

No

Yes

LengdHo~ Cllrve

lnr1slng lengu,;force CUM!

Pilcem~la:r

Response ID stimulus Teblnluble Workl"iilnge

None

Brandied Many

isYIIrial*

-g

iii'"

ft

~

0

AI: peak of

3!:

length.fo~ ClJI"'t''!

( - 2.111)

c ...a.

II

i

R&pona!

to stimulus

:!'

3!:

!...

Potential -

Muscle

ten5ion -

c

0

200

400

600 11\$

0

100

200

300

ms

400

0

10

20

ms

30

2 Nerve and Muscle, Physical Work

::II

" 01

'-I

64

N

Contractile Apparatus of Striated Muscle The skeletal muscle cell is a fiber (~A2) approximately 10 tD 100 l'ffi in diameter. Skeletal muscles fibers can be as long as 15 em. Meat "fibers• visible with the nalced eye are actually bundles of muscle fibers that are MOund 100 to 100011m in diameter (-+A1). Each striated muscle fiber Is invested by a cell membrane called the sarcolemma, which surrounds the sarcoplasm (cytDplasm), several cell nuclei, mitochondria (sarcosomes), substances involved in supplying 02 and energy (-+ p. 76), and several hundreds of myofibrils. So-called Z lines or, from a three-dimensional aspect, Z plates (platelike proteins; ..... B) subdivide each myofibril (-+A3) intD approximately 21-l-Jll long, striated compartments called 5aro~meres (_,B). When observed by (two-dimensional) microscopy, alternating light and dade bands and lines (hence the name "striated muscle") created by the thick myosin II filaments and thin lldln filaments can be identified. Roughly 2000 actin filaments are bound medially tD the Z plate. Thus, half of the actin filament projects into each of two adjacent sarcomeres (-+B). 11le region of the sarcomere proximal to the Z plate contains only actin filaments, which form a so-called 1band (..... B). The region where the actin and myosin filaments overlap is called the A band. The H zone solely contains myosin filaments (ca. 1000 per sarcomere), which thicken toward the middle of the sarcomere to form theM line (Mplate).

The (actin) filaments are anchored to the sarcolemma by the protein clystrophrn, which Is connected to sarcoglycans. Merosln binds the sarcoglycans to the collagen fibrils of the extracellular matrix. Mutation of one of these three proteins leads to muscular dystrophy (Duchenne muscular dystrophy. limb-girdle dystrophy, congenital muscular dystrophy) Implying the degeneration of muscle fibers with increasing muscular weakness.

Each myosin filament, which is l.611m long, consists ofa bundle of ca. 300 dimeric myosin II moleaHs (-+B). Each molecule has two globular heads connected by flexible necks (head and neck • subfragment S1; formed after proteolysis) tD the filamentous tail of the molecule (two intertwined a-helices = subfragment 52) (-+C). Each of the heads has a motordomoin with a nucleotfdt binding pocUt (for All' or ADP + Pt)

and an actin binding site. Two light protein chains are located on this heavy molecule (220 kDa): one is regulatDry (20 kDa), the other so-called essential (17 kDa). Conformational changes in the head-neclc segment allow the myosin hl!ad to "tilt" when interacting with actin (slidingfilamtnts; -+ p. 66). Actin is a globular protein molecule (Gactin). Four hundred such molecules join tD form F-actin, a beaded polymer chain. Two of the twisted protein filaments combine tD form an actin filament(-+ B), the ends of which, unlike a myosin filament. would depolymerize so the length of the actin filament has tD be regulated by the threadlike nebulln (length: 1.151.31-l-Jll); the ends are protected by myopalladin and tropomodulin.

Each nebulln molecule (M, • 600- 800 kDa) extends over the entire length of the actin filament and is anchored to the Z plate at the carboxyl end and to the tropomodulin cap at the amino end. This cap is also bound to the actin filament and tropomyosin. In the absence of nebulln the actin filaments are much shomr(0.8 11m on average). Nebulin also contributes to the regular arr.Jngement of the myolibrils and regulates the CJr" sens/tMty of muscle contraction. These three actions of nebulin are absent when there is a mutation (autDsomal rec~) in the nebulin gene, and patients suffer from extreme muscle

weakness (congenital nemallne myopathy). Tropomyvsln molecules joined end-m-end ( 40 nm each) lie adjacent to the actin filament. and a troponln (TN) molecule is attached every 40 nm or so (-+ B). Each troponin molecule consists of three subunits: TN-C, which has two regulatory binding sites for Ca1• at the amino end, TN-I, which prevents the filaments from sliding when at rest. and TN-T, which interacts with TN-C. TN-I, and actin. The sarcomere also has another system of filaments (-+B) formed by the fllamenmus protein titin (connectin). Titin is more than 1000 nm in length and has some 30 000 amino acids (Me> 3000 kDa~ It Is the longest lcnown polypeptide chain and comprises lOX of the total muscle mass. Titin is anchored at its carboxyl end tD the M plate and, at the amino end, tD the Z plate (-+ p. 70 for functional description). Tubules. The sarcolemma forms a T system with several transverse tubules (tubelike in- ..,.

Muscle biopsy, electromyography (EMC), myotonia congenlta, muscular dystrophy

Plate 2.1 1 Striated Musde Aber

100-lOOOJim

1 Bundle of fibers

65

10-100pm

2 Muscle fiber(~)

3 Myufibril

N

Adin TrvpamJVlin Tropooin

Actin filament

Zdlslc

10nm 6nm

ActfrHlindlng

---------,a."

Nucleotide-pocket (ATP or ADP) - --l

I

r--.., J...-=:;.;:...=~-=::w;:~~~~iliiOto_.......,

2 nm

Contractile Apparatus of Striated Muscle (continued)

66

vaginations) that run perpendicular to the myofibrils (--+ p. 67 A). The endoplasmic reticulum (--+ p.lOif.) of musde fibers has a characteristic shape and is called the sarmpllsmlc reticulum (SR; -+ p. 67 A). It forms closed chambers without connections between the intra- or extracellular spaces. Most of the chambers run lengthwise to the myofibrils, and are therefore called longitudinal tubules (--+ p. 67 A). The sarcoplasmic reticulum is more prominently developed in skeletal muscle than in the myocardium and serves as a Ci"' storage spliCe. Each T system separates the adjacent longitudinal tubules, forming triads (-+p.67 A, B). IJi>

N

Stlmui1Uon of musde flben. The release of acetylcholine at the motor end-plate of skeletal muscle leads to an end-plote current that spreads electro!Dnically and activates fast voltage-gated Ncr channels in the sarcolemma (-+ p. 60). This leads to the firing of an Ktlon potrnt11l (AP) that travels at a rate of 2 m/s along the sarcolemma of the entire muscle fiber, and penetrates rapidly into the depths of the fiber along the T system (--+A). Genetic defects of these Na+ channels slow down their deactivation (--+ p. 46), which leads to hyperexdtability with I!Xmxled contraction and delayed muscle relaxation(~). The extended muscular activity is accompanied by a high number of K+ Ions exiting the muse~ fibers. This ~Its in hyperka~la that reduces the muscular resting potent ial to the point where the Na+ channels cannot be activated any longer and the muscle becomes temporarily paralyzed: famlll1l hyperkllemlc periodic

111lysls. The conversion of this electrical excitation into a contraction is called electrornecflanlcal couplng (--+B). In the slceletul muscle, this process begins with the action potential exciting voltreceptors dihydropyridine age-sensitive (DHPR) of the sarcolemma in the region of the triads. The DHPR are arranged in rows, and directly opposite them in the adjacent membrane of the sarcoplasmic reticulum (SR) are rows of C!J.2+ channels called ryanodine receptors (type 1 in skeletal muscle: RYR1 ). Every other RYRl is associated with a DHPR (--+ B2). RYRl open when they directly "sense" by mechanical means an AP-related conformational change in the DHPR.In the myocardium, on the

other hand, each DHPR is part of a voltagegated Cal+ channel (L-type) of the sarcolemma that opens in response to an action potential. Small quantities of extracellular Ca2 • enter the cell through this channe~ subsequently il!ading to the opening of myocardial RYR2 (socalled ~Jigger e.tfect ofCa2• or Cal+ spark; --+ B3 ). ca~ ions stored in the SR now flow through the opened RYR1 or RYR2 channels into the cytosol. increasing the cytosolic Ca2• concentration (Cal'), from a resting value of ca. O.OljlmolfLto over 1 f!ITIOI/L (-+ B1 ). In skeletal muscle, DHPR stimulation at a single site is enough to trigger the coordinated opening of an entire group of RYRl. This increases the reliability of impulse transmission. The increased cytosolic ea1 • concentration saturates the ea2• binding sites on troponln-C. This cancels the troponin-mediated inhibitory effect of tropomyosin on filament sliding (-+ 01), which now allows for strong (high affinity) actin-myosin II binding. In patients with genetic defects of RYR1, general anesthesia may lead to the massive release of Ca1 +, which causes intense muscle contractions accompanied by a rapid and lifethreatening increase of body temperature: alignant hyperthenmia. ATP (-+ p. 76) is essential for fiiMMnt sliding and, hence, for muscle contraction. Due to their ATPase activity, the myosin heads (-+ p. 64) act as the motu~ (motor proteins) of this process. The myosin n and actin filaments ofa sarcomere(-+ p. 64) are arranged in such a way that they can slide past each other. The myosin heads connect with thl! actin filaments at a particular angle, forming so-called crossbridges. Due to a conformational change in the region ofthe nucleotide binding site ofmyosin II (-+ p. 65 C), the spatial extent of which is increased by concerted movement of the neck region, the myosin head tilts down, drawing, in two separate steps, the thin filament a combined length of roughly 4- 12 nm (power stroke). The second myosin head may also move an adjacent actin fllaml!nt The head then detaches and "tenses· in preparation for the next "oarstroke" when it binds to actin anew. Duty rado. Kinesin, another motor protein (-+ pp. 46 and 62), independently advances on IJi>

Malignant hyperthermia, poliomyelitis, muscular dystrophy, myotonia, paralysis

Plate 2.12 Contraction of Striated Muscle I

67

A. The sarcotubular system of m,ocytes (muscle fibers) - - - - - - - - - - ,

Tsymm

~tullu~)

and

.Ju o 2 SlceletJI muscle ..J..JIOI)>.J

1

~

3 Myocardium

ca2+ release

C. Sliding fllamenbi - - - - - - - - - - - - - - - - - - - - - - , Acti~)'05in II

t-strong- t - -

4-10 nm

1 Strong binding

binding Weak ---t--strong -

36 nm or multiple

2 Wori< ph;ase 3 Resting phase (ca. 9CI% of time; other (ca. 10% of time) myosin heads are meanwhile actfve)

N

68

N

Contraction of Striated Muscle (continued) II> the microtubule by incremental movement stroke, which ultimately results in the fmal of its two heads (8 om increments), as in a tug- positioning of the myosin heads (-> D2b ). The of-war. ln this case, 50% of the cycle time is remaining A-M complex (rigor complex) is "work time• (duty ratio • 0.5). Between two stableandcanagainbetransformedintoamuch consecutive interactions with actin in ske/etu/ weaker bond when the myosin heads bind ATP muscle, on the other hand, myosin II "jumps" anew (•softmingeffect"o/ATP,--+ 04). The high 36om (or multiples of36, e.g., 396 om or more flexibility of the muscle at rest is important for in rapid contractions) to reach the next (or the processes such as cardiac filling (lusitropism, 11th) suitably loc.ated actin binding site (..... 0, p. 206) or the relaxing of the extensor muscles jump from a to b). Meanwhile, the other myo- during rapid bending movement lf the cytosin heads working on this particular actin fila- solic Ca2• concentration remains> 10· 6 mol/1., ment must make at least another 10 to 100 oar- the Dl to D4cyclewill beginanew. This depends strokes of around 4-12 om each. The duty mainly on whether subsequent action potenratio of a myosin II head is therefore 0.1 to tials arrive. Only a portion of the myosin heads 0.01. This division oflabor by the myosin heads that pull actin filaments are •on duty" (low duty ensures that a certain percentage of the heads ratio) tD ensure the smoothness ofcontractions. The eaz- Ions released from the sarcowill always be ready to generate rapid contracplasmic reticulum (SR) are continuously tions. When filament sliding occurs, the z plates pumped back to the SR due to active transport approach each other and the overlap region of by Ca20-ATP•se (-> pp.17 A and 26), also called thick and thin filaments becomes larger, but SERCA. Thus, if the RYR-mediated release of the length of the filaments remains un- Ca20 from the SR is interrupted, the cytosolic changed. This results in shortening of the eaz- concentration rapidly drops below to· 6 I band and H zone(-+ p. 64). When the ends of moi/L and fliament sliding ceases (resting posithe thick filaments ultimately bump against tion;--+ D, upper left comer). Pai"Yillbumkl, a protein that occurs in the cythe Z plate, maximum muscle shortening occurs, and the ends of the thin filaments overlap tosol of fast-twitch muscle fibers {->type F; (-+ p. 71 C). Shortening of the sarcomere there- p.62), accelerates muscle relaxation after fore occurs at both ends of the myosin bundle, short contractions by binding cytosolic Ca2 +in exchange for Mgl•. Parvalbumin's binding afbut in opposite directions. Contraction cycle (-+C and D). Each of the fmity for Ca2• is higher than that of troponin, two myosin heads (M) of a myosin II molecule but lower than that of SR's Ca2 •-ATPase. It binds(withtheaidofMgl+)oneATPmoleculein therefore functions as a •stow" ea2• buffer. The course of the filament sliding cycle as their nucleotide binding pocket The resulting M-ATP complex lies at an approximately 45• described above mainly applies In Isotonic angle to the rest of the myosin filament (--+ D4). contractions, that is, to contractions where In this state, myosin has only a very weak affin- muscle shortening occurs. During strictly ityforactinbindlng.Now,duetotheinfluenceof Isometric contr•ctions where muscular tentheincreasedcytosolicQrZ+concentrotiononthe sion increases but the muscle length remains troponin-tropomyosin complex. actin (A) acti- unchanged, the tilting of the myosin heads and wresmyonn'sA'IPase,resultinginhydrolysisof the filament sliding cannot take place.lnstead, ATP(ATP-o ADP + P,)and the formation ofanA- the isometric force is created through the M-ADP-Pt complex (Pt • inorganic phosphate). d!!formation of the myosin heads. The muscle fibers of a dead body do not proThis causes the myosin II heads to lift again and as a result of this conformational change the duce any ATP. This means that, after death, Ca20 actin-myosinassociationconstantincreasesby is no longer pumped back into the SR, and the four powers often(-> Cl, D1 ). Now Pt detaches ATP reserves needed to break down stable A-M from the complex, which results in a40• tilt of complexes are soon depleted. This results in the myosin heads (--+ D2a). This causes the actin stiffening of the dead body or rtgor mortis, and myosin filaments to slide past each other which passes only aftl!r the actin and myosin (firststep ofthe power stroke). The following re- molecules in the musde fibers decompose. lease of ADP initiates part two of the power Hyperkalemlc and hypokalemic pertodlc panlysls, malignant hyperthermia

Plate 2.1 3 Contraction of str1ated Muscle II

69

D. Work qde of sliding ftlillmenb (IIOtonk mntl'ildlon) - - - - - - - - - - - - . Action potentiaI

N

ATP deavage.

myosin heads erect.

actin-myosin binding \

Loosening of acttn-myasln bond ("softening• ~ct ofATP), myosin heads erect

Myo$1n he;~d$ Ult due to 1'1 rele;ue

3

Stable "rigor complex" persists: rtgar 111111tll

2b

Further Ultlng of myosin heads due ID ADP release

70

N

Mechanical Features of Skeletal and Cardiac Muscle In contrast, the general muscle tone (reflex Action potentials generated in muscle fibers increase the cyiDsolic Ca2 • concentration tone), or the tension of skel!tal muscle at rest, l(al•],, thereby triggering a contraction is attributable to the arrival of normal action (skeletal muscle; -+ p. 67B; myocardium; potentials at the individual motor units. The ..... p. 206). In skeletal muscles, graclp.90).

Gillngllonlc blodcer, autonomic disorders and dysfunctions

Plate 3.1

Organization of ANS

83

A. Sdlernatfc view of llui:Dnomlc nl!n~aus system (ANS) - - - - - - - - - - - - , PllriiiJIIIPIIthl!tlc division {Cr.lniosacral centEn} Transmitter substanceJ: Preganglionic Acetylcholine

Sympatf1etlc: dlvbilon

Controlled

(Thoracic and lumbar cen12n) TransmltMr substances:

by superordinate centers

Preganglionic: Acetylcholine Postg;mgllonlc Norepinephrine (baptlon: s.-t gllllds. samemJoa.olarblood.......,k)

Postganglionic: Aatytchollne

I ..,

Alir«-- PasiQ;Ingllonlc: Cholnergk: -
+- --.--.....,

Stomach, lntatlne (w{o lower +- --.--....,

R

>+-- -&--.......,

Panaeu Glycogenesis

)

A

Exocrine secretion

. .

Preganglionic cholinergic

)

Postganglionic cholinergic

Tone

A

Secretion

A>+- -...--...., R>+-- -1--......,

Sph~

d 9

Cenltills

Erection

(Vasodilatation)

11- ActiYatlon

Urinary bladder Detrusor

Sp/Jincw-

!•Inhibition

C

R>+- -+ ---1

C•Conlrilctlon

R•

~xatlon

Spina/cord

D - Dilatation

Plate 3.3 Fundlons of ANS

15

dtvlllon (Preganglionic cholinergic: NN and M1 receptors, Sym-..u....... ............. postg;lngllonlc mainly adrenergic) a receplllrs (a,: If>,+ DAGt: a,: cAMP")

- - - - - - influx (-.B). Mrcholnoceptors occur mainly in smooth muscles. Similar to M,-cholinoceptors (-+ A. middle panel), M3-cholinoceptors trigger contractions by stimulating Ca2 • influx (-+ p. 74). However, they can also induce relaxation by activating ea2•-dependent nitric oxide synthase, e.g., in endotheliol cells (--+ p. 292). Termln.Uon of ACh adton is achieved by acetylcholinesterose-mediated cleavage of ACh molecules In the synaptic cleft (--+ p. 60). Approximately sm: of the liberated choline is reabsorbed by presynaptic nerve endings (--+B). Antlgonisb.Atropine block.s aU M-cholinoceptors, whereas pirenzepine, methoctnlmine, hexahydroslladlfmldot and tropicamlde selectively block M1-. M2-. MJ-, and Mt-cholinoceptors, respectively, tubocurarine block.s NMcholinoceptors (-. p. 60), and trimetaphan blocks NN'"cholinoceptors.

Cholinomimetic agents, cholinesterase lnhlblton, autonomic neuropathy

Plate 3.4 Choltnergfc Transmission A. Neurotlammtss1on In autonomic g a n g l i a - - - - - - - - - - - - - - .

••

~Peptide as a

• '~ ./

co-tr;msmltter

F-~====~ ~--~~~----~ ~P~ ~~-r~~ U

PIP

I

IP) DAG

Lm! EPSP

·u

~1 d:,_ ~t ~

l'bstpng/lolllc

+ nrc/lUll ~ ~ Peptlderglc EPSP or IPSP

' d i-----~---------·

Postsynaptic action potentials

Slnusnodr

orAV nodt all

Protein kinase A ..

~ Oi'"lnflux ..

87

88

Catecholamines, Adrenergk Transmission, and Adrenoceptors Certain neurons can enzymatically produce Ldopa (L-dihydroxyphenylalanine) from L-tyrosine, and is the parent substance of dopamine, norepinephrine, and epinephrinethe three natural Co~techoliimlnes, which are enzymatically synthesized in this order. oo.,.mlne {DA) Is the flnal step of synthesis In neurons CDntalnlng only the enzyme required for the first ~ (the aromatic L-amina add dmlrbo.Jcyi], t

cr,

~~

W.llllanof

I!IIDCYIDSIS

a2

cantndlan of a, • Blood w~Ris

or lelfttlan • Salivary glands

• Bronchioles • Sphlncll!n

• Insulin • Nore~Jinephrine • Acetylcholine,

• ~111s,

etc.

*-

!

.,.._ heart

Renin release

92

Composition and Function of Blood The blood volume of an adult correlates with his or her (fat-free) body weight (BW) (-+Table) and amounts to ca. 4-4.5 Lin women (11) and 4.5- SL in men(~) of 70kg BW. The funcUons of blood Include the tnmsport of Vilrious molecules ( C and p. 97 D).lg function to neutralize and opsonize antigens and to activate the complement system (see below). These mechanisms ensure that the respective antigen is specljically recognized, then eliminated by relatively nonspecific means. Some of the T and B cells have an immunological

At frrst contact with a virus (e.g., measles virus). the nonspecifiC immune system usually cannot prevent viral proliferation and the development of measles. The specific immune system, with its T-killer cells (-+ 82) and Jg (frrst JgM. then IgC; ->0), responds slowly: primary immune response or sensitization. Once activated, it can eliminate the pathogen, i.e.. the individual recovers from the measles. Secondary immune response: When infected a second time, spedfic JgG is produced much more rapidly. The virus is quicldy eliminated, and the disease does not develop a second time. This type of protection against infectious disease is called Immunity. It can be achieved by vacdnating the individual with a specific antigen (active immunization). Passive immunization can be achieved by administering ready-made Jg (immune serum).

memO!)'.

Precursor lymphocytes without an antigenbinding receptor are preprocessed within the thymus or bone marrow (B). These organs produce a set of up to 101 monospedfic T or B cells, each of which is directed against a specific antigen. Naive T and B cells which have not previously encountered antigen circulate through the body (blood -+peripheral lymphatic tissue -+lymph -+blood) and undergo do1111l exp~nslon and selection after contact with its spedfic antigen (usually in lymphatic tissue). The lymphocyte then begins to divide rapidly, producing numerous monospecific daughter cells. The progeny differentiates into plasma cells or "armed" T cells that initiate the elimination of the antigen.

. stanas encountered by that time are recognized as endogenous (self); others are identified as foreign (nonself). The inability to distinguish self from nonself results In autoimmune disease.

In Nile or Nonspecific lmrrunty

Lysozyme and complementfactors dissolved in plasma (-+Al)as well as naturalldllercells(NK alb) and phagocytes, espedally neutrophils and macrophages that arise from monocytrs that migrate into the tissues (-+ A2), play an important role in nonspecifiC immunity. Neutrophils, monocytes, and eosinophils circulate throughout the body. They have chemokine receptors (e.g., CXCRl and 2 fur IL-8) and are attracted by various chemokines (e.g., Il.-8) to the sites where microorganisms have invaded (chemotaxis). These cells are able to migrate. With the aid of selectins, they dock onto the endothelium (margination), penetrate the endothelium (diapedesis), and engulf and damage the microorganism with the aid of lysozyme, mcidantt (H201). oxygen radicals (Qz-, OH·, 101),and nllrlc oxide (NO). This is followed by digestion (lysis) of the microorganism with lysosomal enzymes. lfthe antigen (parasitic worm, etc.) is too large for digestion, other substances involved in nonspecific immunity (e.g., proteases and cytotoxic proteins) are also exocytosed by these cells. Redudng enzymes such as catalase and superoxide dlsmutase usually keep the oxidant concentration low. This is often discontinued, especially when mac· rophages are activated(-+ ~low and 83), to fully ex· plolt the bactericidal elfect of the oxidants. II>

Active and passive Immunization (vacdnatlon), autoimmune disorders, Jnfedlon,lnflammatlon

Plate 4.4 Immune System I A. Nonspecific lmi'IK.Ine defenses enhanced by ~pKiflc iintlbodles - - - - - - - - , HUIIIOI'ill

Cellular

Damages membr.;mes Interferons (IFN) lfN.a, ~. y inhibit viral proltfer.rtron;

lfN.V ~cttv;~tes m~crophages.

lclllercells,,- - - -....

BandT cells

Complement activation Alternative

dasslcal Clq

C3

1

Antigen;ntibody

Is\

Microorgan

complexes ;

Clq

4

\

,, r ;( lgE

lgA lgE lgM lgG

lgG" " ' '

lgG

+-

1t

lmmunglobullns (MOploteOI

99

100

8iii

Immune System (continued) ~ However, the resulting inflammation (~ A2, 4) also damages cells involved in nonspecifiC de~se

and, In some cases, even other endogenous cells.

Opsonlutlon (-o Al, 2) involves the binding of opsonins, e.g., IgG or complement factor C3b, to specific domains of an antigen, thereby (enhancing) phagocytosis. It is the only way to make ~cteria with a polysaccharide capsule phagocytosable. The phagocytes have receptors on their surface for the (antigen-independent) Fe segment of IgG as well as for C3b. Thus, the antigen-bound IgG and C3b bind to their respective receptors, thereby linking the rather unspecific process of phagocytosis with the specific immune defense system. Carbohydrate-binding proteins (lectins) of plasma, called collec:tins (e.g., mannose-binding protein), which dock onto microbial cell walls, also act as unspecific opsonins. The ~lement cascacle is activated by antigens opsonized by lg (classical pathway) as well as by non-opsonophilic antigens (alternative pathway) (-oAl). Complement components C3a,C4aand CSaactivate ~ophilsand eosinophils (-oM). complement components CS- C9 generate the membrane-attuck complex (MAC), which perforates and kills (Gram-negative) bacteria by cytolysis (-+ Al). This form of defense is assisted by lyscrzyme (• muramidase). an enzyme that breaks down murein-containingbacterialcellwalls.ltoccurs in granulocytes, plasma, lymph, and secretions. Nlltural killer (NK) cells are large, granular lymphocytes specialized in nonspecific defense against viruses, myco~cteria, tumor cells, etc. They recognize infected cells and tumor cells on "foreign surfaces• and dock via their Fe receptors on lgG-opsonized surface antigens (antibody-dependent ctll-medillted cyto~ly. ADCC; .... A3). ~orins exocytosed

by NK cells form pores in target cell walls, through which the NK cells release enzymes, thereby allowing subsequent target cell lysis (apoptosis). This not only makes the virus unable to proliferate (enzyme apparatus of the cell), but also makes it (and other intracellular pathogens) subject to attack from other defense mechanisms. Various lnbrferons (IFNs) stimulate NK crll activity: IFN-a, IFN-fl and, to a lesser degree, IFN-y. IFN-a and IFN-~ are released mainly from leulcllcytes and flbro-

blasts, while IFN-y is liberab!d from activated T eels and NK cells. Virus-inftcted cells release Ia~ quanti· ties oflFNs, resulting In heightened viral resistance In non-virus-infected cells. Defl!nslns are cytotoxic peptides released by phagocytes. They can exert unspeclflc cytotoxic effects on pathogens resistant to NK cells (e.g., by fonming ion channels in the target cell membrane).

Milavphllges arise from monocytes that migrate into the tissues. Some macrophages are freely mobile (free macrophagn). whereas others (fixed macrophages) remain restricted to a certain area, such as the hepaticsinus (Kupffer cells), the pulmonary alveoli, the intestinal serosa, the splenic sinus. the lymph nodes, the skin (dendritic l.angerhans cells), the synovia (synovial A cells), the brain (microglia), or the endothelium (e.g., in the renal glomeruli). lbe mononucle• phagocytk system (MPS) is the collective term for the circulating monocytes in the blood and macrophage$ in the tissues. Dendritic cells have pattern recognition receptors (PRRs) that identify lipopolysaccharides and lipoprotein components on the surface of certain bacteria. These are phagocytosed and broken down to peptide fragments, ultimately leading to antigen presl!ntation in the specific immune system (-->B). Transmembrane PRRs include certain toll-like receptors ('n.Rs). SpecifiC Immunity: Cell-Mecr.ated lmmUM Responses

Since specific cell-mediated immune responses through •armed" T effector cells need a few days to become effective, this is called delllyed-rype immune response. It requires the participation of professional antlg•n-presentlng cells (APes): dendritic cells, macrophages, and B cells. APCs process and present antigenic peptides to the T cells in association with MHC-1 or MHC-H proteins, thereby delivering the costimulatory signal required for activation of naive T cells. (The gene loci for these proteins are the class I [MHC-1[ and class 11 [MHC-11) major histocompatibility complexes [MHC[), HIA (human leukocyte antigen) is the term for MHC proteins in humans. Virusinfected dendritic cells, which are mainly located in lymphatic tissue, most commonly serve as APCs. Such HIA-restricted antigen presentation (--+ 81) involves the insertion of an antigen in the binding pocket of an HIA

Tumor cell, defense against viruses and bacterta, Immune suppression, AIDS

~

Plate 4.5 Immune System II B. Spedllc Immunity: T C, narrow arrows). This amount of thrombin is suffident to activate V, Vlll, IX, and X (-+ c, bold arrows) and then, by way of positive feedback, release the amount of thnxnbin that allows clot fonnalion (see below). The effects of the TF-Pl-Ca1 • -VIla complex are now inhibited by TFPI (tissue factor pathway inhibitor) (.... C. left). The "endogenous" activation (-+ C, IDp right) starts through contact activation of XII. Becaust' patients with a genetic defect of XII do not display hemorrhagic diatheses, it is now believed II>

Vltilmln Kdeficiency, thrombocytopenia and thrombocytopathy, ht'mophllla

Plate 4.9 Hemostasis 11. Tests

c. Blood d o t t i n g - - - - - - - - - - - - - - - - - - - - - - , EIIDgenaus ac:lfvlldan lbr Tf}

EllllagBalslldhdon

(on foreign surf.aces)

(tissue Injury)

-

----+

11uue

---+

----it

camplox Adivote> ca......lbtn nhlblls

HMK

KK

XII~~____,::!_O ..,. J~

PKK

~ *==::::;:=XI

D. Causes and mnsequenms of a biMcllng ~ndency - - - - - - - - - - - - ,

Mlllnly Joint blieeft9 andbl~spob

r-

E. Clotting tests for diagnosing plasmatic hemorrhagic diatheses Cammanfhll.-.,_, of balh IJllleml:

1IIIUe factor system:

factor VII

....___

Quick Vlllue

__ ,

HMK and prekalllkreln

T lh"rombln t~T

--

Pa111al d.-ombopllstln nne (PTT}

_ [ ---~!!.."2..!!~'!---JI L

contect system: factors VIII,IX, XI. XII,

factors II, V. X as "Well as

109

., 8

..

iii

110

Hemostasis (rontinued) II> that this activation type only plays a part on external (test tube) or internal (vasrular prosthesis) foreign surfaces. FIH1n fonMtlon (-+C. bottom~ Xa and Va form an additional complex with PL and CaH. ea2+-mediated assembly of the different factors again takes place on negatively charged PL surfaces. On platelet activation, anionic phosphatidylserine moves out from the cytosol (flipping via the scramblase enzyme), which further promotes clotting. Thrombin is produced by splitting the N-terminal end of prothrombin, which Is fJ.Xed to PL via ca2+. The thrombin liberated in the process now activates not only V, VIII, IX, X, and XI (see above) but also fibrinogen to fibrin, as well as fibrin-stabilizing factor (XIII). The single (monomeric) fibrin threads form a soluble meshwork (fibrin.: "s" for soluble) which XIIIa ultimately stabilizes to Insoluble fibrin (fibrin,). Xllla links the side chains of the fibrin threads via covalent bonds. Thrombin also supports platelet aggregation, resulting In a very stable tight seal (red clot) formed by the aggregated platelets (white clot) and the fibrin meshwork.

F1H1noly5ls •nd lhromboprotectlon 1b prevent excessive clotting and occlusion of major blood vessels (thrombosis) and em-

Thromboprotectlon. Antithrombin III. a serpin, is the most important thromboprotective plasma protein (-+C). It Inactivates the protease activity of thrombin and factors IXa, Xa, Xla, and Xlla by forming complexes with them. This is enhanced by heparin and heparin-like endothelial glucosaminoglycans. Heparin is produced naturally by mast cells and granulocytes, and synthetic heparin is injected for therapeutic purposes. In acute thrombosis, platelet factor 4 inhibits antithrombin III transiently (..... B). The binding of thrombin with endothelial thrombomodulin providts furthtr thromboprotection. Only In this form does thrombin have anticoagulant effects (-+ C, negative feedback). Thrombomodulin activates prottin C to ca which, after binding to proteinS, deactivates Va and VIlla. The synthesis of proteins C and Sis vitamin K-dependent. Other plasma proteins that inhibit thrombin art UJ·macroglobulln and a,-..ntltrypsln (-+C). Endothelial eels secrete tis- factor pathway Inhibitor (TFPI; -+ q , a substance that Inhibits exogtnous activation of coagulation, and prosbcydn (-prostaglandin b), which inhibits platelet adh6ion to the nonnal endothelium. AntkxJagulanb are administered for thromboprotection in patients at mk of blood dotting. Injected he,.m has Immediate action. Oral coumarin derivatM!s (phenprocoumon, warfarin, acenocoumarol) are vlbmln K antagonlds that wort by inhibiting epoxkle reductase, which Is necessary for vitamin Krecycling. Therefore, these drugs do not take effect until the serum concent13tlon of vitamin K-dependent coagulation factors has decrtased. Rlvaroxaban prevents thrombosis by Inhibiting Xa (--+C). Cyclooxygenase lnhlblton, such as aspirin (acetylsallcytlc acid), Inhibit platelet aggregation by blocking thromboxane A, (iXA,) synthesis while dopldogrel inhibits ADP-mediaed plaelet activation. Hemorrhlglc dlathetes (-+ D) can have the following causes: (a) congenital deficiency of certain coagulation factors (lack of VIII or IX, for example, leads to hrmophH/a A or 11. respectively); (b) acquired defkiency of coagulation factors; the main causes are li-m- damage as wei as vitamin K defiCiency; (c) Increased consumption of coagulation factors, by disseminated intrawzsculor coagulation; (d) platelet defiCiency (thrombocytDpenia) or plaelet: de~ (thrombocytopathy): (e) certain vascular diseases; and (f) excessive fibrinolysis.

bolisms due to clot migration, fibrins is re-dissolved (fibrinolysis) and inhibitory factors are activated as soon as vessel repair is initiated. Fibrinolysis is mediated by plasmin (-+F). Various factors in blood (plasma kallikrein, factor Xlla), tissues (tissue plasminogen activator, tPA, at endothelial cells etc.), and urine (urokinase) activate plasminogen to plasmin. Activated platl!lets release plasminogen activator Inhibitor 1 (PAI-l: -+B) to block fibrinolysis temporarily following recent endothelial injury. Therapeutically, streptokinase, urokinase and tPA are used to acttvate plasminogen. This Is useful for dissolving a fresh thrombus located, e.g., in a coronary artety. Fibrin is split into .fibrinopeptides which inhibit thrombin formation and polymerization of fibrin to prevent further clot formation. ar antiplasmln is an endogenous inhibitor of fibrinolysis. 7tanexamlc acid is administered therapeutically for the same purpose. Thrombosis. embolism, antlcoagul;mt therapy, thrombolysis

Plate 4.10 Fibrinolysis and Thromboprotectlon F. Rbrtnolysls - - - - - - - - - - - - - - - - - - - - - - - ,

111

., 8

..

iii

a,-Anllplasmln

G. 5uppn!551on of c o a g u l a t i o n - - - - - - - - - - - - - - - - - . .

Exogenous acttvatfon

X

!

Prvthrombin

l·

-.!......---~ -+

::~I

-+

--+ ~

--+ caw.rts to ----JI

lnhblts

~croglobulrn

ar·Antitryp5ln

!

Abrln

u

I"' a..

112

Lung Function, Respiration The lung is mainly responsible for respiration, in diameter) located on the terminal branches but it also has metabolic functions, e.g. con- of the bronchial tree. They are surrounded by a version of angiotensin I to angiotensin D dense network of pulmonary apllarles and (..... p. 196).1n addition, the pulmonary drcula- have a total surface area of about 100m2. Betion bu!f!n the blood volume (..... p. 216) andfil- cause of this and the small air/blood diffusion distances of only a few 1-1m (..,. p. 22, Eq. 1.7), ters out small blood clots from the venous drculation before they obstruct the arterial sufficient quantities ofO:i can clffuse across the alveolar wall into the blood and col toward the drculation (heart, brain I). External r-.splmlon is the udYnge of alveolar space (-+p.126ff.), ~nat a tenfold gnes between the body and the environment increased ol demand. The oxygen-deficient (intmwl or tissue respiration involves nutrient "venous• blood of the pulmonary arteries is oxidation, ..... p. 240). Convec:Uon (bulk flow) is thus oxygenated ("arterialized") and pumped the means by which the body transports gases back by the left heart to the periphery. over long distances (..... p. 24) along with the The cardiac output (CO) Is the volume of blood flow ofair and blood. Both flows are driven by a pumped through the pulmonary and systemic drcupressure difference. Diffusion is used to trans- lation per unit time (5-6 L/mln at rest). The arterialport gases over short distances of a few tJ.ID- -ous Oz difference (1vDOJ) Is the difference bee.g., through cell membranes and other physi- tween the arterial 0 1 fraction In the aorta and in ological barriers (-+ p. 20ff.). The exchange of mixed venous blood of the right atrium. avDOz Is ca. gas between the atmosphere and alveoli is 0.05 Lof Oz per Lof blood. CO x avDOz gives the Oz wlume transpomd per unit time from the lungs to the called ventilation. Oxygen (02) in the inspired periphery. At ~t. it amounts to (6 x 0.05 ·) 0.3 L/ air is convected to the alveoli before diffusing min, a value matching that of Vo, (see above). lnacross the alveolar w.lll into the bloodstream. W!t'sely, if Vo, and av001 have been measured, CO It is then transported via the bloodstream to Gln be Gllrulated (F'Idl't prtndple): the tissues, where it diffuses from the blood CO = VoJavOo, 15.1] into the cells and, ultimately, to the intracellu- The stroloe VDitJme (SV) Is obtained by dividing CO by lar mitochondria. Carbon di011ide (C01) pro- the heart ratr (pulse ratr). duced in the mitochondria returns to the lung ParUal Preuun!. According to Dalton's /Qw, the in venous blood. total pressure (P~u~o~) ofa mixture of gases is the The tot.l venltladon per unit time, Vr, is the sum of the parUal p...ssuNS (P) of the involume (V) of alr inspired or expired per time. dividual gases. The volume fracUon (F. in L/L; As. the expiratory volume is usually measured, ..... p. 398) of the individual gas relative to the it is also abbreviated ((L (The dot means "per total gas volume times P-1 gives the partial unit time"). At rest, the body maintains a (IE of pressure-in the case of 0:!, for example, Po1 = about 81./min, with a corresponding oxygen F02 x The atmospheric partial pressures consumption me (((02) of about 03 L/min and in dry ambient air at sea level (P-• • 101.3 kPa a C01 ellmlnlltlon me (((col) of about 0.2.5 L/ = 760mmHg) are: F02 • 0.209, Fc02 • 0.0004, min. Thus, about 26 L of air have to be inspired and FN2 •noblopses - 0.79 (-+A. top right). and expired to supply 1 L of 0:! (respiratory If the mixture of gases is "wet,• the partial equiw/ent • 26). The tidal volume (Vr) is the pressure of wamr, P112o has to be subtracted volume of air moved in and out during one res- from Pma~ (usually - atmospheric pressure). piratory cycle. ~E is the product ofVT (ca. 0,5 L The other partial pressures will then be lower, at rest) and respiration me/(about 16/min at since Px - Fx (Ptubl - 1'1120). When passing rest) (see p. 78 for values during physical through the respiratory tract (37 OC), inspired work). Only around 5.6L/min (at/• 16mln-1) air is fully saturated with water. As a result. of the VE of 8 L/min reaches the alveoli; this is 1'1120 rises to 6.27 kPa (47 mmHg), and Po1 known as .,_... wntllatlon (VA). The rest drops 132 kPa lower than the dry atmospheric fills airway space not contributing to gas ex- air (-+ p. 118). The partial pressures in the inchange (dHd space venUiatlon, Yo; ..... pp. 120 spiratory air, alveoli, arteries, veins (mixed and 126). venous blood). tissues, and expiratory air (all The human body contains around 300 mil- "wet") are listed in A. lion alveoli, or thin-walled air sacs (ca. 03 mm Pulmonary embolism and edema, hypoxia, hypercapnia and hypocapnia

P-•·

Plate 5.1 Lung Function, Respiration

113

~c.~~·n~rt----------------------------------------~

Partial pressures kPa(mmHg)

Frxtlon (1../IJ

Fo. •0.21 Fro.•0.0004

15.33(115)

~)

Ill

.038(0.23

80.10 (601)

Ip• 101.3 (760) (Sea level)

13.33(100)

5.2 (39)

6.27 (47) 76.5(574)

12.66(95) 5.33(40) 5.27 (41) 6.0 (45)

6.27 (47)

Veins--' ('lll!li(II'CXJW"t)

6.27(47)

114

Mechanics of Breathing Pressure differences between the alveoli and the environment are the driving "forces• for the exchange of gases that occurs during ventilation. Alveolar pressure (PA • intrapulmonary pressure; -+B) must be lower than the barometric pressure (1\u) during Inspiration (breathing in), and higher during explndon (breathing out).lfthe barometric pressure p,_ is defined as zero, the aiVI!olar pressure is negatiVI! during inspiration and positive during expiration (-+ B). These pressure differences are created through coordinated movement of the diaphragm and chest (thorax), resulting in an increase in lung volume (Vpu1m) during inspiration and a decrease during expiration (-+Al,Z). The lnsplr.tory muscles consist of the diaphragm, srolene muscles, and external intercostal musdes. Their contraction lowers (flattens) the diaphragm and raises and expands the chest, thus expanding the lungs. Inspiration Is therefore octilll!. The external intercostal muscles and accessory respir.~tory muscles are activated for deep breathing. During explr~. the diaphr.~gm and other inspir.~tory muscles rdait. ther~ raising the diaphr.~gm and lowering and reducing the volume of the chest and lungs. Since this action occurs primarily due to the intrinsic elastic recoil of the lungs(-+ p. 122), expiration Is possW>e at rest. In deeper breathing. active mechanisms can also play a role in expiration: the infmlol intm:ostol muscles contract, and the diaphragm Is pushed upward by obdomlnol pressure created by the musdes of the abdominal wall. lntei'C05t.11 musd11. Two adjacent ribs are bound by Internal and external Intercostal muscle. Counteractivity of the muscles Is due to variable leverage of the upper and lower rib (-+ Al). The distance separating the Insertion of the external Intercostal muscle on the upper rib (Y) from the axis of rotation of the upper rib (X) is smaller than the distance separating the Insertion of the muscles on the lower rib (Z') and the axis of rotation of the lower rib (X'). Therefore, X' -Z' is longer and a more powerful lever than X-Y. The chest generally rues when the external Intercostal muscles contract, and lowers when the opposing intennal intercostal muscles contract (X-Y' > X'-Z). To exploit the motion of the diaphragm and chest for ventilation, the lungs must be able to follow this motion without being completely attach~ to the diaphragm and chest. This is achieved with the aid of the pleura, a thin fluid-covered sheet of cells that invests each lung (viscerul pleuru), thereby separating it

from the adjacent organs, which are covered by the pleura as well (parietal pleuru). The lung has a tendency to shrink due to its intrinsic eklstidty and al'tltOiar surflice tmsion (-+ p.124). Since the fluid in the pleural space cannot expand, the lung sticks to the inner surface of the chest. resulting in suction (which still allows tangential movement of the two pleural sheets). Plfilral pnssuN (Pp~) is then negative with respect to atmospheric pressure. Pp~. also called intrupleuml (P~p) or intruthomdc pressure, can be measured during breathing (dynamically) using an esophageal probe (- Ppt). The intensity of suction (negative pressure) increases when the chest expands during inspiration, and decreases during expiration (--> B). Pp1 usually does not become positive unless there is very forceful expiration requiring the use of expiratory muscles. The transmural pressures (P,.) of the respiratory system (internal pressure minus external pressure) are calculated using P", Pp1 (-+I) and the environmental pressure (P~~or • 0, see above): - Ptm ~ lungs: PA-Ppi • transpulnnonary pressure (TP) (.... B, bottom right) - P., of thorax (with diaphragm): Po~ -0 = Po~ = transthoracic pressure - Ptm ~lungs plus thorax: P" -0- P"- transmural pressure of the whole resplratOI)' system. PlotUng the latter pressure (PA) against lung volume gives the resting pressure-volume curve of the respiratDry system (-+ p. 123 A).

Characterlutlon of bNathlng activity. The terms hyperpnea and hypopnea are used to describe abnormal increases or decreases in the depth and rate of respiratory movements. 1l1chypnea (too fast), brudypnea (too slow), and apnea (cessation ofbreathing) describe abnormal changes in the respiratory rate. The terms hypervmtilationandhypoventilationimplythat the volume of exhaled C02 is larger or smaller, respectively, than the rate of COz production, and the arterial partial pressure of COz (Pactll) decreases or rises accordingly (-+ p. 150). Dyspnea is used to describe difficult or labored breathing. and orthopnea occurs when breathing is difficult except in an upright position.

Asphyxia, rtb fr~etures, ankylosis, artificial respiration, pleurisy

Plate 5.2 Mechanics of Breathing

115 c

~

I!

a.

hrng

&!"'

11'1

l'iltton

1

I

ll'illion

B. Alvmlilr pressure PA and pleul"'l pressure Ppt during rapfratton - - - - - - , lnspll'illion

Explr.llfon

tVpurm(l.)~ .. .n OA_--

~§0.2

o~-------~~

kPa em!¥) +0,2 0

-0.2 -OA

-0.6

+2 r - - - - - -

116

Purltlcation of Respiratory Air Inhaled foreign partides are trapped by mucus in the nose, throat, trachea, and bronchial tree. The entrapped partides are locally engulfed by macrophages andfor are driven back to the trachea by the secondary cilia (-+ p. 36) lining the bronchial epithelium. Clllal esalator: The cilia move at a rate of 5-10 s- 1 and propel the mucus toward the mouth at a rate of 1 em/min on a film of fluid secreted by the epithelium. Heavy smoking or cystic fibrosis (mucoviscidosis) can impair ci1ial transport A volume of 10-lOOmL of mucus is produced each day, depending on the type and frequency of local irritation (e.g., smoke inhalation) and vagal stimulation. Mucus is usually swallowed, and the fluid fraction is absorbed in the gastrointestinal tract.

Artlfldal Resplntlon Mouth-to-mouth resuscitation is an emergency measure performed when someone stops breathing. The patient is placed flat on their back. While pinching the patient's nostrils shut. the aid-giver places his or her mouth on the patient's mouth and blows forcefully into the patient's lungs (..... Al). This raises the alveolar pressure (-o p. 114) in the patient's lungs relative to the atmospheric pressure outside the chest and causes the lungs and chest to expand (inspiration). The rescuer then ~ moves his or her mouth to allow the patient to exhale. Expulsion of the air blown into the lungs (expiration) occurs due to the intrinsic elastic recoil of the lungs and chest. This process can be accelerated by pressing down on the chest. Provided that the blood circulation of the patient is intact, the rescuer should ventilate the patient at a rate ofabout 16min-1• The expiratory A2). The patient's body is enclosed from the neck down in a metal tank. To achieve Inhalation, pressure In the tank Is decreased to a level below normal ambient pressure and, thus, below alveolar pressure. This pressure difference causes the chest to expand (Inspiratory phase), and the cessation of negative pressure in the tank allows the patient to breathe out (expiratory phase). This type of respirator Is used to ventilate patients who require long-tenn mechanical ventilation due ro paralytic di~ases, such as polio.

Pneumothorax Pneumothorax occurs when air enters the pleural space and Pp1 falls to zero, which can lead to colapse of the affected lung due ro elastic recoil and resplra· tory failure ( -+ 8). The contralateral lung is also 1mpaRd because a portion of the inspired air travels back and forth between the healthy and collapsed lung and is not available for gas exchange. Closed pneumathorux, I.e., the leakage of air from the alve· olar sp.ace Into the pleural space, can occur spontaneously (e.g., lung rupture due to bullous emphy· sema) or due to lung Injury (e.g., during mechanical ventilation • barotrauma: -> p. 142). Open pneumothorax (-> Ill) can be caused by an open chest wound or blunt chest trauma (e.g., penetration of the pleura by a broken rib). Tension pneumothoru (-+ 83) is a life.threatl!ning form of pneumothorax that occurs when air enters the pleural space with eo~ery breath and can no longer be expelled. Aflap of skin or similar at the trauma site acts like a valve. Positive pressure develops in the pleural space on the ),.,, PH,o at TAmt>)

BTPS: Body temperature pressur~saturated (310 K. Pt..r, PH,o • 6.25 kPa) It follows that: Vswo = M• R • 273/101 000 (m3 ] VIJ~ • M · R · Tornlo/(l'b.r-I'H,o) (m3 ] Vrr~ • M · R · 310/(Pb.t-6250) (ml]. Conftnlon fKtors are derived from the respective quotients (M · R Is a reducing factor). Elcample: Vmsf VSTI'P • 1 .17. If Vms Is measured by spirometry at room temperature (Tomb • 2o•c; PHzo.t • 2.3 kPa) and Par - 101 kPa, Vlll'S - 1.1 VIJPS and VSTl'O - 0.9 VATPS·

Emphysema, restrictive lung diseases, kyphoscoliosis. lung diagnosis

Plate 5.4 Lung Volumes and Their Measurement A. Lung vollmesand ttlelr measurement---------------,

119 c

~

I!

a. &!"' 11'1

Vltill capacity Tolclllung capacity

r

Paper feed Maximum inspiration

Inspiratory rese!VI! volume

(ca.3Q

1

Normal inspiration

Elq)l~tory rt!SI!IV1! volume

(ca.1.7t:)

-------1-1

____!_______

t l

Residual volume (ca. 1.3 t:) (not measurable by splromelry)

-3

120

Dead Space, Residual Volume, Airway Resistance The exchange of gases in the respiratory tract occurs in the alveoli. However, only a portion of the tidal volume (Vr) reaches the alveoli: this islcnown as the alveolar part (VA). The rest goes to dead space (not involved in gas exchange) and is therefore called dead space volume (Yo). The oraL nasaL and pharyngeal cavities plus the trachea and bronchi are jointly known as physiologicol dead spore or conductingzoneoftM airways. The physiological dead space (ca. 0.15 L) is approximately equal to the functional dead space, which becomes larger than physiological dead space when the exchange of gases fails to take place in a portion of the alveoli (-+ p. 126). The functions ofdead space are to conduct incoming air to the alveoli and to purify (-+ p. 116), humidify, and warm Inspired ambient air. Dead space is also an element of the vocal organ (-+p.392). The Bohr equation(-+ A) can be used to estiINite the dead space. Deriwlion: The expired tidal volume VT is equal to the sum of its alveolar part VA plus~ s~Vo(.... A, top). Each of these three variables has il characteristicCOz fraction: Frco, in Vr, F~~eo, in VA. and F~eo, in Vo. fleD, is extremely small and therefore negligible. The product of each of the th~ volumes and theircDITespondlng COz fraction gives the volume of C02 for each. The co, volume In the expired air (VT · FIW,) equals the sum of the co, volumes in its two components, i.e., in VA and Vo (-+A).

Thus, Vr, FEcol and FAcol must be known to determln• the dud space. Vr can be measured using a spirometer, and FEco, and FAce, can be measured using a Bunte glass burette or an infrared absorption spectrometer. FAcol is present in the last expired portion of Vr-i.e., in alveolar gas. This value can be measured using a Rahn valve or similar device. The functional residual capacity (FRC) is the amount ofair remaining in the lungs at the end of normal quiet expiration, and the residual volume (RV) is the amount present aft:rr forced maximum expiration. About 035 L of air (VA) reaches the alveolar space with each breath during normal quiet respiration. Therefore, only about 121 of the 3 L oota1 FRC is renewed at rest. The composition ofgases in the alveolar space therefore remains relatively constant M•asurem•nt of FRC and RV cannot be performed by spiromet ry. This must be done using

indirect techniques such as helium dilution (-.B). Helium (He) is a poorly soluble inert gas. The test subject is instructed to repeatedly inhale and exhale a 1cnown volume (Vsp) of a helium-containing gas mixture (e.g., Fll CEF during inspiration, and CEF > LCF during expiration. The difference between LCF and CEF, i.e., the net force (-+ blue arrows in Al, 3, 5, 6), is equal to the alveolar pressure (PA) if the airway is closed (e.g., by turning a stopcock, as in A1-3, 5, 6) after a known air volume has been inhaled (Vpu~m > 0,-+ A2) from a spirometer or expired into it (Vpu1m < 0, -+Al). (In the RRP, CEF - LCF, and PA - 0). Therefore, the relationship between VpuJm and PAin the lung-chest system can be determined as illustrated by the sbltk rating prnsun-volume (PV) curve (-+blue curve In A- 0). According to Lop/ace's low (d. p. 200): AP = 2y/r (Pa). (5.31

Since y nonnally remains constant for the respective liquid (e.g.• plasma: 10-3 N . m- 1), 1\P becomes larger and larger as r decreases. Soap bubiM IIIOCt.l. If a flat soap bubble is positioned on the opening of a cylinder, r will be relatively large (-A1) and AP small. (Since two air-liquid interfaces have to be considered in this case, Eq. 53 yields 1\P = 4yfr.) For the bubble volume to expand, r must initially decrease and AP must increase(--. A2). Hence, a relatively high "opening pressure" is re-quired. As the bubble further expands, r increases again (- Al) and the pressure require-ment/volume expansion ratio decreases. The alveoli work in a similar fashion. This model demonstrates that, In the case of two alveoli connected with each other (..... A4), the smaller one (L\P1 high) would normally become I!VI!n smaller while the larger one (APt low) becomes larger due to pressure equalization. SurfKbnt (au:face-adive Ggellt) lining the inner alveolar surface prevents this problem by lowering y in smaller alveoli more potently than in ~r alveoli. Surfactant is a mixture of proteins and phospholipids containing dipalmitoyllecithin and surfactant proteins (SPA, 8, C, and D) secreted by alveolar type II cells.

Newborn respiratory distress syndrome (NRDS), a serious pulmonary gas exchange disorder, is caused by failure of the immature lung to produce sufficient quantities of surfactant. Lung damage related to (h toxicity(..... p. 144) is also partly due to oxidative destruction of surfactant, leading to reduced compliance. This can ultimately result in alveolar collapse (atelectasis) and pulmonary edema.

Dynamic Lung Function Tests The maximum brelthlng capadty (MBC) is the greatest volume of gas that can be breathed (for 10 s) by voluntarily Increasing the tidal volume and respiratory rate (..... B). The MBC normally ranges from 120 to 170L/min. This capacity can be useful for monitoring diseases affecting the respiratory muscles, e.g., myasthenia gravis. The forced uplratory volume (FEV or Tiffeneau test) is the maximum volume of gas that can be expelled from the lungs. In clinical medicine, FEV in the first second (FEVtl is routinely measured. When its absolute value is related to the forced vital capacity (FVC), the relative .FEV, (normally> 0.7) is obtained. (FVC is the maximum volume of gas that can be expelled from the lungs as quickly and as forcefully as possible from a position of full inspiration; -C). It is often slightly lower than the vital capacity VC. Maximum expiratory flow, which is measured using a pneumotachygraph during FVC measurement, is around 10 L/s. Dynamic lung function tests are useful for distinguishing restrictive lung disease (RID) from obstructive lung disease ( OID). RID is characterized by a functional reduction oflung volume, as in pulmonary edema. pneumonia. and impaired lung Inflation due to scoliosis, whereas OlD is characterized by physical narrowing ofthe airways, as In asthma, bronchitis, emphysema, and vocal cord paralysis c~a). As with VC (..... p. 118), empirical formulas are also used to standardize FVC for age, height, and sex.

Resplmory distress In pnematune Infants, hyperoxla, obstructive lung diseases

Plate 5.7 Surface Tension, Lung Function Tests

125

Ill

:z

1

4

3

B. Maximum breathing capacity (MBC) - - - - - - - - - - - - - - - - , Maximurn respiratory depth and rate

~~~--~~--~ ~-~ ~~--~-

Nonnal -+if---+--

C. Forced l!Xplred volume In lint second (FEV1)

-------------,

1 MeAJ). The HCDJ- concentration in erythrocytes therefore becomes higher than in plasma. As a result, about three-quarters of the HC01- ions exit the erythrocytes by way of an HCOJ-/0antiporter. This anion uchange is also called Hamburger shift (-> A4). W Ions are liberated when ~ in RBCs circulating in the periphery is converted to HCDJ- and hemoglobin (Hb) carbamate.

tablishment of equilibrium, large quantities of COz can be incorporated in HC03- and Hbcarbamate. Deoxygenated hemoglobin (Hb) can take up more W ions than oxygenated hemoglobin (Oxy-Hb) because Hb is a weaker acid (->A). This promotes COz uptake in the peripheral circulation (Haldane ejftct) because of the simultaneous liberation of Oz from erythrocytes, i.e., cleoxyg~nation of Oxy-Hb to Hb. In the pulmollllfY capllartes, these reactions proceed in the opposite direction (... A, top panel, red and black arrows). Since the Pco, in alveoli is lower than in venous blood, C02 diffuses into the alveoli, and reactions 5.4 and 5.5 proceed to the left. C02 Is rel~ased from HC01- and Hb carbamate whereby W ions (released from Hb) are bound in both reactions (->A7, AI), and the direction ofHCOJ-/Ct- exchange reverses (->A9). Reoxygenation of Hb to Oxy-Hb in the lung promotes this process by increasing the supply of H' ions (Haldant ef-

fect).

co, ~ In bloocl (mmoi/L blood, 1 mmol-22.26mlCOz)

A11ettal blood: Plasma• 0.7 Erythrocytes.. 0.5

13.2 6.5

0.1 1.1

14.0

Blood

19.7

1.2

22.1

Erythrocytes• • 0.6

14.3 7.2

1.4

9.2

Blood

21.5

1.5

24.4

Mixlld venous bloocl: Plasma • 0.8

HC01- + W, Hemoglobin carbamatt /Omtlltion;

1.4

8.1

ca. 0.1 15.2

Artert-nous COa dlfferenctt In bloocl 0.2 1.8 0.3 2.3 Pemi!ntlge of tot.l1rtrrtovenous difference

9:1:

78:1:

13:1:

• Approx 0.55l plasma/l blood; • • G erythrocym/l blood

Bicurbonatt formation; COz + lilO -

7.2

[5.4]

Hb- NHz + COz ~ Hb-NH-coo- + W. [5.5] Hemoglobin (Hb) is a lrey buller for W ions in the red cells (-+ A&; see alsop. 148, "Nonbicarbonate buffers"). Since the removal of W ions in reactions 5.4 and 5.5 prevents the rapid esHyperventilation, hypercapnia, addosls, alkalosis

100:1: .

0.45 L

Plate 5.11

COz Transport In Blood

~~t~n~rtln~---------------------------------.

133 c

~

I!

a. &!"' 11'1

In lung

In periphery

Hemoglobin illS buffer

134

C02 Binding In Blood The total urbon dioxide concentration The concentration ratio of HC03- to dis(=chemically bound "C01" +dissolved CCh) of solved C(h in plasma and RBCs differs (about mixed venous blood is about 24-25 mmol/L; 20:1 and 12:1, respectively). This reflects the that of arterial blood is roughly 22-23 mmoi/L difference in the pH of plasma (7.4) and eryNearly 90% of this is present as H(lh- (->A. throcytes (ca. 7.2) (-+ p.146ff.). right panel, and 14ble on p. 132). The partial pressure ofC(h (Pen,) is the chieffactor that de- COa In CerebrospiMI Fluid (CSF) termines the C02 content of blood. The C:Oz dissoc!Mion curw illustrates how the total C02 Unlike Hco,- and W, C02 can cross the bloodcerebrospinal fluid barrier with relative ease concentration depends on Pen, (-+A). The concentration ofdissolved c~. [CCh), in (..... Bl and p. 328). The Pen, in CSF therefore plasma is directly proportional to the Pc02 in adapts quickly to 1cub d11nges In the Pen, in blood. C01-related (respiratory) pH changes in plasma and can be calculated as follows: the body can be buffered by nonbicarbonate [C~)· aa, · Pen, (mmoi/L plasma or mL/L plasma), [5.6] buffors (NBBs) only (-+p.152). Since the conwhere am, is the (Bunsen) solubility coefjicient centration of nonbicarbonate buffers in CSF is very low, an acute rise in Pro, (respiratory acidror C02. At 37 ·c. osis; -+ p. 152) leads to a relatively sharp am, • 0.225 mmol . L-1 . kPa-1• After converting the amount of C02 into decrease in the pH of CSF (-+81 , pH~~). This decrease is registered by central chemosenvolume C(h (mL • mmol · 22.26), this yields sors (or chemoreceptors) that adjust respiraam, • 5 mL · L-1 · kPa-1• The curve for dissolved col is therefore linear tory activity accordlngly (-> p.140). (In this book, sensory receptors are called sensors in (-+A. green line). Since the buffering and carbamate forma- order to distinguish them from hormone and tion capacities of hemoglobin are limited, the transmitter receptors.) The concentration of nonblcarbonate relation between bound ~ and Pro, is curvilinear. The dissociation curvefor total col is cal- buffers in blood (hemoglobin. plasma proculated from the sum of dissolved and bound teins) is high. When the C01 concentration inC(h (..... A, red and violet lines). creases, the liberated W ions are therefore efC01 binding with hemoglobin depends on fectively buffered in the blood. The actual the degree of oxygen slturation (So,) of HCO,- concentration In blood then rises hemoglobin. Blood completely saturated with (-+ p.154), to ultimately become higher than Ch is not able to bind as much C01 as 02-free in the CSF. As a result, HC03- diffuses (relablood at equal Pen, levels (->A. red and violet tively slowly) into the CSF (-+ 82), resulting in lines). When venous blood in the lungs is a renewed increase in the pH of the loaded with 01, the buffer capacity of CSF because the HC03-/COl ratio increases hemoglobin and, consequently, the levels of (-> p.148). This, in tum, leads to a reduction in chemical C02 bindlng decrease due to the Hal- respiratory activity (via central chemosendane effect (-+p.132). Venous blood is never sors), a process enhanced by renal compensacompletely void of (h, but is always 02-satu- tion, i.e., a pH increase through HC03- retenrated to a certain degree, depending on the tion(-+ p. 152). By this mechanism, the body degree of (h extraction (-+ p. 138) of the organ ultimately adapts to chronk elav1t1on In Pcn,in question. The 5o, of mixed venous blood is i.e., a chronically elevated Pen, will no longer about 0.75. The C(h dissociation curve for 5o,= represent a respiratory drive ( cf. p. 140). 0.75 therefore lies between those for 5o, • 0.00 and 1.00 (..... A, dotted line). In arterial blood, Poo, - 533 kPa and So,- 0.97 (-+A, point a).Jn mixed venous blood, Pen, - 6.27 kPa and 5o, ... 0.75 (-+A. pointv). The normal range of C02 dissociation is determined by connecting these two points by a line called "physiological C02 difsociation curve. • Addosls, alkalosis, reduced respiratory drive, hypercapnia, hypocapnia

Plate 5.12 COz Binding In Blood, COz In CSF

135

A. ~dluoclatlon cui'W! - - - - - - - - - - - - - - - - - - - - ,

CD.z mnCEntriltion of blood (mmolfll 30r----Tol::il CD.z In blood

(-100%) Plasma-~KI>J-

20

10

mmHg

B. Effect of(O,z on pHofCSF - - - - - - - - - - - - - - - - ,

1 Acute

Eximple: ResplratDry acidosis

\

2 O.ronic

~ .,r---"T""\1-----+~ .. !'fCOi .§ ~

~

1.

BIDOCI-CSF banter

~ ~

tr

t

Blood

! \&~ NB

pH f

~/ ~

CSf

Central

chemosensors strong signal for

nespll'lllllry regulitlon

':--.

WNicslgn A3) register changes in the arterial Po.. If it falls, they stimulate an increase in ventilation via the vagus (X) and glossopharyngeal nerves (IX) until the arterial Po, rises again. This occurs, for example, at high altirudes (-+ p.144). The impulse frequency of the sensors increases sharply when the Po, drops below 131cPa or 97mmHg (peripheral ventilatory drtve). These changes are even stronger when Pco, and/or the W concentration in blood also Increase.

The central chernosensors, in particular, in the medulla react to COl and W increases(= pH decrease) in the CSF (..... M). Ventilation is then increased until Pro, and the W concentration in blood and CSF decrease to normal Villues. This mostJy centnll resplr.tory drive is very effective in responding to acute changes. An increase in arterial Pco, from, say, 5 to 9 kPa increases the total ventilation Ve by a factor of ten, as shown in the C02 responst curve (..... A6). When a chronic rise in Pco, occurs, the previously increased central respiratory drive decreases(-+ p. 134).1fD2supplied by artificial respiration tricks the peripheral chemosensors into believing that there is adequate ventilation, the residual peripheral respiratory drive will also be in jeopardy. During physical work (-+AS), the total ventilation increases due to (a) coinnervation of the respiratory centers (by collaterals of cortical efferent motor fibers) and (b) through impulses transmitted by proprioceptive fibers from the muscles. NonfeeclbKk sensors and stimulants also play an important role in modulating the basic rhythm of respiration. They include

+ ln11/Jnt sensors

In the bronchial mucosa, which quickly respond to lung volume decreases by increasing the rnpiratory rate (deflation reflex or Head's re· flex). and to dust particles or ln1tatlng gases by trig· gering the mugh reHex. + j senso~ of free C fiber endings on alveolar and bronchial walls; these are stimulated In pulmonary edema, triggering symptoms such as apnea and lowering the blood pressure. + Higher ce11tllll net110us centm such as the cortex, limbic system, hypothalamus or pons. They are involved in the expression of emotions like fear. pain and joy; in reflexes such as sneezing, coughing, yawning, and swallowing; and In voluntary corrtrol of respiration while speaking. singing, etc. + .Prnrosensors (-+ p. 226), which are responsible for Increasing respiration when the blood pressure decreases. + Heat and cold sensors in the sldn and thermoregu· latory center. Increases (fever) and decreases In body temperature lead to Increased respiration. + cmuin llormoMs also help to regulate respiration. Progesterone, for example, Increases respiration In the second half of the menstrual cycle and during pregnancy.

Stroke, reduced respiratory drtve, high altitude resplntlon, pulmonary edema

Plate 5.1 5 Respiratory Control and Stimulation A. Respiratory oontrol and stimulation - - - - - - - - - - - - - - - - - ,

141 c

~

I!

a. &!"' 11'1

:z Uechanasensors in lungilnd resplrillllry muscles

1

3 Peripheral

chem~rs

6 C02 response curve 10

142

Effects of Diving on Respiration Diving creates a problem for respiration due to the lack of normal ambient air supply and to higher outside pressures exerted on the body. The total pressure on the body underwater is equal to the water pressure (98 kPa or 735 mmHg for each 10m of water) plus the atmospheric pressure at the water surface. A snorkel can be used when diving just below the water surface (-+A), but it incrNSeS dead space (-+pp.120 and 126). making it harder to breathe. The additional pressure load from the water on chest and abdomen must also be overcome with each breath. The depth at which a snorkel can be used is limited 1) because an intolerable increase in dead space or airway resistance will occur when using an extremely long or narrow snorkel, respectively, and 2) because the water pressure in deeper waters will prevent inhalation. The maximum suction produced on inspintion is about 11 kPa, equivalent to 112 em HzO (peak inspintory pressure, -+p. 122).Inspintlon therefore is no longer possible at aquatic depths of about 112 em or more due to the risk of hypoxic anoxia (-+A).

a certain Poo1 has been reached. chemosensors trigger a sensation of shortness of breath, signaling that It is time to resurface. To delay the time to resurface, it is possible to lower the Pea, in blood by hyperventilillting before diving. Experienced divers use this trick to stay under water longer. The course of alveolar partial pressures over time and the direction of alveolar gas exchange while diving (depth: 10m; duration 40 s) Is shown InC: Hyperventilating before a dive reduces the Pro, (solid green ~ne) and slightly increases the Po, (red line) in the alveoli (and In blood). Diving at a depth of 10m doublesthepressun!onthechestandabdominalwall. As a result, the partial pressures of gases in the alveoli (Pro,, Pez,f>NJ Increase sharply. Increased quantities of 0 2 and C0 2 therefore diffuse from the alveoli Into the blood. Once the Pro.. in blood rises to a certain level, the body signals that It Is time to nesurface.lfthe diver resurfaces atthistime, the Po, in the alveoli and blood drops rapidly (O.Z consumption + pressure decrease) and the alveolar 02 exchange stops. Back at the water surface. the Po, reaches a level that is just tolerable. If the diver excessively hyperventilates before the dive, the signal to resurface wll come too late, and the Po, will drop to zero (anoxia) before the person reaches the water surface, which can result In unconsciousness and drowning (-+ C, dotted lines).

Smba diving equipment (scuba • self-con- Barotrauma. The increilsed pressure iiStained underwater ltreathlng apparatus) is sodilted with diving leads to compression of needed to breathe at lower depths (up to about air-filled organs, such as the lung and middle 70m). The inspintory air pressure (from pres- ear. Their gas volumes ;ue compressed to '/• surized air cylinders) is automatically adjusted their normal size at water depths of 10 m. il!ld to the water pressure, thereby permitting the to 'I• ilt depths of 30m. diver to breathe with normal effort he missing volume ofair in the lungs is automatically However, the additional water pressure Increases the replaced by the scuba, butnotthatofthe middle ear. partial pressure of nitrogen PN, (-+ B), resulting in J he middle ear and throat are connected by the higher concentrations of dissolved N2 In the blood. Eustachian tube, which is open only at certain times Jhe pressure at a depth of 60 meters is about seven (e.g., when swallowing) or not at all (e.g., In pharyntimes higher than at the water surface. The pressure gitis). if volume loss in the ear is not compensated for decreases as the diver returns to the water surface, during a dive, the increasing water pressure in the but the additional N2 does not remain dissolved. Jhe outer auditory canal distends the eardrum. causing diver must therefore ascend slowly, in gradual stages pain or l!llel1 eardrum rupture. As a result, cold water so that the excess N2 can return to and be expelled can enter the middle earand impairthe organ ofequifrom the lungs. Resurfacing too quickly would lead lbrium,leading to nausea, dizziness, and disorientato the development of Nz bubbles in tissue (painl) tion. This can be prevented by pressing air from the and blood, where they can cause obstruction and lungs into the middle ear by holding the nose and embolism of small blood vessels. Jhls is called blowing with the mouth closed. dKDmpresslon sickness or a~rsson disuse (-+B). Euphoria (N2 narcosis?), also called rapture of t~ The air in ilir-filled organs expands when the deep, can occur when diving at depths of over 40 to diver ascends to the water surface. Resurfacing 60 meters. Oxygen toxicity can occur at depths of too quickly, i.e., without expelling air at regular 75 m or more(-+ p. 144). interVills, Ciln lead to complications such as When cl1vlng unassisted, i.e., simply by holding lung Iaceriltion ilnd pneumothorax (-+ p. 116) one's breath, Pro, in the blood rises, since the as well as potentially fatal hemorrhage and air ((h produced by the body is not exhilled. Once embolism. Anoxia, caisson disease, barotrauma, eardrum lnjurtes, pneumothorax

Plate 5.16 Effects of Diving on Resplnd:lon

143

A. Snorkl!llng - - - - - - - - - , Normill Too deep

Ill

Wmrpressure

pre~~ents lnhalil:lon

~ DMngun~kmd-----------------------,

-..:!~:1~--L~r~ 911 kPa

atdoplhcrflOm)

0

I

Alveolar partfal pressures

I

20

I

I

40 Dilling time (s)

i- - - - - ,

13.3 5.2

Alveolar gas exchange

(aftor Hong et ol.)

144

Effects of High Altitude on Respiration At sea level, the average barometric pressure (Pw) ... 101 kPa (760 mmHg), the()] fraction in ambient air (Flo,) is 0.209, and the inspiratory partial pressure of()] (Pro,) ... 21 kPa. However, Pw decreases with increasing altitude (h. in km): t'bu(ath) •Pb.r(at sea level). e~m .b [5.9) This results in a drop in Pro, (..... A, column 1 ), alveolar Po, (PAo,). and arterial Po, (Pao,). The PAo, at sea level is about 13kPa (-+A. column 2). PAo, is an important measure of oxygen supply. If the PAo, falls below a critical level (ca. 4.7kPa • 35mmHg), hypoxia (..... p.130) and impairment of cerebral function will occur. The critical PAo, would be reached at heights of about 4000 m above sea level during normal ventilation (-+A. dotted line in column 2). However, the low Pao, triggers chemosensors that stimulate an increase in total ventilation ("VE); this is called O:z deficiency ventilation (-+A, column 4). As a result, larger volumes of (()] are exhaled, and the PAco, and Paco, decrease (see below). As desaibed by the alveolar gas equation, PAo, - Pro, - PRQ>

[5.10)

where RQ.is the respiratory quotient. any fall in PAal, will lead to a rise in the PAo,. Oz deficiency ventilation stops the PAo, from becoming critical up to altitudes of about 7000m (altitude pin,-+A). The maximal increase in ventilation ( ... 2 x resting rate) during acute Ol deficiency is relatively small compared to the increase (- 10 times the resting rate) during strenuous physical exercise at normal altitudes (..... p. 78, D) because increased ventilation at high altitudes reduces the Paco, ( • hyperventilation, -+ p. 114), resulting in the development of respiratory a Iulosis (-+ p. 152). Central chemosensors then emit signals to lower the respiratory drive, thereby counteracting the signals from ()] chemosensors to increase the respiratory drive. As the mountain climber adapts, respiratory alkalosis is compensated for by increased renal excretion of HC03- (-+ p. 152). This helps return the pH of the blood toward normal, and the Oz deficiency-related increase in respiratory drive can now prevail. Stimulation of()] chemosensors at high altitudes also

leads to an increase in the heart rate and a corresponding increase in cardiac output, thereby increasing the ()]supply to the tissues. High altitude also stimulates erythropoiesis. Prolonged exposure to high altitudes increases the hematocrit levels, although this is limited by the corresponding rise in blood viscosity. Breathing ~n from pressurized Oz cylinders is necessary for survival at altitudes above 7000 m, where Pta, is almost as high as the barometric pressure 1\ar (-+A, column 3). The critical PAo, level now occurs at an altitude ofabout 12 km with normal ventilation. and at about 14 km with increased ventilation. Modem long-distance planes fly slightly below this altitude to ensure that the passengers can survive with an oxygen mask in case the cabin pressure drops unexpectedly. Survival at altitudes above 14 km is not possible without pressurized chambers or pressurized suits like those used in space travel. Otherwise, the body fluids would begin to boil at altitudes of20 km or so(..... A~ where 1\. is lower than water vapor pressure at body temperature (37"C).

Oxygen Toxicity Hyperoxia occurs when Plo, is above normal (> 22 kPa or 165 mmHg) due to an increased Oz fraction (oxygen therapy) or to an overall pressure increase with a normal 01 fraction (e.g., in diving,-+ p. 142). The degree of ol toxidty depends on the Pta, level (critical: ca. 40 kPa or 300 mmHg) and duration of hyperoxia. Lung dysfunction (..... p. 124, surfactant deficiency) occurs when a Pta, of about 70 kPa (525 mmHg) persists for several days or 200 kPa (1500 mmHg) for 3- 6 hours. Lung dysfunction initially manifests as coughing and painful breathing. Seizures and unconsciousness occur at Plo, levels above 220kPa (1650 mmHg), e.g., when diving at a depth of about 100m using pressurized air. N-borns will go blind (retinopathy of prematurity)ifexposed to l'lo, levels much greater than 40kPa (300mmHg) for long periods of time (e.g., in an incubator), because the vitreous body then opacities.

Aalte and chronic altitude disease, hypoxia and hyperoxia, alkalosis, aviation and aerospace medicine

A. Raplratlon ilt high illtttucla (without iltdlmatlzilf:lon) - - - - - - - - - - - - - - - - - - - - - - - - - ,

£-8

~

lnspll'ltorypl'elaRS

.a

Balling point

!~ ofbod~~~~

~

t\

•

AIVI!a..r Po. wt- bl'&thlng ;lfr

Nvealllr Po. whl!n br'1!511hhg [b

:z

]

Talllll wnUIIIIIon ~)

4

16

14

Maximum v.tlen breat~d! ngO,

;;

lnctellSed

.....

12 ......

A

10'

""1:1

iii'"

~

ventilation

!f

en breathing 0,

...~ s. :I:

8

~

:::r

~ -;!:"..'E

>

6

4 2

0

lnaeased ventilation

~ m breathing air

! 5

~ ,.A.

~l=tj 5

15

0

::II

m-

'!!.

i

8'

25

::II

PAo,(kPa}

...

5 Respiration

•

VI

146

pH, pH Buffers, Acid-Base Balance The pH indicates the hydrogen ion activity or the "effective" H• concentration of a solution (H' activity = fH •[H•], where square brackets mean concentration; ~ p.400), where (6.1) pH • -log (fH" [W)) In healthy individuals, the pH of the blood is usually a mean pH 7.4 (see p. lSO for normal range), corresponding to W activity of about 40 nmol/1. The maintenance of a constant pH is important for human survival. Large deviations from the norm can have detrimental effects on metabolism, membrane per meability, and electrolyte distribution. Blood pH values below 7.0 and above 7.8 are not compatible with life. Various pH buffers are responsible for maintaining the body at a constant pH (-+p.401). One important buffer for blood and other body fluids is the blartJonn./arbon dioxide ~~-/~) buffer systrm: [6.2) CCh + HJ0""" HC03- + W. The pK, value determines the prevailing concentration rutio of the buffer base and buffrr add ([HCOJ-) and [C01]. respectively in Eq. 6.2) at a given pH (Henderson-Hasselbalch equation; -+A). The primary function of the HC0 3-/C~ buffer system in blood is to buffer If' and OHions. However, this system is especially important because the concentrations of the two buffer components can be modified largely independent of each other: [COl) by respiration and [HC01-) by the liver and lcidney (-+A; see alsop. 184). It is therefore dasslfied as an open buffer system c~p.148). Hemoglobin in red blood cells (320 g Hb/L erythrocytes I -> MCHC, p. 93 C), the second most important buffer in blood, is a nonbi[ill'· boMt. buffer. [63) HbH ,... Hb-+H' [6.4) Oxy-HbH""" Oxy-Hb- + W The relatively acidic oxyhemoglobin anion (Oxy-Hb-) combines with fewer H• ions than deoxygenated Hb-, which is less addle (see also p. 132). If' ions are therefore liberated upon oxygenation ofHb to Oxy-Hb In the lung. ~action 6.2 therefore proceeds to the left, thereby promoting the release of col from its bound forms. This, in tum, increases the pulmonary elimination of C(h.

Ott- nonblarbonab! buffers of the blood indude plasma pro!Wns and inorganic phosphatr (H1P04- """" W + HPO.'-) as well as organic phosphates (in red blood cells). Intracellular organic and inorganic sub· stances In various tissues also function as buffers. The buffer capacity is a measure of the buffering power of a buffer system (moi·L-1 • [.:\pH)-1 ). It corresponds to the number of added H• or OH- ions per unit volume that change the pH by one unit The buffer capadty therefore corresponds to the slope of the titration curve for a given buffer (-> p. 402, B). The buffer capacity is dependent on (a) the buffer concentration and (b) the pH. The farther the pH is from the pi pp. 150 and 154). The buffer base concentration is the sum of the concentrations of all buffer components that accept hydrogen ions, i.e., HC03-, Hb-, Oxy-Hb-, diphosphoglycerate anions, plasma protein anions, HPOi-. etc. Changes In the pH of the blood are chiefly due to changes in the following factors (-> A and p. 150ff.): • Ir Ions: Direct uptake in foodstuffs (e.g., vinegar) or by metabolism, or removal from the blood (e.g., by the lcidney; ~p.184ff.). • OH- ions: Uptake in foodstuffs containing (basic) salts of weak adds, espedally in primarily vegetarian diet. • C02: Its concentration, [C02). can change due to alterations in metabolk production or pulmonary elimination of C(h. A drop in (C01) leads to a rise in pH and vice versa (-+A: [C02 ) is the denominator in the eqlliltion). + HC01-: It can be eliminated directly from the blood by the kidney or gut (in diarrhea). A rise or fall in [HC03-) will lead to a corresponding rise or fall in pH (->A: (HCol-) is the numerator in the eqUiltion).

Add-base homeostasis: dietary Influence, abnonnallt:les and diagnosis

Plate 6.1

pH, pH Buffers, Add-Base Balance

147 Ill

iii ra

t:

2

Dietary lnt:OJIce and metabolism

E 0

:I:

:II ra

ID

I

Ji! ~

HCOi

+

y

HzD+

HCOi

/

Non-bltarbonate

buffers

HendersorH-Iasselbalch equiltton

-log [H.] -

QpH

\:_)

= pK. + log

[He~-] [C~)

148

Bicarbonate/Carbon Dioxide Buffer The pH of any buffer system is determined by the concentration mtio of the buffer pairs and the pi

10

•

161

162

Transport Processes at the Nephron Fltratlon of solutes. The glomerular filtrate also contains small dissolved molecules of plasma (ultroJiltrote) (-+ p. 160). The glomerular siniJig coej]'ieil!ntGSC of a substance (- concentration in filtrate/concentration in plasma water) is a measure of the permeability of the glomerular filter for this substance. Molecules with a radius of r < 1.8 nm (molecular mass < ca. 10 000 Da) can freely pass through the filter (GSC ... 1.0). while those with a radius of r >4.4nm (molecular mass > 80000Da. e.g., globulins) normally cannot pass through it (GSC • 0). Only a portion of molecules where 1.8 nm < r < 4.4 nm applies are able to pass through the filter (GSC ranges between 1 and O). Negatively charged particles (e.g.• albumin: r- 3.4nm; esc .. 0.0003) are less permeable than neutral substances of equal radius because negative charges on the wall of the glomerular filter repel the ions. When small molecules are bound to plasma proteins (protein binding), the bound fraction is practically nonfilterable (-+ p. 24 ). MoieaJies entrapped in t ile glomerular filter are beliewd to be eliminated by phagocytic mesangial macrophages and glornet'Wr podocytes.

TUbular ..,tthellum. The epithelial cells lining the renal tubule and collecting duct are polar cells. As such, their luminal (or apical) membrane on the urine side differs significantly from that of the basolateral membrane on the blood side. The luminal membrane of the proximal tubule has a high brush border consisting of microvilli that greatly increase the surface area ( espedally in the convoluted proximal tubule). The basolateral membrane of this tubule segment has deep folds (basal labyrinth) that are in close contact with the intracellular mitochondria. which produce the ATP needed for Na•-JC>-ATPase (-+ p. 26) located in the basolateral membrane (of all epithelial cells). The large surface areas (about 100m2 ) of the proximal tubule cells of both kidneys are needed to reabsorb the lion's share of filtered solutes within the contact time of a couple of seconds. Postproximal tubule cells do not need a brush border since the amount of substances reabsorbed decreases sharply from the proximal to the distal segments of the t ubules. Whereas permeability of the two membranes in series is dedsive for transcellular

transport (reabsorption, secretion), the tightness of tightjunctions (-+ p.18) determines the paracellular permeability of the epithelium for water and solutes that cross the epithelium by paracellular transport. The tight junctions in the proximal tubule are relatively permeable to water and small ions which. together with the large surface area of the cell membranes, makes the epithelium well equipped for paraand transcellular mass transport (-+ D, column 2 ). The thin limbs of Henle's loop are relatively "leaky." while the thick ascending limb and the rest of the tubule and collecting duct are "moderately tight" epithelia. The tighter epithelia can develop much higher transepithelial chemical and eleclricalgmdients than "leaky" epithelia. Measurement of reabsorption, secretion and uc:retlon. Whether and to which degree a substance flltered by the glomerulus is reabsorbed or secreted at the tubule and collecting duct cannO( be determined based on its urinary concentration alone as concentrations rise due to the reabsorption of water. The urinary/plasma inulin (or creatinine) concentration ratio, U;,/P-..., is a measure of the degree of wall!r reabsorption. These substances can be used as indicators because they are neither reabsorbed nor secreted (.... p. 160). Thus, changes in indicator concentration along the length of the tubule occur due to the H20 reabsorption alone ( .... A). lfUm/Ptn- 200, the inulin concentration in the final urine is 200 times higher than in the original filtrate. This implies thatftuctional excretion ofHlO (FEruo) is 1/200 or 0.005 or 0.5% of the GFR. Determination of the concentration of a (freely filterable and perhaps additionally secreted) substance X in the same plasma and urine samples for which U;0 /Pia was measured will yield UJP•. Considering U1n/P~n, the fractional U£retlon of X. FEx can be calculated as follows (-+A and D, in %in column 5):

FEx =

(UxJPx)f(u..JPl.J

[7.9)

Eq. 7SJ can also be derived from C.}Cta (-+p.160) when simplified for Vu. The fractional reabsorption of X (FRx) is calculated as FRx = 1 - FEx (7.10) Reabsorption in dlffereat: segments of the tubule. The concentration of a substance X (TFx) and inulin (TFtn) in tubular fluid can be

Glomerulonephritis, renal tubular failure, protein-binding drugs

~

Plate 7.4 Transport Processes at the Nephron I B. Tubu..r lnln5p0rt - - - - - - - ,

Filtration Act1ve

reabsorption

l';mlve

reabsorption

AdfWo

transcellular secretion Passive

cellular secretion

C. Owrvlew oflmporbnt transport proa!51e5 along the nephron - - - - - - - - ,

Glucose, imino iCids,

~~a!J!, sulfite

Trarupat proussos: see 1.1-ti

Na+

163

164

Transport Processes at the Nephron (continued) measured via micropuncture (~ A).The values an electrochemical gradient; -+seep. 26ff.). at can be used to calculate the nonreabsorbed least one of the two serial membrane transport fraction (froctional dtliYtry, FD) of a freely fil- steps must also be active. lntenctlon of tnnsporb!rs. Active and pastered substance X as follows: sive transport processes are usually closely inFD • ('JllxJPx)/(TFuJP~n), where Px and P~n are the respective concentra- terrelated. The active absorption of a solute tioll5 in plasma (more precisely: in plasma such as Na• or D-glucose, for example, results in the development of an osmotic gradient, water). Fructional reabsorption (FR) up to the sam- leading to the passive absorption of water. pling site can then be derived from 1- FD [IC')o), second, a mem- complete reabsorption is achieved by secondbrane potential (inside the cell is negative rela- ary active transport (Na'-glucose symport) at live to the outside) which represents an elec· the luminal cell membrane (-+Band p. 29 Bt }. trlcal gradient and can drive ion transport About 95% of this activity occurs in the proxi(-+ pp. 32ft'. and 48). mal tubule. Transcellulw transport implies that two Glucow carriers. Low-affinity transporters membranes must be crossed, usually by two in the luminal cell membrane of the pars condifferent mechanisms. lf a given substance (D- voluta (sodium- glucose transporter type 2 = glucose, PAH, albumin, etc.) is actively trans- SGLn) and high-affanlty carriers (SGLTl) in ported across an epithelial barrier (i.e., agaill5t the pars recta are responsible forD-glucose re- ~ Excretion of drugs, retention, and hyperexcretlon of electrolytes

Plate 7.5 Transport Processes at the Nephron II D. Rubsarptlon, secretion and frac:ttanal exaetlan 3

2

4

~

5

Ill

..

j

I'Aidlonal relbtwption (FR) ("]

£

I II

i li 12: ,;

~

I

j}

.!

E"

~

.II

j

...a

i

,; ~

e-_ -1!

~ t::c

... j

jl ..1

'as

.5 ~

~

I

.,B

~~

~!!.

~

P• Pl;>sm~

252: (0.4)

95S-99.5X 0.52:-52:

4.6

65% (1.0)

1o:li-ZOX

secretion possible

Free-: 1.6

60%

30%

95X-99l

c -a

111lses FE

f lowers FE

Aldosll!rone:

ADH: ANP: 2X-150X Aldosterone: 1S-5X

Pni:

15:1 (2.5)

c.a. 70X

112

55 X (1.3)

c.a.2ox

24

93:1 (0.2)

2.2

65X (1.0)

s 5

IOX-95%

n-n

t

•

95X-99.5X 0.5:1i-5X

11-ZX

Alkalosis:

15X

80X-97X

n-2os

Prise: Plll: Cal" falls: Addosis:

96% (0.1)

4%

•100%

•OX

50% (1A)

secreuon

ca.60X

ca.40X

OS

ox

ox

100X

Secretion

Secretion

•500:1

secretion

t

Prise:

9U-99X

(2.9)

• t• . t t

Addmls:

Free: 0.6

c-

t

~

65X (1.0)

0.1

"'ii

In tubular ...no

93 X-99.5X 0.5X-72: ADH:

J

""""'-"

Tf•CDntll!-

lOX

(1.1)

..

-a c

65X 153

165

t

i

Sharp P rise:

t

Diuresis:

t

Sharp P rise: •

Ill

~

52

.....

166

Reabsorption of Organic Substances (continued) II> absorption. The cotransport of D-glucose and Na• occurs in each case, namely at a ratio of 1:1 with SGLT2 and 1 :2 with SGLT1. The energy required for this form of secondary active glucose transport is supplied by the electrochemical Na• gradient directed IXlWard the cell interior. Because of the cotransport of two Na+tons, the gradient for SGLTt is twice as large as that for SGLT2. A unlpomr (Gum= glucose transporter type 2) on the blood side facilitates the passive transport of accumulated intracellular glucose out of the cell (fucilitated diffusion; -+ p. 22). D-g•l•ctose also makes use of the SGLT1 carrier, while D·fructose is passi~ly absorbed by tubule cells (GLUTS). If the plasma glucose concentration exceeds 10-15 mmol}L, as in diabetes mellitus (normally 5 mmoi/L), glycosur11 d~lops, and urinary glucose concentration rises (-+A). Glucose reabsorption therefore exhibits saturation kinetics (Michaelis-Menten kinetics; -+p.28). The above example illustrates prerenal glycosuria. Renal glycosurla can also occur when there is a defect in SGLT2 (familial renal glycosuria) or cum (Fanconi-Bickel syndrome). In Debr~-de Toni-Fanconi syndrome (DTFS), there is a disturbance of the energy metabolism of the tubule cells, resultIng in reduced reabsorption of amino adds, phosphate, and HC03- as well as glucose. The plasma contains over 25 amino acids, and about 70 g ofamino adds are filtered each day. like D-glucose, most L-amino adds are reabsorbed at proximal tubule cells by Na•-coupled secondary active transport(-+ Band p.29B3). There are different amino add transporters in the proximal tubule, and there is some overlap in their specificities. Jmu and I4.t (-+ p. 28) and, therefore, saturabllity and reabsorption capacities vary according to the type of amino add and carrier involved. Fractional excretion ofmost amino adds .. to 1% (ranging from 0.1% for L-valine to 6% for L-histidine).

are hyperexcreted one of the two subunits (SLC3A [• eBAT] or SLC7A9) of the apical carrier Is defectl\le, leading to urinary cystine stonfs. The SLC6A 19 carrier Is affected in Hartnup disease (tryptoi)Nn and neutral amino adds). Certain substances (lactate [SLCSA8 carrier], sulfate [N.lS1 c.1rrier], phosphate [-+ p. 180], dicarboxylates, and citrate [NaDC1 c.1nier]) are also reabsOibed at the proximal tubule by way of Na' symport, where 1), via the ural:!! 1 c.lrrier/MRP4 pump and oxalal:l! Sat1 canier, respectively. If the urinary concentration of these poorfy soluble substances rises above normal, they will start to precipitate (increas· lng the risk of urtn•rye~lculus formltlon).lllcewlse, the excessive urinary excretion of the amino acid cystine can lead to cystine calculi. Ollgopeptldes such as glutathione and angiotensin II are broken down so quickly by lumina/ peptidases in the brush border that they can be reabsorbed as free amino acids(-+ Cl ). Dlpeptldes ll!Sistant to luminal hydrolysis (e.g., carnosine) must be reabsorbed as intact molecules. A symport carrier (Pep12) driven by the inwardly directed W gradient (-+p.184) transports the molecules Into the cells (tertiary ac:tiw W symport; -+ p. 29 BS). The dipeptides are then hydrolyzed within the cell (-+a). The PepT2 carrier is also used by certain drugs and toxins. Proteins. Although albumin has a low sieving coefficient of0.0003 (-+p.162), 2400mg/ day are filtered at a plasma concentration of 45 g{L (180 L}day ·45 g{L · 0.0003 • 2400 rng}day). Only 2 to 35 mg of albumin are excreted each day (FE .. 1%). In the proximal tubule, albumin, lysozyme, a1-microglobulin, ~1-microglobulin and other proteins are reabsorbed by receptormediated endocyto.ris (-+ p. 28ff.) and are "digested" by lysosomes or cross the basolateral membrane intact: trunscytosis (-+D). Since this type of reabsorption is nearly saturated at normal filtered loads of proteins, an elevated plasma protein concentration or increased protein sieving coefficient will lead to proteinuria.

Increased urinary excretion d arnino adds (hyperllllinoldcluril) c.1n occur. Pmrnol hyperaminoacidurfa occurs when plasma amino add concentrations are elevated (and reabsorption becomes saturated. as In A). whereas renal hyperamlnoacldurla oocurs Calcidiol, which is bound to D8P (vitamin D-binding due to deficient transport, which may be non- protein) in plasma and glomerular filtrate, is reabspeciflc, as in DTFS (see above), or specific. In cys- sorbed In combination with DBP also by receptortinuria, where only l-cystine. l-arginine, and l-lysine medial:l!d endocytosis(-+ p. 306). Glycosuria, hyper•mlnolcklurla, Fanconl syndrome, proteinuria

Plate 7.6 Reabsorption of Organic Substances

20

Normal

30 40 Plil$1T1a gii.ICO$e

mncentralllln (mmoi/L)

Lumlnol

Na• .,.,port

C. Reabsolptlon of ollgopeptldes Dlpeptides

Oligopeptides Albumin and

~I 1

other piW!ns

--Tr.~ns­

cytnsis .,...---+~•

:z

j 11/ood Amino acid$

Blood

167

168

Excretion of Organic Substances Food provides necessary nutrients, but also contains inert and hanDful substances. The body can usually sort out these substances already at the time of Intake, either based on their smell or taste or, ifalready eaten. with the help of specific digestive enzymes and intestinal absorptive mechanisms (e.g~ D-glucose and L-amino acids are absorbed, but L-glucose and D-amino acids are not). Similar distinctions are made in hep.~tlc exaetlon (~bile~ stools): useful bile salts are almost completely reabsorbed from the gut by way of specific carriers, while waste products such as bilirubin are mainly eliminated in the feces. Ukewise, the kidney reabsorbs hardly any useless or harmful substances (including end products such as creatinine). Valuable substances (e.g., D-glucose and L-amino acids), on the other hand, are reabsorbed via specific transporters and thus spared from excretion(...... p. 164). The liver and kidney are also able to modify endogenous waste products and foreign compounds (xenobiotics) so that they are "detaxlfled" if toxic and made ready for rapid elimination. In unchanged form or after the enzymatic addition of an OH or COOH group, the substances then combine with glucuronic acid, sulfate, acetate or glutathione to form conjuptes. The conjugated substances are then secreted into the bile and proximal tubule lumen (with or without further metabolic processing). Tubular Secretion The proximal tubule utilizes iiCtlvt! tl'ilnsport med!ilnlsms to secrete numerous waste products and xenobiotics. This is done by way of carriers for organic anions (OA-) and organic cations (OC'). The secretion of these substances makes it possible to raise their clearance level above that of inulin and, therefore, to raise their fractional excretion (FE) above 1.0 = 100% in order tD eliminate them more effectively (-+ A; compare red and blue curves). Secretion is carrier-mediated and is therefore subject to saturation kinetics. Unlike reabsorbed substances such as D-glucose (..... p. 167 A), the FE of organk anions and cations decreases when their plasma concentrations rise (-+ A; the PAH secretion curve reaches a plateau, and the slope of the PAH excretion curve decreases). Some organic anions

(e.g., urate and oxalate) and cations (e.g.• choline) are both secreted and reabsorbed (bidirectional transport), which results in net reabsorption (urate, choline) or net secretion (oxalate). The secreted Of9Mik anions (OA-) include indicators such as PAH (p-aminohippurate; ...... p. 158) and phenol red; endogenous substances such as oxalate, urate, hippurate; drugs such as penicillin G, barbiturates, and numerous diuretics (..... p.182); and conjugated substances (see above) containing glucuronate, sulfate or glutathione. Because of its high affmity for the transport system, probenecid is a potent inhibitor of OA- secretion. The active stl!p ofOA- secretion (-+B) occurs across the bosolarmll membrane of proximal tubule cells and accumulates organic anions In the cell whereby the inside-negative membrane potential has to be overmme. The membrane has a broad specificity carrier (OAT1 • organic anion trnnspomr type 1) that transports OA- from the blood Into the tubule cells In exchange for a dlcarboxy~te, such as sucdnate'· or a-la!toglutarate2 - ; -+ 81). The latter substance arises from the glutamine metabolism of the cell (-+ p. 187 02); the human Na' -dlcarboxytate transporter hNaDC-1 also conveys diarboxylates (in rom· bination with 3 Na') into t he cell by second.Yy active transport (-+ 82). The transport of OA- Is therefore caled fl!rtiory active tronsport. The efflux of OA- into the lumen is passive (fad Nt* 84).

The org•nlc cations (OC') secreted include endogenous substances (epinephrine, choline, histamine, serotonin, etc.) and drugs (atropine, quinidine, morphine, etc.). In contrast to OA- secretion, the active step ofOC' secretion occurs across the luminal membrane of proximal tubule cells (luminal accumulation occurs after OYI!rcoming the negative membrane potential Inside the cell). The membrane contains (a) direct ATP-drM!n carriers for Ol'gKomes increasingly hypertonic toward the papillae (see below) and if the vasa recta are permeable to warer. Part of the water diffuses by osmosis from the descending vasa

recta to the ascending ones, thereby "bypassing" the inner medulla (-+M). Due to the extraction of water, the concentration of all other blood components increases as the blood approaches the papilla. The plasma osmolality in the vasa recta is thel'l!fore continuously adjusted to the osmolality of the surrounding interstitium, which rises toward the papiDa. The hematocrit in the vasa recta also rises. Conversely, substances entering the blood in the renal medulla diffuse from the ascending to the descending vasa recta, provided the walls of both vessels al'l! permeable to them (e.g~ urea; -+ C). The countercurrent exchange in the vasa recta permits the necessary supply of blood to the renal medulla without significantly altering the high osmolality of the renal medulla and hence impairing the urine concentration capacity of the kidney. In a countercurnnt multlpU•r such as the loop of Henle, a concentration gradient between the two limbs is maintained by the expenditure of energy (-+AS). The countercurrent flow amplifies the relatively small gradient at all points between the limbs (local gradient of about 200 mOsm/kg H~) to a relatively large gradient along the limb of the loop (about 1000mOsm/kgH20). The longer the loop and the higher thE! one-srep gradient, the steeper the multiplied gradient. In addition, it is inversely proportional to (the square of) the flow rate in the loop. Reabsorption of Water Approximately 65% of the GFR is reabsorbed at the proximal convolut:H tubul•. PCT (-+ Band p. 165 D). The driving "force· for this is the reabsorption of solutes, especially Na' and This slightly dilures the urine in the tubule, but H10 immediately follows this small osmotic gradient because the PCf is "leaky"(-+ p. 162). The reabsorption of water can occur by a paracellular route (through leaky tight junctions) or transcellular route, i.e., through the water dumnels (aquaporin type 1 • AQ.P1 ) in the two cell membr.mes. ThE! urine in PCl' therefore remains (virtually) isotonic. Onrotic pressure (~p. 400) in the peritubular apillaries provides an additional driving force for water reabsorption. The more water filtered at the glomerulus, the higher this oncotic pressure. .,..

Hyperusmolallty, hypoosmolallty, disorders of water balance, diabetes Insipidus

a-.

Plate 7.9 Wab:!r Reabsorptlon. Concentrat1on of Ultne I

173

e c:

Ill

.

j

B

,~c:

Ill

li ~

~

c:

!

2 Countercurrent exchange

..... 600

800 000

Ice

3 Countercurrent exchange (heat) In loop

4 Countercurrent exchanr (water)

in loop (e.g. vasa recta

1200

5 Countercurrent multiplier

(Henle's loop)

6 CountErcurrent systems in renal medulla

174

Reabsorption of Water, Formation of Concentrated Urine (continued) II> Thus, the reabsorption of water at the proximal tubule is, to a certain extent, adjusted in accordance with the GFR (glommdotubular balance). Because the descending limb of the loop of Henle has aquaporins (AQ.Pl) that malce it permeable to water, the urine in it is largely in osmotic balance with the hypertonic interstitium, the content of which becomes increasingly hypertonic as it approaches the papillae (~A5). The urine therefore becomes increasingly concentrated as it flows in this direction. In the thin descending limb, which is only sparingly permeable to salt, this increases the concentration of Na• and ct-. Most water drawn into the interstitium is carried off by the vasa recta (~B). Since the thin and thick ascending limb! of the loop of Henle are largely impermeable to water, Na• and o- passively diffuses (thin limb) and an actively transported (thick limb) out into the interstitium (-+ 8). Since water cannot escape. the urine leaving the loop of Henle is hypotonic. Active reabsorption of Na• and a- from the thick ascending limb of the loop of Henle (TAL; -+ p.170) creates a loal gradient (ca. 200m0sm/kg H;zO; -+AS) at all points between the TAL on the one side and the descending limb and the medullary interstitium on the other. Since the high osmolality of fluid in the medullary interstice is the reason why water is extracted from the collecting duct (see below), active NaCl transport is the ATI'-consuming "motor" [or the kidney's urine-concentrrlting mechanism and is upregulated by sustained stimulation of ADH secretion. Along the course of the dlsbil convoluted tubule and, at the latest, at the connecting tubule, which contains aquaporins and ADH rt!ceptors of type V2 (explained below}, the fluid In the tubule will again become isotonic (in osmotic balance with the isotonic interstice of the ~I cortex) if ADH is present (-+ p. 170), I.e., when ant/diu~ occurs. Although Na' and d - are still reabsotbed here, the osmolality does not changt! significantly because Hz() Is reabsorbed (ca. 5% c:l the GFR) Into the Interstitial space due to osmotic forces and IKf!CJ increasingly determines the osmolality c:l the tubular fluid.

Final adjustment of the excreted urine volume occurs in the collecting duct. In the presence of antidiuretic hormone,ADH (which binds to basolateral V2 receptors, named after vasopressin, the synonym for ADH), oquaporim (AQP2) in the (otherwise water-impermeable) luminal membrane of prindpal cells are used to extract enough water from the urine passing through the increasingly hypertonic renal medulla. Thereby, the u.,,. rises about four times higher than the P01m (Uo,.,JPollll ... 4), corresponding to maximum antidiuresis. The absence of ADH results in water diuresis, where u..m/P..mcan drop to < 0.3. The Uo1111 can even fall below the osmolality at the end of TAL, since reabsorption of Na• and a- is continued in the distal convoluted tubule and collecting duct (~ p. 170) but water can hardly follow. Urea also plays an important role in the formation of concentrated urine. A protein-rich diet leads to increased urea production, thus increasing the urine-concentrating capacity of the kidney. About 501 of the filtered urea leaves the proximal tubule by diffusion (-+ C). Since the ascending limb of the loop of Henle, the distal convoluted tubule, and the cortical and outer medullary sections of the collecting duct are only sparingly permeable to urea. its concentration increases downstream in these parts of the nephron (-+C). ADH can (via V2 receptors) introduce urea carriers (urea transporter type 1, UTt) in the luminal membrane, thereby malcing the inner medullary collecting duct permeable to urea. Urea now diffuses back into the interstitium (where it is responsible for half of the high osmolality there) via UT1 and is then transported by UT2 carriers back into the descending limb of the loop of Henle, comprising the ntelrcul.tlon of u111a (-+C). The nonreabsorbed fraction of urea is excreted: FE,,.. ... 40%. Urea excretion increases in water diuresis and decreases in antidiuresis, presumably due to upregulation of the lJI2 carrier. Urine C:OIJUtllratlon disorders primarily occur

due to: (a) excessive medullary blood flow (washingoutNa•.ct- and urea); (b)osmoticdiuresis; (c) loop diuretics (-+ p.182); (d) delident secretion or effectiveness ofADH, as seen In central or peripheral dklbttes insipidus, respectively.

Diabetes melllbls, effects of diuretics, retention of waste urinary substances

Plate 7.1 0

Water Reabsorption, Concentration of Urine II

B. w.tl!r rNMorptfon lind Da1!tlon - - - - - - - - - - - - - - - - ,

175

~

Ill

..

j 0

£

~e = ...

.!

~

~f

1~ Q.~

-a c

~

£t:l

"'ii

E

OS

F :I

"'

..

J

Ill

~

c -a

52

.....

176

Body Fluid Homeostasis Water is the Initial and final product of count- plasma Wflter (0.045 BW) and in •rranscellulessbiochemicalreactions.ltservesasasolvent, Jar• compartments (0.015 BW) such as the transport vehicle, heat buffer, and coolant, and pleural, peritoneal and pericardia! spaces, CSF hasa varietyofotherfunctions. Water is present space, and chambers of the eye as well as intestinal lumen, renal tubules, and glandular in cells as intrucdlular fluid, The volume of fluid cirrulating in the body ducts (-+C). Blood plasma is separated from remains relatively constant when the water the interstice by the endothelium, while the ~(-+A) Is properly regulated. The averepithelia divide the interstice from the transagefluld lnblbofca. 2.5 Lper day is supplied by cellular compartments. The protein concentrabewnws. solid foods, and metabolic oxidation tion of the plasma is significantly different (-+ p. 241 C). The fluid intake must be high from that of the interstitial fluid. Moreover, enough to counteractwattlrlossesdue to urina- there are fundamental differences in the ionic tion, respiration, perspiration (..... p. 235 83), and composition of the ECF and the ICF (..... p. 97 C). defecation. The mean daily H20 turnover is Since most of the body's supply of Na• ions is 2.5L/70kg (1/30th the body weight (BW]) in located in extracellular compartments, the adults and 0.7liters/7 kg (1/loth the BW) in in- total Na• content of the body determines its fants. The water balance of infants is therefore ECFvolume. Measurement of fluid compartments. In more susceptible to disturbance. Significant rises In H20 turnover can occur, clinical medicine, the body's fluid compartbut must be adequately compensated for if the ments are usually measured by indicator dilubody is to function properly (regulation). Res- tion techniques. Provided the Indicator subpiratory H20 losses occur, for example, due ID stance, S, injected into the bloodstream hyperwntiladon at high altitudes, and per- spreads to the target compartment only ( ..... C), spiration losses occur due to exertion at high its volume V can be calrulated from: V(l) •lnj«ted llmOUnt of lndlator temperatures (e.g., hiking in the sun or hot 5 [mol)/(4 [moljl) (7.12) work environment as in an ironworks). Both can lead to the Joss of several liters ofwaterper where Cs is the concentration of S after it hour, which must be compensated for by in- spreads throughout the target compartment creasing the intake of fluids (and salt) accord- (measured in collected blood specimens). ingly. Conversely, an increased intake of fluids Indicators. The ECF volume Is generally measured wiU lead to an increased volume of urine being using Inulin or sodium bromide as the Indicator (does excreted. not enter ~lis), and the TBW volume Is detennined Body wlter cont.nt (-+B). The fraction of using anUpyrtne, heavy water (1>20) or radlolabeled H,O. The ICF volume Is approximately equal to the total body water (TBW) to body weight {BW • 1.0 •100%) ranges from 0.46 (46%) to 0.75 de- antipyrine distribution volume minus the inulin dispending on a person's age and sex(-+ B). The tribution volume. Radlolabeled albumin or EVans TBW content in infants is 0.75 compared to blue, a substance entirely bound by plasma proteins, can be used to measure the plasma volume. The in· only 0.64 (0.53) in young men (women) and terstitial volume can be calculated as the ECF volume 0.53 (0.46) in elderly men (women). Gender- minus the plasma volume, and the blood volume as related differences (and interindividual differ- the plasma volume dMded by (1 - hematocrit). ences) are mainly due to differences in a per- (Since 1/10 of the plasma remains Interspersed with son's total body fat content. The average frac- the erythrocytes after centrifugation, replacing 1 tion of water In most body tissues (in young with 0 .91 in this formula gives a more precise re5ult.) adults) is 0.73 compared to a fraction of only The blood volume can also be determined by injection of 51Cr-labeled erythrocytes, so that the plasma about 0.2 in fat 110lume is then calculated as blood volume times Auld compirtmenls (-+ C).In a person with (0.91 - Hct). an average TBW of ca. 0.6, about 3/5 (0.35 BW) of the TBW Is intracellular fluid (ICF), and the other 2/5 (0.25 BW) is extraceUular (ECF). ICF and ECF are separated by the plasma membrane of the ceUs. ExtraceUular fluid is located between cells (interstice, 0.19 BW), in blood Abnormalities of water balance, measurement of fluid comparbnents

Plate 7.11 Body Fluid Homeostasis ~vv~~~~-----------------------------------------,

Deficit

llll:illr. Cll. 2.5L/day

Supplied by;

Output· Cll. 2.51./day

B. Total body w.ter (11MI) CDIIIBit 1.00

0

~

.S!'

r

~

0.46 - 0.75 L/kg

body weight

0.2

OQ Fat

Other body

0.75

.8

0.64

s ~

0.53

cr

'0 c 0

E

;:

tissues

Men 1rmnt

C. F111d compartments of the body Fraction of body weight

ca. 0.19

ICF

til. 0.35

0.53

9

cr

Women

Men

Young

0.46

9 Women Old

177

178

Salt and Water Regulation Osmoregulation. The osmolality of most body fluids is about 290 mOsmfkg H,O (-+ p.399), so that the intracellular fluid (ICF) and extracellular fluid (ECF) are generally in osmotic balance. Any increase in the osmolality of ECF due, for example, to Nad absorption or water loss, results in an outflow of water from the intracellular space (Cell shrinbge.-+A1 and p. 183 A2 and 6~ A fall in extracellular osmolality due to drinking or infusion of large volumes of water or to sodium loss (e.g., in aldosterone deficit) results in an Inflow of water to the cells from the ECF (atllswalllng, -+A2 and p. 183 A3 and 5 ). Both volume fluctuations endanger the cell's functioning, but the cell can protect against them. Regulation of cell volume. The cell's plasma membrane contains mec:hanosensors that stimulate balancing ion flow accompanied by water, for example K+ and a- outflow in cell volume expansion and Na•, K•, and a- inflow in cell shrinkage. Such mechanisms also balance a volume expansion resulting from increased absorption of Na+ and glucose in intestinal mucous cells or from a momentary hypoxy ofa cell (with deaeasing Na+-K+-ATPase activity). Orpnk osmolytt!s. Cells which are physiologically exposed to large osmolality fluctuations (e.g.. in the kidney), are further able to regulate their Intracellular osmolality through formation/absorption, or release/reabsorption of small molecular substances known as organic osmolytes (e.g., betaine, taurtne, myo-inositol, sorbitol).

The osmolality of the ECF as a whole must be tightly regulated to protect cells from large volume fluctuations. Osmoregulation is controlled by central osmosensol'! (or osmoreceptor!) located in circumventricular organs (SFO and OVLT, see below). H20 fluctuations in the gastrointestinal tract are monitored by peripheral osmosensors in the portal vein region and communicated to the hypothalamus by vagal afferent neurons. Wat. deftdt (-+ B1 ). Net water losses (hypovolemia) due, for example, to sweating make the ECF hypertonic. Osmolality rises of only 1-U (• 3-6mOsmfkgH,D) are sufficient to increase the secretion of ADH (antidiuretic hormone • vasopressin; -+p.294), from the posterior lobe of the pituitary (-+ Cl ). ADH

decreases urirwy H20 excretion. Fluid intake from outside the body Is also required, however. The likewise hypertonic cerebrospinal fluid (CSF), via osmosensors in the OVLT (organum vasculosum laminae terminalis) and SFO (subfornical organ). stimulates the secretion of (central) angiotensin II (AT II) which triggers hyperosmotic thirst (-+C). lsotDnlc: h~. for example following blood loss or secondarily following hyponatremia (D1 ), also stimulates thirst (hypovolemic thirst, -+C), but the percentage deficit of the ECF in this case must be greater (> 10%) than the percentage increase in osmolality for hyperosmot!c thirst (1-2%). The sensors for hypovolemia are primarily the atrial volume sensors (-+ p. 2261f.). Via their afferent pathways and the nucleus ofthe tractus solitarius (NTS), secretion of central AT Ills triggered in the SFO (-+ C. D1 ), and the peripheral renin-AT-11 system (RAS) is activated via the sympathetic nervous system and lhadrenoceptors in the kidney (-+ A4 and p.196). A drop in mean blood pressure below approximately 85 mm Hg triggers very high renin secretion directly in the kidney. Like central AT II, peripherai!J II can also contribute to thirst and to increased Na• appetite, because the SFO and OVLT are located outside the blood-brain barrier. Reluln, a peptide hormone produced by the corpus luteum in pregnant women, binds to receptors in the SFO and OVLT. It causes thirst and stimulates ADH secretion. Despite the reduced plasma osmolallty during pregnancy, which would suppress thirst and ADH secretion, relaxln evidently provides for normal or even Increased fluid Intake during pregnancy. Thirst Is a subjective perception and motivation to search for fluids and drink. The thirst that is a homeostatic response to hyperosmolality or hypovolemia (> 0.5% of body weight: thirst threshold) triwrs primary drinldng. Drinlcing quenches the thirst before osmolality has completely normalized. This preabsorptive thirst quenching is astonishingly accurate as regards the estimate of volume, due to afferent signals from volume sensors and osmosensors in the throat, gastrointestinal tract, and liver. Primary drinking, however, is actually the exception under normal conditions where adequate fluids are available for drinking. A person usually drinks .,..

Abnorm1lltles of volume regulation and Naa balance, water lntoxlc:at:Jon

Plate 7.12 Regulation of body fluid homeostasis A. Wata-outputand lnblbfram the c e l l - - - - - - - - - - - - - . . . ,

2

~

Hypertonic envlronllll!nt

"

~

~

.,

~

.+ ~

.., ..

~

Cell shrinks

Cell swells

B. Regulatton of salt and water balance - - - - - - - - - - - - - - - - , W....dl!fldt Osmolality

t

1

A1r1al pressure

deaeases

fJ

Water excretion:

Osmolality

f.

179

180

Salt and Water Regulation {continued) .,. because he or she has a dry mouth or while eating a meal, but also out of habit, because it is customary or part ofsocial ritual. This everyday form of drinking is called secondary drinkIng. In older age thirst decreases, and 30% of 65-74year-olds and 50% of the over 80s drink too little llutds. Since In older age the urine concentration capacity and AOH and aldosterone secretion also decrease, a substantial fluid dl!lkit is common. This is a cause ofcorluslon and forgetfulness, so that In tum the fluid intake drops further and sets off a vicious circle. Some older people also try to rom bat nocturia and pollakluria by drinking less, whkh further dehydrates the body_ Wmr eX(:e$5 (--. B2). The absorption of hypotonic fluid including, for example, gastric lavage or the infusion of glucose solutions (where the glucose is quickly metabolized into C02 and water) reduces the osmolality of ECF_ This signal inhibits the secretion of ADH. resulting in water diuresis (--> p. l74) and normalization of plasma osmolality within less than 1 hour. Wmr lntoxlmlon occurs when excessive volumes d water are absorbed too quickly, leading to symptoms of nausea, vomiting, and shock. The condition Is caused by an undue drop In the plasma osmolality due to drinking before adequate inhibition of ADH secnetion has occurred.

Volume regulation. Around 8-15 g of NaCl are absorbed each day. The ltidneys have to excrete the same amount over time to maintain Na• and ECF homeostasis. Since Na• is the major extracellular ion (a- balance is maintained secondarily), changes in total body Na• content lead to dtcm,ges in ECF volume. It is regulated mainly by the following fKton: + Renin-angiotensin systMt (RAS). AT II not only induces thirst and salt appetite, but also reduces the GFK and promotes the secretion of ADH and aldosterone, which inhibits Na+ excretion (--. 02 and p.171 89) and, despite recent water intake, maintains a stable salt appetite. + Oxytocin, a neurotransmitter and hormone produced in the hypothalamus, inhibits the neurons that uphold the continued salt appetite and causes increased Naa excretion via neuronal pathways.

+ ANP (atrial natriuretic peptide • atriopeptin) is a peptide hormone secreted by specific cells of the cardiac atrium in response to rises in ECF volume and hence atrial pressure. ANP inhibits thirst and reduces ADH secretion. It also promotes the renal excretion of Na• by raising the filtration fraction (--+ p. 160) and inhibiting Na• reabsorption from the collecting duct(--+p.171 B9).ANP is therefore effectivt!ly an antagonist to RAS. + ADH (antidiuretic hormone • vasopressin). ADH secretion is stimulated by (a)increased plamul and CSF osmolality; (b) the GauerHenry rejle1e, which occurs when a decrease (> 10%) in ECF volume (-atrial pressure) is communicated to the hypothalamus. AT II is the key agent for this. + Pressure diuresis (--. p.l82) results in increased excretion ofNa+ and water. It is caused by an eleva~ blood pressure in the renal medulla. e.g. due to an elevated ECF volume (-.p.228). Salt clefldt (--> D1). When hyponatremia (e.g~ in aldosterone defidt) occurs in the presence of a primarily normal H20 content of the body, blood osmolality and therefore ADH secretion decrease, thereby increasing transiently the excretion ofH20. Although the hypoosmolality is mitigated to some extent, the ECF volume, plasma volume, and blood pressure consequently decrease (--. Dl ). This, in turn, activates the RAS, which triggers hypovolemic thirst by secreting AT II and induces Na• retention by secreting aldosterone. The retention of Na• increases plasma osmolality leading to secretion of ADH and, ultimately. to the retention of water. The additional intake of fluids in response to thirst also helps to normalize the ECFvolume. Salt auas (--+ D2). An abnormally high Nacl content of the body, e.g., after drinking salt water, leads to increased plasma osmolality (thirst ~ drinking) as well as ADH secretion (retention of H20). Thus. the ECF volume rises and RAS activity is curbed. The additional secretion of ANP, perhaps together with a natriuretic hormone with a longer half-life than ANP ( ouabain?),leads to increased excretion ofNaO and H~.

Chronic dehydration, hypodlpslaln elderfy patients

111-

Plate 7.13 Thirst and Salt Regulation C. Thirst: acUViltfon and Inhibition - - - - - - - - - - - - - - - - - - ,

+

ECF and/or ICF \'Glum~

(Vomldng, dlant.ea, hemcuThage, duret!a, bums)

Tlllrsl: sllnUIII:

Osmola llty of ECF (S.ItateSS o r - doftdt)

t

Hormones onglcltensln II, "'luln

per"""""

Cllitl!ll'- - - t - -.... (eJP. dngu/cR lhht Inhibition:

!l)niS, Island)

ANP

i

CognftM l"l!ildlanli -~ness of thirst - seeking water

-

("whoroll the-bllllle1')

Peripheral pressllre and volume sensors

"• na blllod-lorlfn bonier

-------------+

OVLT- orgarnm vasH2P04- (pK.. • ca. 6.8), the reaction NH] + W ;r=> NH4• does not function in the body as a buffer because of its high pJ0.990.8 0.6 0.4 0.2 Mb, D) and what remains in t he lumen is then excreted. There is an apical epithelial Mg2• channel (TRPM6 - transil!nt recl!ptor potential melastatin) in the DCTl (> DCT2) but how Mg2• is passed through (Mg2• -binding protein?) and out of the cell {Mgl+-Na• exchanger? Mgl•ATPase?) is still unclear. Control of tubular Mg2• transport(-> D). Estrogens, Mgl• defidency, and alkalosis increase TRPM6 synthl!sis. TRPM6 activity is incrl!ased by EGF (epidermal growth factor) and diminished by extra-and intracellular Mg2• and also by extracellular Ca2•. PfH and other hormones inhibit Mg2• excretion. Mgl• excretion is stimulated by hypermagnesemia, hypercalcemia, hypervolemia and loop diuretics, and is inhibited by Mg2• dl!fidt, ea2• defidt, and volume deficit.

(KCNJ10) in the ocr(-> p. 171 B8) also lead to increased Mg2• excretion and resulting hypomagnesemia. Cal+ and Mgl• sensors (casR) exist at the basolateral side of the TAL (-+ p. 338). When activated, the sensors inhibit Naa reabsorption in the TAL which, as with loop diuretics, reduces the driving force for paracellular cation reabsorption, thereby diminishing the normally pronounced Mgl• reabsorption there. CiiSRs in the lumen of the proximal tubule are involved in PTH-dependent phosphate reabsorption and in renal caldtriol production, which in tum influences CaSR expression, apparently providing local feedback for fine control ofea2• and phosphate reabsorption.

Cenetlc defects: Mutations ofthe TRPM6 chan-

nel have been discovered in patients with hypomagnesemia and sl!condary hypocalcl!mia (HSH). Mutations of the NaO symporter ('ISC) and basolateral r recirculation channel Abnormalities of phosphate, caldum and magnesium balance, urolithiasis

Plate 7.18 Phosphate. C,a2• and Mg2 • II

=::.

B. Tubular reabiorpCfon of p h o s p h i t e - - - - - - - - - - - - - - - .

1\PO.---~~~

2~·~~~~~==~-~

Pt clefldency

Ptdlflclenty, nonresp. acidosis,

eaz.. , PTH t , ANP,

Alkalosis

Cilucocortlcolds, dopamlne,ldotho.

PTH . "f'

phosphatonins "f'

c:r•t

Pt•......,...nt

Pt ...._rpllan f

C. Transc:ellular C;il+ rea'*"lrtfon In tile distal convoluted tubule - - - - - - - . DCI'2

D. ltan:soellular Mjf+ 1'111bsorpCfon In the dial c:onvalll'bl!d tubule l.wnm

191

192

Potassium Balance The dietary Intake of potassium (K') is about in nonrespiratory acidosis, i.e., by 0.6 mmoi/L tOOmmol/day (minimum requirement: per 0.1 unit change in pH). Alkalosis results in 25 mmolfday). About 901 of intake is excreted hypokalernla. in the urine, and 10% is excreted in the feces. Chronic regu!Mion of K' homeostasis is The plasma IC' concentration normally ranges mainly achieved by the kldrMy (-+ 8 ~ K' is subfrom 3.5 to 4.8 mmolfL, while intracellular K' ject to free glomerular filtration, and most of concentration can be more than 30 times as the filtered K' is normally reabsorbed (net high (due to the activity of Na•-K'-ATPase; reabsorption). The excreted amount can, in -+A). Therefore, about 911% of the ca. some ca.ses, exceM the filtrred amount (net 3000 mmol of K' ions in the body are present secretion, see below). About 65% of the filtrred in the cells. Although the extracellular K' con- K' is reabsorbed before reaching the end of the centration comprises only about 2% of total proximal tubule, regardless of the K' supply. body K"", it is still very important because (a) it This is comparable to the percentage of Na• is needed for regulation of K"" homeostasis and and HlO reabsorbed (..... 81 and p. 165, column (b) relatively small changes in cellular K' (in- 2). This type of K' transport is mainly paraflux or efflux) can lead to tremendous changes cellular and therefore passive. Solvent drag in the plasma K• concentration (with an as- (-+ p.24) and the lumen-positive transsodated risk of cardiac arrhythmias). Regula- epithelial potential, LPTP (-+ 81 and p.170), in tion of IC' homeostasis therefore implies dis- the mid and lab! proximal segments of the tribution of r to the intracellular and extra- tubule provide the driving forces for it In the cellular compartments and adjustment of r loop of Hen~. another 15% of the filtered K' is excretion according to r inmke. reabsorbed by trans- and paracellular routes Acut..-.guliltlonoftheextracellularK•con- (--+82). The amount of K• exaetrd is detercentration is achieved by lntel"'liil shifting ol K' mined in the connecting tubu~ and colltcting between the extracellular fluid and intracellu- duct. Larger or smaller quantities of K' are then Jar fluid (.... A). This relatively rapid process either reabsorbed or secreted according to prevents or mitigates dangerous rises in extra- need. In extreme cases. the fractional excretion cellularK' (hyperkalemia) incaseswherelarge of! 83). The driving force for I 0.04s and Qwave amplitude > 25% of total amplitude of the QRS complex. These changes appearwtthln 24hours of Ml and are caused by fa ilure of the dead myocardium to conduct electrical impulses. Preponderance of the excitatory vector In the healthy contralateral side of the heart therefore occurs while the affected part of tfle myocardium should be depolarizing (firSt 0.04s of QRS). The so-called "0.04·sec vector" Is therefore

said to point away from the Infarction. Anlmor Ml Is detected as highly negative Q waves (with smaller R waves) mainly in l~ads VS. V6,1, and aVL. Q w~ abnormalities can persist for years afterMI(-+12,3), so they may not necessarily be Indicative of an acute infarction. sr ekvotioo pointJ to ischemic but not (yet) necrotic parts of the myocardium. This can be observed: (1) in myocardial ischemia (angina pectoris), (2) in the initial phase of transmural Ml, (3) in nontransmural MI. and (4) along the margins of a transmural Ml that occurred a few hours to a few days prior (->14). The ST segment normalizes within 1 to 2 days of MI. but the Two~ remains inverted for a couple of weeks (->15 and :Z).

Excitation In Electrolyte Disturbances Hyperkalemia. Mild hyperkalemia causes various changes, like elevation of the MDP (--> p. 192) in the SA node. It can sometimes have positive chronotropic effects (-. p. 193 B3c). In severe hyperkalemia, the more positive MDP leads to the inactivation of Na' channels (_. p.46) and to a reduction in the slope and amplitude of APs in the AV node (negative dromotropic effect;_. p. 195 84~ Moreover, the JC+ conductance (lie) rises. and the PP slope becomes flatter due to a negative chronotropic effect (-> p. 195 B3a). Faster myocardial repolarization decreases the cytosolic ca2• concentration In extreme cases, the pacemaker is also brought to a standstill (cardiac parolysis). Hypokalemia (moderate) has positive chronotropic and inotropic effects ( _. p. 195 B3a), whereas hypercalcemia Is thought to raise the 11e and thereby shortens the duration of the myocardial AP. ECG. Changes in serum r and Ca2' induce characteristic changes in myocardial excitation. Hyperkalemia (> 6.5 mmol/L): tall, peaked T waves and conduction disturbances associated with an increased PQ interval and a widened QJtS. Cardiac arrest can occur In extreme cases. Hypokalemia (< 25 mmolfL): ST depression. biphasicTwave (first positive, then nl!giltive). followed by a positive Uwave. Hypercalctmia (> 2.75 mmolfL total caldum): shortened Q:r interval due to a shortened sr segment Hypocalcemia (< 2.25 mmol/L total caldum): prolonged QT interval.

ECG diagnosis, coronary Infarction, hyperblemla, hypokalemh1, hyperc1lcemla, hypoCillcemla

Plate 8.7 Electrocardiogram (ECCi) II

211

E

!

00

G. Determlnltfon of largest rnNn QRS vector (QRS axls) llllng ECG IHd.s 1-111 "Vertical"

"lntennedlate"

(a = +fiO" to +!0')

(a = +30" to +60")

(a= +30" to -30')

+

_).

_A_

_l .

+

..A_

_A_

.A_ +

Ill +

..A_

J.

II

v

,

H. Electrtc:.JI axis of tile heart

v

+

-

II

Ill

I. ECG dainges In mroniiiY lnt.JrcUon

~~

Q + T·~

-fl-' L ' +~ . stage2 (daystowlcs lab!r)

Q

PQS

+60"

+120" .. g()"

Stage 1

T

Stage 3

~ h~ to days._., (mcnlhs toYB later)

212

Cardiac Arrhythmias Arrhythmias are pathological changes in car- cidents and can usually be mrrecb!d by timely elecdiac impulse generution or conduction that can trical ckfibrillotioo. be visualized by ECG. Dlsturb.nces of Impulse generation change the sinus rhythm. Sinus Extrasystoles (ES). The spread of Impulses arising from a supraventricular (atrial or nodal) ectopic focus mchycardia (-> AZ): The sinus rhythm rises to to the ventricles can disturb their sinus rhythm, lead100 min-1 or higher, e.g., due to physical exer- Ing to a suprrM!fltricular otrhythmia. When atlbl b · tion, anxiety, fever (a rise of about 10 beats/ trasystoles occur, the Pwave on the ECG is distorted min for each 1 •c), or hyperthyroidism. Sinus while the QRS complex remains normal. Nodal b · trasysto1es lead to retrograde stimulation of the brud~ardia:The heart rate falls below60min·1 (e.g., due 10 hypothyroidism~ In both cases the atr1a, which Is why the Pwave is negative and is either rhythm is regular whereas in sinus arrhythmias masla!d by the QRS complex or appears shortly thereafter (-+ 81 right). Since the SA node often is the rate varies. In adolescents, sinus arrhythdischarged by a supraventricular extrasystole, the Inmias can be physiological and respiration- terval between the R wave of the extrasystole (R.,) dependent (heart rate increases during inspira- and the next nonnal Rwave Increases by the amount tion and decreases during expiration). of time needed for the stimulus to travel from the Ectopic paDI!makers. Foci in the atrium, AV focus to the SA node. This is called the post~­ node or ventricles can initiate abnormal ec- tole pause. The RR /~Is are then as follows: RESR > mpic (heterotopic) impulses, even when nor- RR and (RR.s + Ru R) < 2 RR (-> Bl). V.ntrlcular (or imranodal) ES (->illl,ll) distorts mal (nomotoplc) stimulus generation by the SA the QRS complex of the ES. If the sinus rate is slow node is taking place (..... A). The rapid discharge enough, the ES wil cause a Yl!lltricular CDntraction of impulses from an atrial focus can induce between two normal heart beats; this is called an inatlbl tachyandla (serrated baseline instead of mpoiii!N (or Interposed) ES (-+ 82). If the sinus rate normal P waves), which triggers a ventricular Is high, the next sinus stimulus reaches the ventricles response rate of up to 200 min-1• Fortunately, while they are still refractory from the ectopic exdta· only every second or third stimulus is trans- tion. Ventricular contraction Is therefore blocked mitted to the ventricles because part of the im- until the next sinus stimulus arrives, resulting in a comfM!nsatory pause, where RR.s + RuR- 2 RR. pulses arrive at the Purldnje fibers (longest APs) during their refractory period. Thus, Dlsturbana1s of Impulse conduction: AV block. Purkinje fibers act as impulse frequency .filters. First-d~t AVblock: prolonged but otherwise Elevated atrial contraction rates of up to normal impulse conduction in the AV node (PQ. 350 min-1 are defined as atrial flutter, and all interval > 0.2 sec). Second-degree AV block: higher rates are defined as atrial tlbrlbtlon only every second (2:1 block) or third (3:1 1 (up to 500 min- ). Ventricular stimulation is block) impulse is conducted. Third-degree AV then totally irregular (absolute arrflythmla). block: no impulses are conducted; sudden carVentricular tachycardia is a rapid train of im- diac arrest may occur (Adam-Stokes attack or pulses originating from a ventricular (ectopic) syncope). Ventricular atopic pacemakers then focus, starting with an extrasystole (ES) (-> B3; take over (ventricular bradycardi.a with norsecond ES). The heart therefore falls to fill ade- mal atrial excitation rate). resulting in partial quately, and the stroke volume decreases. A or total disjunction or QJ!S complexes and ventricular ES can lead to wntrtcular flbrtlla- Pwaves (-> 85). The heart rate drops to 40 to tlon (extremely frequent and uncoordinated 55 min-1 when the AV node acts as the pacecontractions; ..... 84). Because of failure of the maker (->85), and to a mere 25 to 40min·1 ventricle to transport blood, ventricular fibril- when tertiary (ventricular) pacemakers take lation can be fatal. over. Artificial pacemakers are then used. V.ntricular fibrillation mainly occurs when an ectopicfocus fires during the rellltlve refractory pe- Bundle branch block: disturbance of conducrtocl of the previous AP (called the "vulnerable phose" tion in a branch of the bundle of His. Severe synchronous with T wave on the ECG; -> p. 205 A). The APs triggered d~ing this period have smaner QJ!S changes occur because the affected side of the myocardium is activated by the healthy ~. tower propagation wlodties, and shortEr- durations. This leads to re-udtation of myocardial areas side via abnormal pathways. that have already been stimulated (runtry ~). Vl!lltricular fibrillation can ~ caused by '*drical acAtrlal 11nd ventricular tachycardia, flutter and flbrtllatlon, extrasystoles

Plate 8.8 Cardiac Arrhythmias r-

A. Nomotoplc impulse generation with normal wnduction

111111111 li

j

8

~c ~ "::·

~~

1 Normal sinus rflythm

node

·~

II

~lng c-c~

IIIII I

R-

.

~

SA

1

E

~

..

1i .!!

-I\ VelrtrfclesI

_p......,

~~e~rog._ion

'A:J

Q s 0.1 0.2

0

0.3

ii

ol:

! 0.4s

2 Sinus tachycardia r-

B. Heterotopic Impulse generation (1-5) and disturbances of Impulse wnductlon (5)

1

1111111~

SA node activation ~ Retrograde atrial and ,--G- SA node

\ I IT1

A

1 Nodal (AV) extrasystole (ES) with post-extrasystolic pause

II

-F~'QRS

~~~ ·f

SAnode~

-micleactivation - 1\- l

vJ.,

fl -

2 Interpolated ventricular extrasystole (ES)

3 Ventricular tachycardia following extrasystole (ES)

I 4 Ventricular fibrillation 5 Total AV block with ventricular escape rtlythm

Negative P

\

....h .... QRSVP QRS

-

/

-

T

UJI~Iftllllllllllllllilttllllllnlllll llllfffl

a j 1! a 1ft

I

T ~

213

ao

214

Ventricular Pressure-Volume Relationships The relationship between the volume (length) and pressure (tension) of a ventricle iUustrates the interdependence between muscle length and force in the specific case of the heart (--. p. 70ft'.). The-'rdlagram ofthe heart can be constructed by plotting the changes in wntricular presswe ovtr volume during one complete cardiac cycle (--.A1, points A-D-S-VA, pressure values are those for the left ventricle). The following pressure-volume cutws can be used tn ronstruct a work dlagl'lm of the ventrtdes: + Passive (or resting) pressure-volume curve: Indicates the pressures that result passively (without myocardial contraction) at various ventricular volume loads (-+Al, 2; blue curve). + lsOYOiumlc peak curw (-+Al, 2, green curves): Based on I!Xpt!!rimental measurements made using an Isolated heart. Data are generated for various volume loads by measuring the peak ventricular pressure at a constant ventricular volume during rontractlon. The contraction Is therefore lsoKIIumet1ic (isowlumic), I.e.• ejection does not tala! place(-+ A2, vertical arrows). + Isotonic: (or Isobaric) peak curve(-+ A1, 2, violet curves). Also based on experimental measurements takrn at various volu~ loads under isotnnic (Isobaric) rondltlons, l.e., the ejection Is rontrolled In such a way that the ventricular pressure remains constant while the volume decreases (-+ A2, horizontal

arrows).

+ Afterl011ded pe11k curve: (A1, 2. orange curves). Systole consists of an isovolumlc rontraction phase (-+ A1, A-D) followed by an CJIIIO!onlc ejection phase (volume decreases while pressure continues tn rise) (-+ Al, D-S). This type of mixed contraction is called an Cl(ttrlooded conr:roctlon (see also p. 71 B). At a given volume load (preload)(-+ A1, point A), the afterloaded peak value changes (-+ Al, point S) depending on the aortic end·diastollc pressure(-+ A1, point D). All the afterloaded peak values are repreSI!ntl!d on tht!! curve, which appears as a (nearly) straight line connecting the lsovolumlc and Isotonic peaks for each respective volume load (point A) (-+Al, points T and M). Ventrkubir worll diagram. The pressurevolume relationships observed during the cardiac cycle(-+ p.202) can be plotted as a work diagram, e.g., for the left ventricle (..... A1 ): The end-diastolic volume (EDV) is 125mL (..... A1, point A). During the iscwolumetric contraction phase, the pressure in the left ventricle rises (all valves closed) until the diastolic aortic pressure (80mmHg in this case) is reached (--.A1, point D). The aortic valve then opens.

During the ejection phase, the ventricular volume is reduced by the stralce volume (SV) while the pressure initially continues to rise (-+p. 200, Laplace's law, Eq. 8.4b: P,. t be~use r .1. and w t). Once maximum (sy5tolic) pressure is reached (-+A1, pointS), the volume will remain virtually constant, but the pressure will drop slightly until it falls below the aortic pressure, causing the aortic valve to dose (-+A1. point K). During the isovolumetric rehooltion phase, the pressure rapidly decreases to (almost) 0 (-+Al, point V). The ventricles now contain only the end-systolic volume (ESV), which equals about 60 mL in the illustrated example. The ventricular pressure rises slightly during the filling phase (passive pressure-volume curve).

Since work 0 • N • m) equals pressure (N · m - 2 • Pa) times volume (m3) , the area within the working diagram (-+A1, pink area) represents the presswe/volume (PM wortc achieved by the left ventricle during systole (13 333 Pa· 0.00008 m 3 • 1.07J; right ventricle: 0.16J). In systole, the bulk of cardiac work is achieved by active contraction of the myocardium. while a much smaller portion is attributable to passive elastic recoil of the ventricle, which stretches while filling. This represents diastolic JiUing work (-+A1, blue area under the blue curve}, which is performed by the ventricular myocardium (indirectly), the atrial myocardium, and the respiratory and skeletal muscles (-+ p. 216, venous return). Total e~nllacwortc. In addition to the ~rdiac work performed by the left and right ventricles in systole (ca. 1.2 J at rest), the heart has to generate 201 more energy (0.241) for the pulse wave (-+p.200, windkessel). Only a small amount of energy is required to accelerate the blood at rest ( 1% of total cardiac work), but the energy requirement rises with the heart rate. The total Clrdlac power (•work/time) at rest (70min- 1 • 1.17 s- 1 ) is approximately 1.45J · 1.17 s-1 = 1.7W.

Valve defects, hypertflyroldlsm, hypothyroidism, perlcanllallbnormalltles

Plate 8.9 Venbtcular Pressure-Volume Relationships

215

A. Work diagram oftM heart (left ventricle) - - - - - - - - - - - - - ,

E

mmHg 3011

i

1

ml Blood Wllume In left ventrlde

End-diiSiollc

volume (EDV) B. EffKb of pl"'!tenslon (preload) (1), hurt ~te and sympathetic lllmull (2) - - - ,

on rnyac:anllll force and mnb'adlon velocity

(Aftor Somenbld A2, point~). SV will then normalize (SVl) despite the increased aortic pressure (point D2), resulting in a relativrly large increase in ESV (ESV1). Preload- or afterload-indepenclent changes in myocardial contraction force are referred to as c:ontnctllty or lnotroplsm. It increases in response to norepinephrine (NE) and epinephrine (E) as well as to increases in heart rate (p1 adrenoceptor-mediated, positive inotropic effect and frequency inotropism, respectively; ; p. 206). This causes a number of effects, particularly, an increase in isovolumic pressure peaks (--+ A3, green curves). The heart can therefore pump against increased pressure levels(--+ A3, point~>]) and/or eject larger SVs (at the expense of the ESV) ( -+A3, SV4 ). While changes in the preload only affect the form of contraction (-+p. 215 Bt), changes in contractility also affect the ~~~tloclty of contraction (-->p.215 B2). The steepest increase in lsovolumic pressure per unit time (maximum dP/dt) Is therefore used as a measure of contractility in clinical practice. dP/dt is increased by E and NE and decreased by bradycardia (--+ p. 215 B2) or heart failure.

Venous Retum Blood from the capillaries is collected in the veins and returned to the heart. The driving forces for this venous return ( ..... B) are: (a) vis a tergo, i.e., the postcapillary blood pressure (BP) (ca. 15 mmHg); (b) the suction that a rises due to lowering of the cardiac valve plane in systole; (c) the pressure exerted on t he veins during skeletal muscle contraction (maude pump); the valves of veins prevent the blood from flowing in the wrong direction; (d) the increased abdominal pressure together with the lowered intrathoradc pressure during inspiration (Pp~; ---. p. 114), which leads to thoracic venous dilatation and suction (--> p.218). Orthostatic reflex. When rising from a supine to a standing position (orthostatic change), the blood vessels in the legs are subjected to additional hYdrostatic pressure from the blood column. The resulting vasodilatation raises blood volume in the leg veins (by ca. 0.4 L). Since this blood is taken from the centro/ blood volume, i.e., mainly from pulmonary vessels, venous return to the left atrium decreases, resulting in a decrease in stroke volume and cardiac output. A reflexive increase (ortlwstatic reflex) in heart rate and peripheral resistance therefore occurs to prevent an excessive drop in arterial BP (--+ pp. 7 E and ~24ff.); orthostutic collapse can occur. The drop m central blood volume is more pronounced when standing than when walking due to muscle pump activity. Conversely, pressure in veins above the heart level, e.g., in the cerebral veins, decreases when a person stands still for prolonged periods of time. Since the venous pressure just below the diaphragm remains constant despite changes in body position, it is referred to as a hydrostatic indijference point. . 1becantr.. wnouspressui'I!(CVP; -+p. 202) ts measured at the right atrium (normal range: 0-12 em HzO or 0-9 mmHg). Since CVP is mainly dependent on the blood volume, the CVP is used to monitor the blood volume in clinical medicine (e.g., during a transfusion). Elevated CVP (> 20 em HzO or 15 mmHg) may be pathological (e.g., due to heart failure or other diseases usociated with cardiac pump dysfunction), or physiological (e.g., in pregnancy).

Hypervolemia, hypovolemia, hypertension, valve defects, orthostatic abnormalities

Plate 8.10 Regulation of Stroke Volume, Venous Return A. Fllctan Influencing ardiK action - - - - - - - - - - - - - - - . . . , 1 hrelse In Hllllll (preload) (See pn!a!Cing Plate A far~nafcurws)

217 E

!.. "'

] "E!

d

aa

3 lncreaeln conb'Ktlllty

B. Venous return - - - - - - - - - - l

Suction via

l~ringof

cardiac

valwplane

218

ao

Arterial Blood Pressure The tenn blood pressure (BP) per se refers to the arterial BP in the systemic circulation. The maximum BP occurs in the aorta during the systolic ejection phase; this is the systolic pressure (Ps); the minimum aortic pressure is reached during the isovolumic contraction phase (while the aortic valves are dosed) and is referred to as the diastolic pressure (PD) (-+A1 and p.203, phase I in A2). The systolicdiastolic pressure difference (Ps-PD) represents the blood pres5Ure amphtvde, also called puiM pressure (PP), and is a function of the stroke volume (SV) and arterial compliance (C • dV{dP, ..... p. 200). When Cdecreases at a constant SV, the systolic pressure Ps will rise more sharply than the diastolic pressure PD. i.e., the PP will increase (common in the elderly; described below). The same holds true when the SV increases at a constant c. lfthetvt.l pe!1phenl ~ (TPR.-+ p. 200) lnCrHSel while the SV ejection time remains constant. then Ps and the Po will incre~ by the same amount (no ch~nge In PP). However, Increases In the TPR normally lead to retardation of SV ejection and a decrease in the ratio of arterial volume rise to peri ph· eral drainage during the ejection phase. Consequently, Ps rises less sharply than Po and PP decreases. NonrNII 4ll1d elevated blood pressure (applies to all age groups). Po optimally ranges from 60 ID 80mmHg and Ps from 100 ID 130mmHg at rest (while sitting or reclining). A Ps or 130139mmHg and/or a PD of 80-89mmHg are considered to be prehypertensive QNC-7 dassification) while a Po of 90-95 and Ps of 140- 160 mmHg are "borderline" hypertensive. Definitive hypertension is diagnosed with a Po >95 and Ps > 160 mmHg. Optimal BP regulation (-+p.224) is essential for proper tissue perfusion. Abnormally low BP (hypob!nslon) can lead to shock (-+p.230). anoxia (-+p.138), and tissue destruction. Chronically elevated BP (hyperten· slon; -+p.228) also causes damage because important vessels (especially those of the heart, brain, kidneys, and retina) are injured. The mean BP (-the average measured over time) is the decisive factor for peripheral perfusion(-+ p. 200). The IT'Iftn BP can be demnnlned by continuous BP measurement using an arterial catheter, etc. (-+A).

By attl!nuating the pressure signal, only the ll Is recorded. It is calculated as folows: 11- 'I• (2 Po + Ps). Although the mean BP falls slightly as the blood traVl!ls from the aorta to the arteries, the P5 in the large arteries (e.g .• femoral artery) is usually higher than In the aorta (Al v. A2 ) because their compliance is lower than that of the aorta (see pulse wave velocity, p. 202). Direct invasive BP measurements show that the BP curve in arteries distaiiD the heart is not synchronous with that ofthe aorta due to the time delay required for passage of the pulse wave (3-10 m/s; -+ p. 202); its shape is also different (-+A1, A2; recorded BP curves). The BP Is routinely measured externally (at the level of the heart) according to the Ri1111-Rocd method by sphygmomanometer (-+B): An inflatable cuff is snugly wrapped around the upper arm and a stethoscOIH! is placed over the brachial artery at the crook of the elbow. Whle readIng the manometer, the cuff Is Inflated to a pressure higher than the expected P5 (the radial pulse disappears). The air in the cuff is then slowly released (2-4 mmHg/s). The first sounds synchronous with the pulse (IA). The contribution of both arteries to blood flow in the septum and posterior wal of the left ventricle varies.

Coronary blood flow (0a,.) is phasic, Le., the amount of blood in the coronary arteries fluctuates during the cardiac cycle due to extremely high rises in extravascular tissue pressure during SYStole (..... B, C). The blood flow in the epicardial coronary artery branches and subepicardial vessels remains largely unaffected by these pressure fluctuations. However, the subendocardial vessels of the left ventricle are compressed during systole when the extravascular pressure in that region (- pressure in left ventricle, l'JY) exceeds the pressure in the lumen of the vessels (-+C). Consequently, the left ventricle is mainly supplied during diastole(-+ B middle~ The fluctuations in right ventricular blood flow are much less distinct because right ventricular pressure (Pav} is lower (-+B. C). MyocardJ.a 01 consumption ('O'ot) is defined as Q.. times the arteriovenous 02 concentration difference, (C.-C.)o2. The myocardial (C.-C.)o2 is relatively high (0.12 I.fL blood), and oxygm extraclton at rest ([C.-C.[ot/C.ot = 0.12/ 0.21} is almost 60% and, thus, not able to rise much further. Therefore, an increase in ()..,, is practically the only way to increase myocardial \1o2 when the Oz demand rises (-+ D, right side). Adaptation of the myocardial 02 supply according to need is therefore primarily achieved by adjusting vascular resistance (--> D,left side). The (distal) coronary vessel resistance can normally be reduced to about '/• the resting value (coronary reserve}. The coronary blood fiowQ.. (approximately 250mL/min at rest} can therefore be increased as much as 4-5 fold. In other words,approximately4-5 times more02 can be supplied during maximum physical exertion. ~(~~)oftheroro~ry

arteries leads to luminal ~rrowing and a resultant decrease In poststenottc pressure. Dilatation of the distal vessels then occurs as an autoregulatory response (see below). Depending on the extent of the stenosis, It may be necessary to use a fraction of the

coronary reserve, even during rest. As a result, lower or in.suffkient quantities of Oz will be available to satisfy Increased 0 2 demand, and r:t11011C1fY Insufficiency may occur(-+ D). MyocMd~ 02 demand increases with cardiac output (increased pressure- volume-work/time: ..... p. 214ft.), i.e., in response to increases in heart rate and/or contractiUty, e.g., during physical _ . dse (--> D, right). It also Increases as a function of mural tension (T-) times the duration of systole (tf!nsion-time index). Since T....,- P- · r-/2w (l.a· place's low-+ Eq. 8.4b, p. 200), Oz demand Is greater when the ventricular pressure (P,...-) Is high and the stroke volume small than when P,.,.. is low and the stroke volume high. even when the same amount of wort (P •V) is performed. In the first case, the ~­ dency of the hurt is reduced. When the ventricular pressure P...., Is elevated, e.g., In hyptiUnslon, the myocardium therefore requires more 02 to perform the same amount of work (-+ D, right). Since myocardial metabolism is aerobic, an increased 02 demand quicldy has to lead to vasodilatation. The following factors are involved in mrDnary vasoclllat.tlon: + Met.bollc fKtors: (a)oxygen deficiency since Oz acts as a vasoconstrictor; (b)adenosine; oxygen deficiencies result in insufficient quantities of AMP being reconverted to ATP, leading to accumulation of adenosine, a degradation product of AMP; this leads to vasodilatation; (c) accumulation of lactate and W ions (from the anaerobic myocardial metabolism); (d) prostaglandin h. + Endothelial factors: ATP (e.g., from platelets), bradykinin, histamine and acetylcholine are vasodilators. They liberate nitric oxide (NO) from the endothelium, which diffuses into vascular musde cells to stimulate vasodilatation (-+ p. 293 E). + Neurohumol'ill factors: Norepinephrine released from SYmpathetic nerve endings and adrenal epinephrine dilate the distal coronary vessels via P2 adrenoceptors. MyocMdlll energy ICIIII'OS. The myocardium c.an

use the available glucose, free fllny adds, lactate and other molecules for ATP production. The oxidation of each of these three energy substrates con.sumes a certain fraction of myocardial Oz (Oz extraction coefficient); acoordingly, each contributes approximately one.tflird of the produced ATP at rest. The myocardium consumes Increasing quantities of loc· tate from the skeletal muscles during physical exercise(--> A,--> pp. 76 and 296).

Coronary disease, hypoxia and dilatation, pressure load and workload of myocardium

Plate 8.1 3 Myocardial Oxygen Supply

:Z:Z3

E

i

~

1/3 Glumse

1/3 Free fatty acids

~

0.12

Coronary blood flCPN Q....(ml/min) ArtEriovenous Oz difference {C.~C.)~(L/Lblood)

1/7Giucose 1/5 Free fatty adds 0.15

2/3 Lactate

(fromi~

slaeletal muscles)

JO P.z ~ Vo,•IJa..· (C. -C.)o.,(ml/min ,----

1/3 L'ld:ilt2

B. Coronary blood flow--------,

~phase)

C. Systolic pressures in heart - - - - - ,

Aoi :

120

Right

Left

coronary a!Ury: 120

UD

015 0.2

0.4 0.6 0.8 Tlme (s)

1.0

~

Right

0

All pressures: mmHg

D. component5 ofO:zbillanCll!! In myocardium - - - - - - - - - - - - - - .

COronary dilatation (coronary reserw)

l

Coronary resistance .J Diastolic

perfusion pressure t .Arterial Oz concentration t

r 4

O..dem~nd

PhyJic;d wort (sympathetic tone) Hyper11!nslon, etc. Mural tension T t

Heart rate t CDntractllltyt

224

ao

Regulation ofthe Orculatfon The blood flow must be regulated to ensure an adequate blood supply, even under changing environmental conditions and stress (cf. p. 78). This implies (a) optimal regulation of cardiac activity and blood pressure (homeostasis), (b) adequate perfusion of all organ systems, and (c) shunting of blood to active organ systems (e.g., muscles) at the expense of the resting organs (e.g., gastrointestinal tract) to keep from overtaxing the heart (..... A). Reguloition of blood flow to the Ol'gilll5 is mainly achieved by changing the diamerer of blood wssels. The musde tone (tonus) of the vascular smooth musculature changes in response to (1) local stimuli (..... B2alb), (2) hormonal signals(..... B3 alb), and (3) neuronal signals (..... Bl alb). Most blood vessels have an intermediary musde tone at rest (resting tone). Many vessels dilate in response to denei'Viltion, resulting in a basal tone. This occurs due to spontaneous depolarization of smooth musde in the vessels (see alsop. 74). l..oClll Regul.tlon of Blood Flow (Autoregulation)

Autoregulation has two functions:

+ Autoregulatory mechanisms help to maintain a const4nt blood flow to certain organs

+ Local mehbollc (dJemlciJI) ellects: An increase in local concentrations of metabolic products such as C(h, H., ADP, AMP, adenosine, and K' in the interstitium has a vasodilatory effect, especially in precapillary arterioles. The resulting rise in blood flow not only improves the supply of substrates and lh. but also accelerates the efflux of these metabolic products from the tissue. The blood flow to the brain and myomrdlum (..... p.222} is almost entirely subject to local metabolic control. Both local metabolic effects and (h defJCiendes lead to an upto-5-fold increase in blood flow to an affected region in response to the decreased blood flow (reactive hyperemia). + Vasoactlnsubstances: A numbl!r ofvasoactive substances such as prostaglandins play a role in autoregulation (see below). Hormonal Control of CirciAtion Vasoactive substalla!l. Vasoactive hormones either have a direct effect on the vascular muscle (e.g., epinephrinl!} or lead to the local release of vasoactive substances (e.g., nitric oxide, endothelln) that exert local paracrine effects (-+B). + Nitric (mon)oxlde (NO) acts as a vasodi/atory agent. NO is released from the endothelium when acl!tylcholine (M receptors), ATP, endothelin (ET• receptors), or histamine (H, receptors) binds with an endothelial cell (..... p. 292 ). NO then diffuses to and relaxes vasrular myocytes in the vicinity. + Endothelln-1 can lead to vasodi/at4tion by inducing the release of NO from the endothelium by way ofETB receptors (see above), or can cause vasoconstriction via ET" receprors in the vasrular musculature. When substances such as angiotensin II or ADH (antidiuretic hormone • vasopressin; Vt receptor) bind to an endothelial cell, they release endothelin-1, which diffuses to and constricts the adjacent vascular muscles with the aid of ETA receptors. + Eplnephrtne (E): High concentrations of E from the adrenal medulla (..... p. 90) have a vasoconstrictive effect (a1-adrenoceptors), whereas low concentrations exert vasodilatory effects by way of ~-adrenoceptors in the myocardium, skekt41 muscle, and liver (-+C). The effect of E mainly depends on which type of adrenoceptor Is predominant in the organ. IJJlo

when the blood pressure changes (e.g., renal vessels constrict in response to rises in blood pressure; ..... p. 158). + Autoregulation also functions to adjust the blood flow according to changes in metabolic activity ofan organ (met4bollc autoregulation); the amount of blood flow to the organ (e.g., cardiac and skeletal muscle; ..... A and p. 222) can thereby increase many times higher than the resting level. Autoregulatory mechanism: + Myogenic effects arising from the vasrular musde of the lesser arteries and arterioles (Bayliss ejJrd) ensure that these vessels conInlet in response to blood pressure- related dilatation (..... B2a) in certain organs (e.g., kidneys, gastrointestinal tract, and brain), but not in others (e.g., skin and lungs). + Oxygen deficiencies generally cause the blood vessels to dilate. Hence, the degree of blood flow and 02 uptake increase with increasing 02 consumption. In the lungs, on the other hand, a low l'll2 in the surrounding alveoli causes the vessels to contnlct(~vaso­ constriction;--. p.128). Hypoxia, Ischemia, organ perfusion abnormalities. centrallmlon of circulation

Plate 8.14 Regulation of the Circulation I 225 A. Blood flow to o r g a n s - - - - - - - - - - - - - - - - - - - - - .

1

i

Vessd strm:h

~ Myogenic reaction ----+ 2a loml

E

I

Po.zt - - - - ·

r

I •,

Endothelln-1 t (ET..) _____;, PGFz,,

I

·~

~

·

throm : OIIilne _ ;

ADH (V,), eplnephllne (a1), ingKrtenHnll

E'plnephllne(llz)

3a Honnon•l

3b

Honnonal

ketylchohne (M), AlP, histamine (H,), endott!ell~l (ETll

22&

Regulation ofthe Orculatlon {continued) II- at-adrenoceptors are predominant in the

ao

blood vessels of the kidney and skin. + Elcosanolds (--+ p. 283): Prostaglandin (PG) f20 and the thromboxanes A,. (released from platelets) and B2 have vasoconscrlcttve effects. while PGI2 ( • prostacyclin, e.g., released from endothelium) and PGE1 have vasodi/atory effects. Another vasodilator released from the endothelium (e.g., by bradykinin; see below) opens r channels in vascular myocytrs and hyperpolarizes them, leading to a drop in the cytosolic Ca2• concentration. This endothelium-derived hyperpolarizing factor (EDHF), has been identified as an 11,12-epoxyeicosatrienoic acid (11,12-EET). + Bradykinin and kallidin are vasodilatory agents deaved from lcininogens in blood plasma by the enzyme kallikrein. Histamine also acts as a vasodilator. All three substances also influence vessel permeability (e.g., during infection) and blood clotting. Neuronal Regulation of Circulation

Neuronal regulation of blood flow (--+ Bla, b) mainly involves the lesser arteries and greater arterioles ( 4 p. 200), while that of venous rerum to the heart (--+p.216) can be controlled by dilating or constricting the veins (changes in their blood storage capacity). Both mechanisms are usually controlled by the sympathetic nervous system (-+ Blil and p.82ff.), whereby norepinephrine (NE) serves as the postganglionic transmitter (except in the sweat glands). NE binds with the a1-adrenoceptors on blood vessels, causing them to constrict(-+ B). Vasodilatation is usually achieved by decreasing the tonus of the sympathetic system (--+ Blb). This does not apply to blood vessels in salivary glands (increased secretion) or the genitals (erection), which dilate in response to parusympathetic stimuli. In this case, vasoactive substances (bradykinin and NO, respectively) act as the mediators. Some neurons release caldtonin gene-related peptide (CGRP), a potent vasodilator. Neuronal regulation of blood flow to organs occurs mainly: (a) via central coinnervation e.g., an impulse is simultaneously sent from the cerebral cortex to circulatory centers when a muscle group is activated, or (b) via neuronal foedback from the organs whose activity level

and metabolism have changed. If the neuronal and local metabolic mechanisms are conflicting (e.g., when sympathetic nervous stimulation occurs during skeletal muscle activity). the metabolic factors will predominate. Vasodilatation therefore occurs in the active muscle while the sympathetic nervous system reduces the blood flow to the inactive musdes. Blood flow to the skin is mainly regulated by neuronal mechanisms for the purpose of controlling heat disposal (temperature conlrol; -.p.236). Hypovolemia and hypotension lead to centralization of blood flow, i.e., vasoconstriction in the kidney (oliguria) and skin (pallor) occurs to increase the supply of blood to vital organs such as the heart and central nervous system ( 4 p. 230). During exposure to extremely low temperatures, the enid-Induced vasoconstriction of cu· taneous veuels is periodically int=upted to supply the sldn with blood to pm p. 218). Untreated or inadequately managed hypertension results in stress and compensatory hypertrophy of the left ventricle which can ultimately progress to left heart failure. Individuals with hypertension are also at risk for arteriosclerosis and its sequelae (myocardial infarction, stroke, renal damage, etc.). Therefore, hypertension considerably shortens the life expectancy of a large fraction of the population. The main uuses of hypertension are (a) Increased extracellular fluid (ECF) volume with Increased venous retum and therefore increased cardiac output (wlume hypemnslon) and (b) increased total peripheral resistance (reslswnce hypemnsion). As hypertension always leads to vascular changes re5Uitlng in increased perip/lerai resistance, type a hypertension eventually proceeds to type b which, regard· less of how it started, ends in a vicious circle. The ECF volume increases when more NaCI (and water) Is absorbed than excreted. The usually high In· take of dietary salt may therefore play a role In the development of essential hypenension (primary hypertension), the most common type of hypertension, at least In patients sensitive to salt. Volume hypertension can even occur when a relatively low salt Intake can no longer be balanced. This can occur In renal insufficiency or when an adrenocortical tumor produces uncontrolled amounts of aldosterone, resulting In Na• retention. Another Important cause of hypertension Is pheochromocytoma, a tumor that secretes epinephrine and norepinephrine and therefore raises the CO and TPR. Renal hypel"t2nslon can occur due to renal artrry stenosis and renal disease. This results In the Increased secretion of renin, which In turn raises the blood pressure via the renin-angiotensinaldosterone (RAA) system(--+ p. 196).

•nd consequences of hypertension, renal failure

Plate 8.1 6 Regulat1on of the crrculat1on Ill

229

E

! X

00

4c

:k A~nt

aRrent

Stretdl receptors

Va$odilatiltion 1.

venous rebn If•

2. sensors

d) Atrial and venous

sumu1.. PressosenSOR In: a)Aorh b) carotid arteiY c) l.l!ft ventricle

a) Glossopharyngeel nerve (lxth nerve) b) vagus nerve (Xlh nerve) a) Stimulation of parasympathetic system b) Inhibition of

/

stretch senSOR

c) Vigus neNe (XIh n.,....) 4.

EHerent peth

c) Stimulation of

symi,Nthetic system

symrsystem

Vasodlliltallon Cardiac output clecreeses

Abtel , _ ... rt.s

Tachycardia.

~

Peripheral resistance decreases

myocardial contractility increases

..

Goal adlleued

230

Circulatory Shock Circulatory shock is characterized by acute or subacute progressive generalized failure of the circulatory system with disruption of the microcirculation and failure to maintain adequate blood flow to vital orgaJU. In most cases, the onlac output (CO) Is lnsufllclent due to a variety of reasons, which are explained below. Hypovolemic shock Is characterized by reduced central venous pressure and mluced III!IIOUS return, resulting in an inadequate stroke volume (FrankStarling mechanism). The blood volume can be reduced due to bleeding (hemorrhagic shoclc) or any other conditions associated with the extemalloss of fluids from the gastrointestinal tract (e.g., severe vomiting, chronic diarrhea), the kidneys (e.g., india· betes mellitus, diabetes Insipidus, high-dose diuretic treatment) or the skin (burns, profuse sweating without fluid Intake). An intErnal loss of blood can also occur, e.g .• due to bleeding into soft tissues, into the mediastinum or into the pleural and abdominal

spa~~dlogenlc shock: Acute heart faUurr can be caused by acute myocardial infarction, acute decompensation of heart failure or Impairment of cardiac filling, e.g., in pericardial tamponade. The central Vl!l'louspressurelshigherthanin l!ypovolemicshock. Shock can occw d~ to hormonal QU~es, such as adrenocortical insufficiency, dlabellc coma or Insulin owrdose (hypoglycemic shock). V.agenk shade Reducrd cardiac output can also be due to peripheral vasodilatation (absence of pallor)andaresultantdropofvenousreturn. Thisoccurs in Gram-positive septicemia (Sl!J'tic shock), anaphylactic shock, an immediate hypersensitivity reaction (food or drug allergy, Insect bite/sting) in which vasoactive substances (e.g., histamines) are released. Symptoms. Hypovolemic and cardiovascular shock are characterized by decreased blood pressure (weak pulse) increased heart rate, pal/arwith cold sweats (not observed with shock caused by vasodilatation), reduced urinary output (oliguria) and extreme thirst.

blood pressure and slower-acting mechanisms compensate for volume losses both play a role. Blood pn!SIUil! compensation (_.A left): A drop in blood pressure increases sympathetic tm1e (-+A1 and p.226). Arterial YOSOCOJUtri£tfon (absent in shock due to vasodilatation) shunts the reduced cardiac output from the skin (pallor), abdominal organs, and kidneys (oliguria) to vital organs, such as the coronary arteries and brain. This is known as centralization of blood flow (-+A2). Sympathetic constriction of venous capacitance vessels (which raises ventricular filling), tachycardia, and pasitive inotropism increase the diminished cardiac output to a limited extent Comp•nsfilon for volum• deficits (-+A, right): When shock is imminent, the resultant drop in blood pressure and peripheral vasoconstriction lead to a reduction of ropil/ary filtrotlon pressure, allowing interstitial fluid to enter the bloodstream. Atrial stretch sensors detect the decrease in ECF volume (reduced atrial filling) and transmit signals to stop the atria from secreting ANP and to start the secretion of antidiuretic hormone (ADH) from the pasterior lobe of the pituitary (Gauer-Henry to

reflex;_. p. 180).ADH induces vasoconstriction

CVt receptors) and water retention (Vl recep-

tors). The drop in renal blood pressure and sympathetic stimulation triggers an increase in renin secretion and activation of the reninangiotensin-aldosterone (RM) system (..... p.196). Conversely, angiotensin II increases sympathetic norepinephrine release. If these measures are successful in warding off the 1mpending shock, the lost red blood cells are la.ter replaced (via increased renal erythropoietin secretion, ..... p. 92) and the plasma protein concentration is normalized by increased he-

5hock ind•lL The ratio of pulse rate (beats/min) to patic synthesis. SYStolk: blood pressure (mmHg), or shoclc Index, proManlfest(orprogresslve) shock will develop vides a rough estimate of the extent of volume loss. if these homeostatic compensation mechaAn index of up to 05 indicates normal or < 10:1: nisms are unable to prevent impending shock blood lon; up to 1.0 • < 20- 30:1: blood loss and lm- and the patient does not receive medical treatpending shock; up to 1.5 - > 30-501: blood loss and ment (infusion, etc.). Severe hypotension (< 90 manifest shock. mmHg systolic or < 60 mmHg mean blood Most of the symptoms described reflect the pressure) can persist for extended periods, cuunterregulatury meu..-es taken by the even in spite of volume replacement The rebody during the nonprogressive phase of shock suiting development of hypoxia leads to organ in order to ward off progressive shock damage and multlpl• 0111•n hlllurw, ultimately (-+A). Rapid-acting mechanisms for raising the culminating in In-eversible shock and death. Circulatory shock: ciluses, symptoms, compensatory mechilnlsms ilnd treetment, shock Index

Plate 8.1 7 Orculatory Shock

231

A. Compensation mechllnllnu for Impending Jtrpovolemlc shodr - - - - - - - - , Aclte hurtfillklre

l~re

•

Anaerobict

1\l,f

glymlysls

... ...

Locti< acid

I

Homlonill auses

E

Volume deficit

i

,r--~~~~ -:-~ -a-: dvabne -:----,

1

CMmoseiiSOIS ~·

t

pH t-

Stimulation of - -......;;..&-;-.:;---¥' sympathetic system

bA2).Tokeepwarm,thebodymayhave tD generate additional voluntary (limb movement) and involuntary (shivering) muscle contractions. Newborns also have tissue known as brown fat, which enables them to produce additional heat without shivering (.... p. 237). Cold stimulates a reflex pathway resulting in norepinephrine release (fh-adrenergic receptors) in fatty tissues, which in turn (1) stimulates lipolysis and (2) increases the expression of lipopromn lipase (IPL) and thennogmin (UCP1 ). LPL increases the supply of free fatty acids(-+ p. 268). Thermogenin localized in the inner mitochondrial membrane is an uncoupling protein (UCP) that functions as an W uniporter. It short-circuits the W gradient across the inner mitochondrial membrane (-+p.17 82), thereby uncoupling the (heat-producing) respiratory chain of ATP production. Rrcent research has shown that muscle work leads to secretion of the hormone irisin from muscle cells. Irisin stimulates UCP-1 expression in fat cells, thereby increasing energy consumption and reducing obesity(-+ p.242). Heat produced in the body Is absorbed by the bloodstream and conveyed to the body surface. In order for this lnt•rn•l flow of heat to occur, the temperature of the body surface must be lawer than that of the body interior. The blood supply to the skin is the chief determinant of heat transport to the skin(-+ p. 236).

Heat loss occurs by the physical processes of radiation, conduction, convection, and evaporation(.... B).

1. Radiation (-+ B1, C). The amount of heat lost by radiation from the skin is chiefly detennined by the temperature of the radiator (fourth power of Its absolute temperature). Heat net-radiates from the body surface to objects or individuals when they are cooler than the skin, and net-radiates to the body from objects (sun) that are wanner than the skin. Heat radiates from the body into the environment when no radiating object is present (night sky). Heat raclatlon does not require any vehicle and 1$ hardly alh!cted by the air temperature (air Itself Is a poor radiator). Therefore, the body loses heat to a cold wall (despite warm alr In between) and absorbs radiation from the sun or an infrarl!d radiator without air (space) or cold air, respectively, in between. 2. Conduction and convedlon (--> 82, C). These

processes involve the transfer of heat from the skintocoolerairoracoolerobject(e.g.sittingon rock) incontactwith the body(conduction). The amount of heat lost by conduction to air increases greatly when the warmed air moves away from the body by natural convection (heated air rises) or forced convection (wind). This explains the "wind chill effect": at a temperature of -25"C and a wind speed of 60km/h, the wind chiU IEmperat:ure is ca. -43"C. 3.EVlllporllldon(-->B3,C).Thefll'Sttwomechanisms alone ilre unable to maintain ildequate temperature homeostasis at high environmental temperatures or during strenuous physical activity. Evaporation is the means by which the body copes with the additional heat. The water lost by evaporation reaches the skin surface by diffusion (insensible perspiration) and through neuron-activated sweat glands (..... 83, pp. 82ff. and 237 D). About 2428 kJ (580 kcal) of heat are lost for each liter of water evaporating and thereby coolingthe skin..At temperatures above 36"( or so, heat loss occurs by evaporation only (--> C, right). At even higher environmental temperatures, heat is even absorbed by radiation and conduction/convection. The body must lose largeramountsofheatbyevaporation to make up for this. The surrounding air must be relatively dry in order for heat loss by evaporation to occur. Humid air retards evaporatio!L Whentheairisextremelyhumid(e.g.,inatropical rain forest), the average person cannot tolerate temperatures above 33"C, even under resting conditions.

Hyperthermia, heat mllapse, heatstroke, sunstroke, hyperthyroidism

Plate 9.1 lbennal Balance A. Rdiltfft contribution of orgua; to body wefght -.nd hNt produc:Uon - - - - - .

1

~

:z

Percentage of body weight

~entageof

(-100X)

heat procluction 2X

(-1001)

Brain

•

At rest Thor~cic ~nd

hydratl!s

·I

Ene{Wj content ( /d;,y)

Xof energy requirement

Gn

17t) 1g

17.L) 370

'

• llemml!ll'nded valu..for an adult ,...,-lghlng 70 kg. durtng light physlc.ol a;Ia,:-> p. 126). This method is used in humans. To determine t_he total metabolic rate (or TEE; --+ p. 238) from Yo,, the caloric •qulvalent (CE) of a foodstuff oxidized in the subject's metabolism during the measurement must be known. The CE is calculated from the PFV and the amount of 0 1 needed to oxidize the food. The PFV of glucose is 15.7kj/g and 6mol of02 (6x 22.4L) are required to oxidize 1 mol (= 180 g) of glucose (->C). The oxidation of 180 g of glucose therefore generates 2827 kj of heat and consumes 134.4 L of 02 resulting in a CE of 21 kj/L This value represents the CE for glucose under st.mdard conditions (O"C;...., C). The mean CE of the basic nutrients at 37 "Cis 18,8 kj/L 0 2 ( carbohydrates), 17.6kj/LOl (fats) and 16.8kj/L 0 1 (proteins). The oxidized nutrients must be known in order to calculate the metabolic rate from the CE. The resplratury quotient (RQ) is a rough measure of the nutrients oxidized. RQ • Yeo,/ 'O'o, (-+ p. 126). For pure carbohydrates oxidized, RQ • 1.0. This can be illustrated for glucose as follows: [10.1] C&H1zOs+ 6 ~ - 6 C02 +6 H20 The oxidation of the fat tripalmitin yields: 2 Cs!H,aOs + 145 02 ~ 102 C~ + 98 H2 0 110.2] The RQoftripalmitin is therefore 102/145 • 0.7. Since the protein fraction ofthe diet stays relatively constant, each RQbetween 1 and 0.7 can be assigned aCE(--+ D). Using the known CE, the TEE can be calculated as CE ·Yo,.

Food increases the TEE (diet-Induced tflermoge.sls, DIT) because energy must be consumed to absorb and store the nutrients. The DIT of protein Is higher than that of other substances, e.g., glumse.

Diets for losing and gaining weight, Impact of physical activity

Plate 10.2 Energy Metabolism and calorimetry B. Direct cabimetry (Lavoisier)

241 c

i .,iS

Ill al

Iii c

Insulation

0

E ...

...

Wmr --+-+--

::II

z

Combustion chamber ~l--l....!:>f.

c.

0 ....

Oxklatlon of glucose: fuel value, a lnd RQ - - - - - - - - - - - - - , H,(:OH

Energy

I

r/~-o,r

f,rc-cr/fH

HO

~

)))

+

bH

Ci~cose

l1mol=180 !jl

rl

l 21n l:l 1aol •15.7 kl/g Fuelwlue

+

• •

+~

Decomposition (combustion)

~

=:c:1 --l r-

A. C). Muscular activity consumes a lot of energy (ATP) and is very important for normal energy homeostasis. Mor~. it has recently been shown that working skeletal muscles also secrete a hormone (itsln) that leads to the formation of brown (or beige) f.!t. Thtreln, UCPl (- thermogenin) is able to dissipate energy 'Jery effectively(--> below and p. 236). F•t depots are by far the body's largest energy reserve. Accurate long-term homeostasis of energy absorption and consumption (->B) is necessary to keep the size of the fat depotS constant, i.e., to maintain lipostasis, as normal energy metaboli.sm is necessary for systemic glucose and lipid homeostasis. Too little fat tissue leads to metabolic disorders (lipoatrophy with diabetes mellitus and hypertriglyceridemia) just as much as eJU:essive fat depob. Since a person's body weight mainly varies with the weight of the fat depots, it is obvious that energy homeostasis is largely synonymous with the reguliltlon of body weight (-+ B). The body lnil55 lndu (BMI) is commonly used to determine whether an individual is underweight, overweight, or in the normal weight range. BMI is calculated from body weight (kg) and height (m) as follows: BMI" body weight (kg)f(helght [m))1 [10.3]

The Body weight Is nomnal when the BMI range Is 19-24 in women and 20-25 in men. The •normal" BMI range Is defined as the values between which mean life expectancy is highest. An abnormaUy high body mass index (BM I > 24 or 25 - overweight; BMI > 30 • obese) reduces life expectancy since this Is often associated with metabolic syndrome (diabetes mellitus type 2, hypertension, and cardiovascular disease). Too high a level of fat stores in the abdominal and visceral region Is especially dangerous as t his is an important mkfactorfor met~lic syndrome. This is why the circumference of the wllst Is measured to provide additional information. It should be < 102cm (If) and < 88 cm

B). Effects of leptln. Leptin binds with type b leptin reaprors (LRb - Ob-Rb) of the hypothalamus (mainly in the arcuate nucleus, but also the paraventricular nucleus and other locations),leading to weight loss. The effecl3 ofleptin are chiefly mediated by two neurotransmitters located in the hypothalamus: a-MSH and NPY p. 294). a-MSH, via MC4 receptors (MC4-R) in various area s of the hypothalamus and the dorsal nucleus of the vagus nerve, inhibits the absorption of nutrients and increases sympathetic nervous activity and energy consumption. An ~

Diagnosis, treatment and behavior of under and overweight, anorexia, cachexlil

Plate 10.3 Energy Homeostasis and Body Weight I

243 II:

.2

ii

al

2S AbsorptSon of: ~Ill$

Fats Carbohylhtl!s

'a II:

Ill

j

..

1:! ::II

z

...a

htraerw

t

Food lntilke t Energy conJumption • Parasympathetic adivlty t

Food lntakl!

•

Energy consumption

t

SympatheUc actMty

t

244

c

~

a -g I'll

..~ c

.5!

z

Q

Energy Homeostals and Body Weight (continued) .,.. involuntary increase in ordinary skeletal muscle activity and tone increases energy consumption and the sympathetic tone. In addition, there are una>upllng proteins (type UCP2 and UCP3) in skeletal muscle and white fat that make the membranes of the mitochondria more penneable to H• ions, thereby uncoupling the respiratory chain(-+ p.41 C). As aresult, chemical energy is converted into more heat and less ATP. The action of these UCPs, the expression of which is directly or indirectly stimulated by a-MSH, is therefore similar to that of thennogenin (UCPt; see above).

+

NPY. Leptin and a-MSH (via MO-R), as well as insulin, inhibit the release of NPY (neuropeptide Y) in the arcuate nucleus, a neuropeptide that stimulates hunger and appetite via a series of neurons, increases parasympathetic activity, and reduces energy consumption.

+ Besides this chronic infonnation about fat

laU! the appeliU! (orexlgenic effec:t). Shortly before food is required, secretion increases, triggering "stomach rumbling.· Ghrelin secretion falls when chyme reaches the duodenum after a meal In Prader-WilU syndrome the obesity is a consequence of elevated ghrelin production in the gastrointestinal tract. Like ghrelin, orexin A and B and norepinephrine (a2-adrenoceptors) are also onudgenlc. Psydlologlul aspects. just thinking of tasty little chunks of cheese often triggers increased salivation and the desire to eat The wish persists even after eating the third chunk but diminishes greatly after up to 30 chunks; this habituation can be largely explained by the repeated sensory stimuli (odor, taste, appearance) and by the feedback described above (e.g., via CCK). It has been shown recently that specific mental imagining (memory without actual sensory input) also leads to this habituation.

stores provided by leptin, it has been shown that the plasma leptin level is reduced acutely by fasting and rises again rapidly after ingestion of food. Cenetlc defects which affect leptln production, LRb or, most commonly, MC4-R. result in obesity early in childhood. The body weight can w:eed 100 leg by age ten. L.eptln deficiency Is treated wtth recombinant leptin. Since NPY Increases the secretion of gonadollbertn (GnRH). extreme weight loss results In amenorThea (-> B).

The hypothalamus and rhombencephalon receive information regarding giUC051! availabilIty from the sweet sensors of the tongue, intestinal glucose transporters (SGLT), endocrine release of serotonin (5-HT, 5-hydroxytryptarnine ), and Gf1>1 (glucagon-like peptide amide from the distal small bowel), as well as from the Insulin concentration (p. 296!f.) and amylin secreted at the same time as insulin from pancreatic fl-cells. These signals have a postprandial -nexlgenlc effi!d This is also true for cholecystokinin (CCX. p. 236ff.~ which signals the intestinal uptab of fats and prot.lns. The stretch receptors of the stomach wall inhibit food consumption in a general way. Ghrelln, secreted by the gastric mucosa when the stomach is empty, is known to stfmuDiagnosls, tn!abnent 1nd behavior of under- and overweight, anorexia, cachexia

Plate 10.4 Energy Homeostasis and Body Weight II

C. Regulation of appetite and energy balance - - - - - - - - - - - - - , Environment and lifestyle

Genes, eplgenetics

Pl!rsonallty, eartychlldhood expafence

Energy consumption

Distribution of nutrients

l

AlP mnsumpllon

Energy metabolism

245

246 c

~

a -g I'll

..~ c

.5!

z

Q

Gastrointestinal (GI) Tract: Overview, Immune Defense, Blood Flow Food must be swallowed, processed, and broken down (dlgntlon) before it can be abSOibecl from the intestines. The Gl musmlature ensures that the Gl contents are properly mixed and transported. The passage tfme through the different Gl segments varies and is largely dependent on the composition of the food (..... A for mean passage times). Food is ch~ed and mixed with saliva, which lubricates it. The esophagus rapidly transports the food bolus to the stomach. The lower esophageal sphincter opens only briefly to allow the food to pass. The proximal stomad! mainly serves as a food reservoir. Its tone determines the rate at which food passes to the distal stomach, where it is further processed (chyme formation) and its proteins are partly broken down. The distal stomach (including the pylorus) is also responsible for portioning chyme delivery to the small intestine. The stomach also secretes intrinsic foetor (-+ p. 94 ). In the small Intestine, enzymes from the pancnas and small intestinal mucou break down the nutrients into absorbable components. HC03- in pancreatic juices neutralizes the acidic chyme. Bile u lts in bile are essential for fat digestion. The products of digestion as well as water and vitamins are absorbed in the small intestine. Waste products (e.g., bilirubin) to be excreted reach the feces via bile secreted by the llvl!r. The liver has various other metabolic functions. It serves, for example, as an obligatory relay station for metabolism and distribution of substances absorbed from the intestine (via the portal vein, see below), synthesizes plasma proteins (incl. albumin, globulins, clotting factors, apolipoproteins, etc.) and detoxifies foreign substances (biotronsfunnalion) and metabolic products (e.g., ammonia) before they are excreted. The large Intestine is the last stop for water and ion absorption. It is colonized by bacteria and contains storage areas for feces (cecum, rectum~

Immune defense. The large internal surface area of the Gl tract (roughly 100m2) requires a very effective immune defense system. Saliva contains mucins, immunoglobulin A (fgA) and lysozyme that prevent the penetration of pathogens. Gastric juice has a bactericidal ef-

feet. Peyer's parches supply the Gi tract with immunocompetent lymph tissue. M ceUs (special membranous cells) in the mucoul epithelium allow antigens to enter Peyer's patches. Together with macrophages, the !'eyer's patches can elicit immune responses by secreting lgA (--+ p. 98ff.). lgA is transported to the intestinal lumen by transcytosis (-+p.30). In the epithelium, (gA binds to a secretory component, thereby protecting it from digestive enzymes. Mucosal epithelium also contains introepithelial lymphocytes (IEL) that function like T killer cells ( .... p. 102). Thl! physiological bowel nora consists of some 1014 bacteria belonging to about 100 species. Most live in symbiosis with us and are in close communication with intestinal cells. Until adulthood, they make a crucial contribution to the development of the Gl immune system. Not only do they fight pathogenic microbes in the bowel but they also "program• the specific immunity of intestinal T cells(-+ p. tOOfi.). They also digest complex carbohydrates and provide us with essential nutrients. Macrophages ofthe hepaticsinusoids (KupfferceUs) are additional bastions of immunl! defense. JgA from breast milk protects the Gl mucou of neonates. Blood flow to the stomach, gut, liver, pancreas, and spleen (roughly 30% of cardiac output) is supplied by the three main branches of the abdominal aorta. The intestinal circulation is regulated by local reflexes, the autonomic nervous system, and hormones. Moreover, it is autoregulatory, i.e., largely independent of systemic blood pressure fluctuations. Blood flow to the intestines rises sharply after meals (acetylcholine, vasoactive intestinal peptide VIP, etc. function as vasodilatory transmitters) and falls during physical activity (transmitters: norepinephrine, etc.). The venous blood carries substances absorbed from the intestinal tract and enters the liver via the portal win. Some components of absorbed fat are absorbed into the intestinal lymph, which transports them to the greater circulation while bypassing the liver.

Digestive abnormalities, constipation, stomach, bowel, biliary and pancreatic dlse1se

Plate 10.5 Gl Tract: Overview. Passage Trmes A. function ofg;~litnllntestfnal organs - - - - - - - - - - - - - - - - .

247 c 0

i!!' c

'! IV

taste, dlewtng, formiltlonof foodbolu5

I

SalMI: lubrication,

...

z

0

11nslng,

digestion

Llllllr:

bile (eccrdion, lipid digestion), metabcillsm, di!IDICiflatlon Glllbllddar: bile storage Pan~:.- (emkrine): dlgestM enzymes, H~-

as W buffer

DIIIIIIIIDmllch: processing, digestion, poi11onlng

SmalllntMIIne: digestion, abSorpUon

Colan: absorption IIKblm:

storage, eccretion

248 c

~

a -g I'll

..~ c

.5!

z

Q

Neural and Hormonal Integration Endocrine and paracrine hormones and neurotransmitters control Gl motility, secretion, ptifusion. and growth. Reflexes proceed within the mesenrericand submucosal plexus (enteric nervous sysrem, ENS). and exrernal innervation modulates ENS activity. l..oail reflexes are triggered by stretch sensors in the walls of the esophagus, stomach, and gut or by chemosensors in the mucosal epithelium and trigger the contraction or relaxation of neighboring smooth muscle fibers. Pl!ristaltic reflexes extend further toward the oral (ca. 2mm) and anal regions (20-30mm). They are mediared In part by inremeurons and help to propel the contents of the lumen through the Gl tract (peristalsis). External Jnnennrtlon of the Gl tract ( cf. p. 82ff.) comes from the parasympathetic nervous system (from lower esophagus to ascending colon) and sympathetic nervous system. Innervation is also provided by viscerul afferent fibers (in sympathetic or parasympathetic nerves) through which the afferent impulses for supraregional reflexes flow. ENS function is largely Independent of external innervation, but ut«nnl lnMI'Valion has some advantages: (a) riljlid transfer of signals between relatively distant parts of the Gltract via the abdominal ganglia (short visceral a~nts) or CNS (long visceral afferents); (b) Gl tract function can be ranked subordinate to overall body function; and (c) Gl tract activity can be processed by the brain so the body can become aware of It (e.g., stomach ache).

Neurotransmltt.n. Norepinephrine (NE) is released by the adrenergic postganglionic neurons, and acetylchoUne (AOI) is released by pre- and postganglionic (enteric) fibers (--+ p. 78ff.). VIP (vasoactive intestinal peptide) mediates the relaxation of circular and vascular muscles of the Gl tract. Met- and JeuenlwpiNIIJn intensify contraction of the pyloric, ileocecal, and lower esophageal sphincters by binding to opioid receptors. GRP (gastrin-releasing peptide) mediates the release of gastrin. CCRP (calcitonin gene--related peptide) stimulates the release of somatostatin (51H). All endocriM hoi'II'IOI'MIS effective in the Gl tract are peptides produced in endocrine cells of the mucosa. (a) Gaslrin and cholecystokinin (CCK) and (b) secretin and CIP (see below) are

structurally

similar; so are glucagon and VIP. High concentrations of hormones from the same family therefore have very similar effects. Gastrin occurs in short (G17 with 17 amino acids, M) and long forms (G34 with 34 M). G17 comprises 90% of all antral gastrin. Gastrin is secreted in the antrum and duodenum. Its release (--+A1) via guslrin-rrleasing peptide (CRP) is subject to neuronal control; gastrin is also released in response to stomach wall stretching and protein fragments in the stomach. Its secretion is inhibited when the pH of the gastric/duodenal lumen falls below 3.5 (-.A1). The main effects of gastrin are add secretion and gastric mucosal growth (--+ A2). Cholecystokinin, CCK (33 M) is produced throughout the small intestinal mucosa. Longchain fatty adds, M, and oligopeptides in the lumen stimulate the release of CCK (--+A1). It causes the gallbladder to contract and inhibits emptying of the stomach. In the pancreas, it stimulates growth, production of enzymes, and secretion of HCOJ- (via secretin, see below)(-.A2). Secretin (27 M) is mainly produced in the duodenum. Its release is stimulated by addic chyme (.... A 1). Secretin inhibits acid secretion and gastric mucosal growth and stimulates HCoJ- secretion (porentiated by CCK). pancreatic growth, and hepatic bile flow(--+ A2). CIP (glucose-dependent insulinotropic peptide, 42 M; formerly called gastric inhibitory polypeptide • enterogastrone) is produced in the duodenum and jejunum and released via protein, fat, and carbohydrate fragments (e.g., glucose) (--+A1). GIP inhibits add secretion (--+ A2) and stimulates insulin release (this is why oral glucose releases more insulin than intravenous glucose). Motllln (22M) is released by neurons in the small intestine and regulates interdigestive motility (--+A1, 2). Pillraatne tn1nsrn1tten.. Histamine, somatostatin (SIH) and prostaglandin are the main paracrine transmitters in the Gl tract. (~p.298ff.)

Complications of stomach and bowel surgery, stomach and bowel ulcers, malabsorption

Plate 10.6 Neural and Honnonallntegratlon A. C.!lrolntstfnal harmanl!!l - - - - - - - - - - - - - - - ,

1 Sti ulus for release and site of s

r1I II I

l

I

.

r J I i ., I J t t I 1 .. t I I ~ I Il i ~i l !

D

"--""

..

i

E

5I

.5

I

~ i

~

le

2 Main effects of gastroint:estinaI hormones

Jt

e.

d

I

(Partly llftor L R. Jolman)

249

250 c

~

a -g I'll

..~ c

.5!

z

Q

Saliva The functions of saliva are reflected by its constituents. Mudns ~rve to lubricate the food, making it euler to swallow. and to keep the mouth moist to facilitate masticatory and speech-related movement Saliva dissolves compounds in food, which is a prerequisite for taste bud stimulation (-+ p.360) and for dental and oral hygiene. Saliva has a /ow NaCI concentration and is hypotonic, making it suitable for rinsing of the taste receptors (Nacl) while eating. Infants need saliva to seal the lips when sodding. Saliva also contains a-amylase, which starts the digestion of starches in the mouth, while immunoglobulin A and lysozyme are part of the Immune defense system (-+p.98ff.). The high HC03 concentration in saliva results In a pH of around 7, which is optimal for a -amylase-catalyzed digestion. Swallowed saliva is also important for buffering the addle gastric juices refluxed into the esophagus (-+ p. 256). The secretion of profuse amounts of saliva before vomiting also prevents gastric iiCid from damaging the enamel on the teeth. Saliva secretion is very dependent on the body water content. A low content results in decrea~d saliva ~etion-the mouth and throat become dry, thereby evoking the sensation of thirst. This is an important mechanism for maintaining the fluid balance (-+pp.178and 196). Secretion rate. The rate of saliva secretion varies from 0.1 to 4mL/min (10-250J..LL/min per gram gland tissue), depending on the degree of stimulation (-+B). This adds up to about 0.5 to 1.5 L per day. At 0.5 mL/min, 95% of this rate is secreted by the parotid gland (serous saliva) and subiiUlndibular gland (mucinrich saliva).lbe rest comes from the sublingual glands and glands in the buccal mucosa. 5111,. secretion occurs in two steps: The acini (endpieces) produceprtmarysallva (-+ A. C) which has an electrolyte composition similar to that of plasma (--+B). Primary saliva secretion in the acinar cells is the result of transcrilular transport: a- is actively taken up into the cells (secondary active transport) from the blood by means of a Na•-K•-2acotransport carrier and is released into t he lumen (as with HCOJ· ) via anion channels, resulting in a lumen-negative t ransepithelial potential (LNIP) that drives Na• paracellularly

a-

into the lumen. Water also follows passively (osmotic effect). Primary saliva is modified in exuetory ducts, yielding HCOI1daly sallvill. As the saliva passes through the excretory ducts, Na• and c1· are reabsorbed and JC' and (carbonic anhydrase-dependent) Hco,- is secreted into the lumen. The saliva becomes hyporunic(far below tOO mOsm/kg H~; ..... B) because Na• and CJ- reabsorption is greater than K• and HC03- secretion and the ducts are relatively impermeable to water (-+B). If the secretion rate rises to values much higher than 100 J.'L/(min ·g), these processes lag behind and the composition of secondary saliva becomes similar to that of primary saliva (-+B). Salivant stimuli. Reflex stimulation of saliva secretion occurs in the larger salivary glands (-+D). Salivant stimuli include the smell and taste of food, tactile stimulation of the buccal mucosa, mastication. and nausea. Conditioned re~ also play a role. For Instance. the routine clattering of dishes when preparing a meal can later elidt a salivant response. Sleep and dehydration inhibit saliva secretion. Saliva secretion is stimulated via the sympathetic and parasympathetic nervous systems (-+ C2): + Norepinephrine triggers the seaetion of highly viscous saliva with a high concentration of mucin via lh adrenoreceptors and cAMP. VlP also increases the cAMP concentration of acinar cells. + Acetylcholine: (a) With the aid of Mt cholinoceptors and IPJ (..... pp. 86 and 288), acetylcholine mediates an increase in the cytosolic Ca2• concentration of acinar cells. This, in tum, increases the conductivity of luminal anion channels, resulting In the production of watery saliva and Increased exocytosis of salivary enzymes. (b) With the aid of M:! cholinoceptors, ACh mediates the contraction of myoepithelial cells around the acini, leading to emptying of the acini. (c) ACh enhances the production of kallikreins, which cleave brudykinin from plasma kininogen. Bradykinin and VIP(-+ p. 248) dilate the vessels of the salivary glands. This is necessary because maximum saliva secretion far exceeds resting blood flow.

Carles, reflux esophagitis, salivary calculi, xerostomia, hypovolemia

Plate 10.7 Saliva

251

B. Electl"'llytei In saliva - - - - - - - - - - - ,

A. Silllvil seaetfon

2501---

::::r ~

1200 1 - - - 1-+ -+---+----1--/-+-----1 c

.5!

i

150

i __ 1-+-- + - - + -1 -----1----1

8

... a

1-,oo

j

Blood side

stmull

Smell Taste Touch

Manlutlon

Nausea

etc.

-:.- Pr!ratkl gland

l

252

c

~

a -g I'll

..~ c

.5!

z

Q

Deglutition The upper third of the esophageal wall consists of striated muscle, the rest contains smooth muscle. During the process of swallowing. or deglutition, the tongue pushes a bolus of food intD the throat (~A1 ). The nasopharynx is reflexively blocked, (--+ A2), respil'iltion is inhibited, the vocal chords close, and the epiglottis seals off the trachea (-+ Al) while the upper esophageal :sphincter opens (..... A4). A peristaltic wave forces the bolus into the stomach (-+AS, B1,2).1fthe bolus gets stuck, stretching of the affected area triggers a secondary perIstaltic wave.

The 1-er esophageal sphincter opens at the start ofdeglutition due to a vagovagal reflex. (receptive relaxation) mediated by VIP- and NO-releasing neurons (--+ 83). Otherwise, the lower sphincter remains closed to prevent the reflux of aggressive gastric juices containing pepsin and HCL EsophagNI motility is usually checked by musurlng pressure In the lumen, e.g., during a peristaltic waVI! (-+ 11 , 2). The rest ing pressure within the lower sphincter is normally 20-25 mmHg. During receptive relaxation, esopllageal pressure drops to match the low pressure in the proximal stomach (-+ 83), indicating opening of the sphincter. Pressure In the lower esopllageal sphincter Is decmzsed by VIP, CCK, NO, GIP, secretin, and progestero~ (-+ p. 248) and incrmsecl by acetylcholine, gastrin, and motllln. Increased abdominal pressure (I!Xternal pressure) also Increases sphincter pressure because part of the lower esophageal sphincter is located in the abdominal cavity. In •ch•l•sl•, receptive relaxation fails to occur and food collects in the esophagus.

Castroesophageel reflux. The sporadic reflux of gastric juices into the esophagus occurs fairly often. Reflux can occur while swallowing (lower esophageal sphincter opens for a couple of seconds), due to unanticipated pressure on a full stomach or to tmnsient opening of the :sphincter (lasts up to 30 seconds and is part of the eructation reflex~ Gastric reflux greatly reduces the pH in the distal esophagus. ProtKtlw mechanisms to prevent damage to the esophageal mucosa after gastroesophageal reflux include 1. Volume dNranc:e, i.e., the rapid return of ~'!!fluxed fluid to the stomach via the esophageal peristaltic reflex. Arefluxed volume of 15 mL. for example. remains in the esophagus for only 5 to 10s (only a small

amount remains). 2. pH cle••nce. The pH of the residual gastric juice left after volume clearilnce is still low, but is gl'ildually increased during each act of swallowing. In other words, the saliva that is swallowed buffers the residual gastric juice.

Vomiting Vomiting mainly serves as a protective reflex but is also an important clinical symptom of conditions such as intl'ilcranial bleeding and tumors. The act of vomiting is heralded by nausea, increased salivation, and retching (-.C). The vomiUng center Is located in the medulla oblongata within the reticular formation. It is mainly controlled by chemosensors of the area postrema, which is located on the floor of the fourth ventricle; this is called the chemosensory trigger zone (CIZ). The bloodbrain barrier is less tight in the area postrema. The CIZ Is lldlvMed by nicotine, other toxins, and dopamine agonists Mke apomOiphine (uwd as an ernetk:). Cells of the C1Z have receptors for neurotransmitters responslble for their neuronal control. The wmiting center can also be activated independent of the CTZ, for tlli!mple, due tD abnormal stimulation of the organ of balance (ldnesla, motion sidness), OVI!rextension ofthe stomach or intestines, delayed gastric emptying. and inflammation of the abdominal organs. Nausea and vomiting often occur during the first trimester of pregnancy (morning sic/cness) and can exacerbate to hyperf!f'MSis gravidarum leading to vomiting-related disorders (see below).

During the act of vomiting, the diaphragm remains in the inspiratory position and the abdominal muscles quickly contract exerting a high pressure on the stomach. Simultaneous contraction of the duodenum blocks the way to the gut; the lower esophageal sphincter then relaxes, resulting in ejection of the stomach contents via the esophagus. jThe sequelae ofdwonkwmltlng are attributable to rreduced food Intake (malnu!ritlon) and the related loss of gastric juices, swallowed saliva, fluids , and intestinal secretions. In addition to hypovokmio. nonrespiratory o#a:llosls due to the loss of gastric add (10-l OOmmol W/L gastric juice) also dew!lops. This is accompanied by hypo/a1lemio due tD the loss of K• In the vomitus (nutrients, saliva, gastric juices) and urine (hypovolemia-related hyperoldostPronism; --+ p. 194ff.).

Gastric juice reflux, bulimia, achalasia, vomiting as symptom (Increased lntraa11nlal pressure)

Plate 10.8 Deglutition, Vomiting

253 c

i .,iS

Ill al

Iii c 0

E ...

... ::II

(Alber Rush,_ a. HendA)n)

z

0 ....

Vomiting D!lltl!r

with dlemorecepmr tr1gger zone

\. Herillded by: Nausea

Dllmd pupils

Salivation

t

Retdllng

Outbl1!ilk of s-..t

Paleness

' '----+

'\. "Vbmltlng

254 c

0

';;

:c

~ 1ra c

t z

0

Stomach Structure and Motility stnKture. The o:1rdfo conn«U the eso~us to the upper siDmach (fundus), which merges with the body (corpus) foll~d by the antrum of the stomach. The lower outlet of the stomach (pylorus) merges with the duodenum (--.A). Stomach size is dependent on the degree of gastric filling, but this distension Is mainly limited to the proximal stomach (-+A, B). The stomach w11ll has an outer layer of longitudinal muscle fibers (only at curvatwes; regulates stomach length), a ~ of powerful circular muscle fibers, and an inner~ af oblique muscle fibers. The mucosa af the tullular glllrlcls of the fundus and COipUS contain chief cells (CC) and parldDI crHs(PC) (-+A) that produe2the constituents of gastric juice (-+ p. 256). The gastric mucosa also contains endocrine cells (that produa! gastrin In the antrum, etc.) and mucous neck cells (MNC).

Functlon•l •natomy. The stomach can be divided into a proximal and a distal segment (-+A). A vagovagal reflex triggered by swallowing a bolus or food causes the lower esophageal sphincter to open (-->p.246) and thl! proxlmlll stomKh to dilate far a short period (receptive relaxation). This continues when the food has entered the stomach (vagovagal accommodation reflex). As a result, the Internal pressure hardly rises In spite ofthe increased filling. Tonic contractions of the proximal stomach, which mainly serves as a reservoir, slowly propel the gastric contents to the cllsUI stomach. Near Its upper border (middle third of the corpus) is a pomnaker zone (see below) from which peristaltic waves of contraction ari.se dul! mainly to local stimulation of the stomach wall (in response to reflex stimulation and gastrin; -+ 01 ). The peristaltic waves are strongest in the antrum and spread to the pylorus. The chyme is thereby driven toward the pylorus (-+ CS, 6, 1 ), then comprl!ssl!d (-+C2, 3) and propelll!d back again after the pylorus clOSI!S (-+ C3, 4). Thereby, the food is proctssed, i.e., ground, mixed with gastric juices, and digested, and fat i.s emulsified. The distal stomach contains pacemaker cells (interstitial Cajal ctlls), the membrane potential of which oscillates roughly every 20 s, producing characteristic slow waws (-+ p. 258). The velocity (0.5-4cm/s) and amplitude (0.5-4mV) of the waves incrl!ases as they spread to the pylorus. Whether and how often contraction follows such an excitatory wave depends on the sum of all neuronal and hor-

monal influences. Gastrin increases the response frequency and the pacemaker rate. Other hormones like GIP inhibit thi.s motility directly, whereas somatostatin (SlH) does so indirectly by inhibiting the release of GRP (-+D1 andp.248). G•strlc emptying. Solid food remains in the stomach until it has been broken down into small particles (diameter of< 1 mm) and suspendl!d in chyme. The chyme then passes to the duodenum. The time required for 50% of the ingested volume to leave the stomach varies, e.g., 10-20 min for water and 1-4 hours for solids (carbohydrates< proteins< fats). Emptying is mainly dependent on the tone of rhe proximo! stomach and pylorus. Motilin stimulaks emptying of the stomach (tone of proximal stomach rises, pylorus dilates), whereas decreases in the pH or osmolality of chyme or increases in the amount of long-chain free fatty adds or (aromatic) amino acids inhibit gastric emptying. Chemosensitive enterocytes and brush cells of the small intestinal mucosa. enterogastric reflexes, and certain hormones (CCK, GIP, secretin and gastrin; -+ p. 248) mediate these regulatory activities (-+ D2). The pylorus is usually slightly open during the process (free flow of"finished" chyme).lt contracts only 1) at the end of"antral systole" (see above) in order to Rtain solid food and 2) when the duodenum contracts in order to prevent the reflux of harmful bile salts. If such reflex does occur, refluxed free amino adds not normally present in the stomach elicit Rflex closure of the pylorus (--> 02). lndlgndbl• subst•nces (bone, fiber, foreign bodies) do not leave the stomach during the digestive phase. Special contraction waves called mi&Juting motor complexes (MMC) pass through the stomach and small intestine roughly every 1.5 hours during the ensuing lntl!nllgestM phue, as determined by an intrinsic "biological clock.• These peristaltic waves transport Indigestible substances from the stomach and bacteria from the small intestine to the large intestine. This "clearing phase" is controlled by motllln.

Castrtc bleeding, tumors, consequences of surgery, m•ldlgesdon, vomiting

Plate 10.9 Stomach Structure and Motility A. An•tamy afthestDnuch - - - - - - - - - - , Esop/raglls Conlic!

"l'n»dmoo" stomad!

Hypoglycemia,

psydlologlcal factors, taste, smell, etc

Pain,

~ psydlologlcal factors, etc. Verger~

ctX,GIP

1 Distal stomach (mixing and processing)

Seaetln

:z Proximal stomach and pylonJs (emptying)

255

256 c

~

a -g I'll

..~ c

.5!

z

Q

Gastric Juice The lllbular glands of the gastric fundus and Gntrk 11dd secretion is stlmul11ted in corpus sKrete 3-4 L of gastric juice each day. phases by neuru~ local gastric, and intestinal Ptpsinogms and lipases are released by chief factors (..... B). food intake leads ID reflex SKrecells and HCI and Intrinsic /aCIDr ( -+ p. 274) by tion ofgastric juices, but deficient levels of gluparietal cells. Mucins and HC03 - are released by rose in the brain can also trigger the reflex. The mucous neck cells and other mucous cells on optic, gustaiDry, auditory, and olfactory nerves the surface or the gastric mucosa. are the atrerents for this partly conditioned rePepsins function as endopeptidases in pro- flex (..... p. 250), and efferent impulses flow via tein digestion. They are split from pepsinogens the vagus nerve. ACII directly activates parietal exocyiDsed from chief cells in the glandular cells in the fundus via PIP2 and (al+ (MJ and gastric lumen at a pH of < 6. Acetylcholine cholinoceptors -> 82). CRP (gastrin-releasing (ACh), released locally in response ID W (and peptide) released by neurons stimulates thus indirectly also to gastrin) is the chief actf- gastrin secretion from G cells in the antrum \Ill tor of this reaction. (..... B3). Gastrin released into the systemic Ci1strlc 1cld. The pH of the gastric juice circulation in tum activates the parietal cells drops to ca. 0.8 during peak HCI secretion. via CCKa receptors ( • gastrin rKeptors ). The swallowed food buffers it to a pH of 1.8-4, glands in the fundus contain H (histamine) which is optimal for most pepsins and gastric cells or ECL cells (enterochromaffin-like cells), lipases. The low pH contributes to the denatu- which are activated by gastrin (CCKB receptors) ration of dietary proteins and has a bactericidal as well as by ACh and ~3-adrenergic substances ejJect. (-> B2). The cells release histumine, which has a Hasecretlon(-+A).TheW-K'-ATPaseinthe paracrine effect via cAMP on neighboring luminal membrane of parietal cells drives W parietal cells (lil rKeptor). Local gastric and ions into the glandular lumen in exchange for intestinal factors also influence gastric acid K' (primary active transport,-+ Al and p.26), secretion because chyme in the antrum and thereby raising the W concentration in the duodenum stimulates the secretion of gastrin lumen by a factor of ca. 107• K' taken up in the (-> B1 and p. 249 A). process drculates back to the lumen via lumiFactors that inhibit gastric: juice secretion: nal K' channels. In activated parietal cells, (a) A pH of< 3.0 in the antral lumen inhibits C these chaMels form a heterodimer consisting eels (negative feedback,-+ Bl,l) and activates of the subunits KCNE2 and KCNQ1. For every W antral D cells, which secrete SIH (-+ p. 248), ion secreted, one HC03- ion leaves the blood which in tum has a paracrine effect SIH inhibside of the cell and is exchanged for a CJ- ion via its H cells in the fundus as well as G cells in the ananionantlporter(->Al).(TheHC03-ionsare antrum (->B:Z,l). (b) CGRP released by neuobtained from C02 + OH-, a reaction catalyzed rons (..... p. 248) activates D cells in the antrum by carbonic anhydrase, CA). This results in the and fundus,(-> B2,l). (c) Secretin and GIP reintracellular accumulation of ct- ions, which leased from the small intestine have a retrodiffuse out of the cell to the lumen via chan- grade effect on gastric juice secretion (-+ Bl ). nels (-+Al). Thus, one a- ion reaches the This adjusts the composition of chyme from lumen for each W ion secreted. A basolateral the stomach to the needs of the small intestine. Na• -2a--K• symporter also helps to maintain Protedlon of the gastric mucosa from dethe high intracellular ct- concentration. structive gastric juices is chiefly provided by The ilctlv1don of plliftll mils (see below) (a) a layer of mucus and (b) HC03- SI!CI"'!tion by leads to the opening of canaliculi, which ex- the underlying mucous cells of the gastric tend deep iniD the cell from the lumen of the mucosa. HCOJ- diffuses through the layer or gland (-+B). The canaliculi are equipped with a mucus and buffers the add that diffuses into it brush border that greatly increases the lumi- from the lumen. Prostaglandins PGE1 and PGb nal surface area which is densely packed with promote the si!Cretion ofHCOJ-. membrane-bound W-K'-ATPase molerules. Antl-lnn.tlmltoly drugs that inhibit cyThis permits an increase in the secretion of W clooxygenase 1 and thus prostaglandin proions from 2mmolfhour at rest to over duction(->p.283)impairthismucosalprotec20 mmol/hour during digestion. tion and can result in ulcer development Gastric ulcen, antadds, gastrlnoma, vitamin 812 deficiency, cyclooxygenase Inhibitors

a-

Plate 10.10 Gastric Juke

257 1:

.2

@-,_

9

9@

~ CA

otr + COz

Lumen ofgland

Secretin, GIP

"V

1:

•1:

....

:!::!

Blood side

Na•/H+ exchanger

3 Antrum

c

.2 CD.!

Hz() - i

1

li

.!!)

:II

z

Cl

258 c

~

a -g I'll

..~ c

.5!

z

Q

Small Intestinal Function The main function of the small intestine (SI) is to finish digl!sting the food and to absorb the accumulated breakdown products as well as water, electrolytes and vitamins. Structure. The Sl of live human subjects is 3-5m in length. It arises from the pylorus as the duodenum and continues as the Muoom. and ends as the ileum, which merges Into the large Intestine. From outside inward, the Sl consists of an outer serous coat (tunica sero.ro, -+ A1), a layer of longitudinal musde fibers (-+ A2), the myenteric plexus (Auerbach's plexus, -+ A3), a l~r of circular muscle fibers(-+ .M), the submucous plexus (Meissner's plexus, -+AS), and a mucous Ioyer (tunica mucosa, -+ A6), which is CO\'ered by epithelial cells(-+ All-15). The Sl is supplied with blood vessels (-+ A8), lymph vessels (-+A 9), and nerves (-+ Al 0) via the mesentery (-+ A7). The surface area of the eplthellal-lumlnallnterface Is roughly 300- 1600 times larger(> 100m2) than that of a smooth cylindrical pipe because of the Kerdcring's folds (-+All), the lntntinol villi (-+A12), and theenarocytic mlaoYI//1, or the brush bo•(-+ All).

Ultrastructu.- and function. Goblet cells (-+ A15) are interspersed between the absorbing enterucytes (-+A14). The mucus secreted by goblet cells acts as a protective coat and lubricant.Inrmtnal glands (crypts ofUeberldlhn. -+A16) located at the bases of the villi contain (a) undifferentiated and mitotic cells that differentiate into villous cells (see below). (b) mucous cells, (c) endocrine and paracrine cells that receive information about the composition of chyme from chemosensor cells, and (d) immune cells (-+ p. 248). The chyme composition triggers the secretion of endocrine hormones and of paracrine mediators (-+ p. 246). The tubuloadnar duodenal glands (Brunner's glands}, located deep in the intestinal wall (tela submucosa) secrete an HC03--rich fluid containing urogastrone (human epidermal growth factor), an important stimulator of epithelial cell proliferation. Cell~. The tips of the villi a~ continualy shed and rep~ed by new cells from the crypU of Liebettdihn. Thereby, the entire Sl epithelium is renewed ~ry 3-6 days. The dead cells disintegrate in the lumen, thereby releasing enzymes, stored Iron, infected enterocytes, etc.

longitudinal muscles) and segmentation (contraction/relaxation of circular muscle fibers) of the SI serve to mix the intestinal contents and bring them into contact with the mucosa. This is enhanced by movement of the intestinal villi (lamina muscularis mucosae). Reflex peristaltic wcrm (3D-130cm/min) propel the intestinal contents toward the rectum at a rate of ca. 1 em/min. These waves are espedally strong during the interdigestive phase (-+ p. 258). Pertsblltlc reflex. Stretching of the intestinal wall during the passage of a bolus (-+B) triggers a reflex that constricts the lumen behind the bolus and dilates that ahead of it. Controlled by intemeurons, cholinergic type 2 motoneurons with prolonged excitation simultaneously activate circular muscle fibers behind the bolus and longitudinal musculature in front of it. At the same time the drcular muscle fibers in front of the bolus are inhibited (accommodation) while those behind it are disinhibited (-+Band p. 248). P~ The intestine also contains pacemaker cells (intersCiCial Cajal cells). The membrane potential of these cells osdllates by 10 to 20 mV every 3-15 min, produdng slow wcrm (-+Cl). Their amplitude can rise (less negative potential) or fall in response to neural, endocrine or paracrine stimuli. A series of action potentials (spike bursts) are fired once the membrane potential rises above a certain threshold (ca. - 40 mV) (-+C). Muscle spasms occur if the trough of the wave also rises above the threshold potential (-+ CJ). Impulse conduc:tlon. The spike bursts are conducted to myocytes via gap junctions (-+pp. 19 and 74). The myocytes then contract rhythmically at the same frequency (or slower). Conduction in the direction of the anus dwindles after a certain distance (-+ D, pacemaker zone), so more distal cells (with a lower intrinsic rate) must assume the pacemaker function. Hence, peristaltic waves of the small intestine only move in the anal direction.

Intestinal motllty is autonomously regulated by the enteric nervous system, but is influenced by hormones and external innervation (-+ p. 248). Local pendular movements (by Bowel surgery, cytostatic drugs, constipation, paralytic Ileus, Hlrschsprung disease

Plate 10.1 1 Smalllntesdnal Structure and Function A. Structure of the smallntestlne (schematic) - - - - - - - - - - - - , 13 14

259 c

i .,iS

Ill al

Iii c 0

E ...

... ::II

z

0 ....

y,......,._ Lru~x~nln

? ACh ACh

'g

~

d i~

VIP

D. Pacemaker rate - - - - - - - - ,

Intrinsic rate l'nlldm•l

Distil

~-------------TI_m __ e_(s_)__~~~~·G~~~nl L---------~-5_w_~ __m_s_m_a_n_;~ __n_in_e____~

260

c

~

a -g I'll

..~ c

.5!

z

Q

Pancreas The exocrine part of the pancreas secretes 1-2L of pamnatic juice into the duodenum each day. The pancreatic juice contains HC01-. which neutralizes (pH 7-8) HO-rich chyme from the stomach, and mostly inactive precursors or digestive enzymts. PllrKrHtk seaetlons are produced in two stages: (1) As in saliva (-+p.251 C1 ), o- is secreted in the «A). Most of these actions are predominately autDnomous functions subject to central control by the hypothalamus, which is controlled by higher centers of the brain (-+ p. 348). Neurotr•nsmltters released at chemical synapses of nerve endings transmit signals ID postsynaptic nerve fibers, muscles or glands (-->p. 54ff.). Some neuropeptides released by presynaptic neurons also exert their effects in neighboring synapses, resulting in a kind of "paracrine· action. Neurons can also secrete hormones, e.g~ epinephrine, oxytocin, and antidiuretic hormone. Some transmitter substances of the immune system, e.g., thymosin and various cytokines, also have endocrine effects.

Plate 11.1

Integrative Systems of the Body

281

A. Regulation of autonomic nl!rvous sy!b!m functions (CJWI'llleow) - - - - - - - - , /

Signals

Psychological factors

fromthe -...,._ environment "ll.

Mess;~gesfrom

wlll11n the body (e.g.• faedbock canbd)

...... Immune .,am

EnciDatn• .,.t.m

! Defl!nsl!

--.,-...

I'Btph!1811'11!-.,.... IUIDnodc tomltlc

(

~

nervau~.,.mm

I

~rHXI ~rlic

0

j..

llel\'011$

..

u

"t:

,mns

~

~

1

:; "'tl 1:

..!ll

Jl

Control and regulidlon of Behavior Temperature

arculatlon

Nutrttlon Metabolism

Wall!rand

electrolyte balance

....____..... Hormone,.!....,

Growth and maturation Reproduction

282

.,.... .,....

Hormones Hormones are messenger substances that con- ond messengers (and sometimes as third mesvey information signals relevant to cell func- sengers; ..... p. 288ff.). Some peptide hormones tion (-+p.280). Endocrine hormones, i.e~ like insulin, prolactin, atrial natriuretic pepthose transported In the bloodstream, are pro- tide (ANP). and numerous growth factors bind duced in endocrine glands such as the hy- to cell surface receptors with cytosolic pothalamus, thyroid, parathyroid glands, domains with enzymatic activity (-op. 290). adrenal medulla, pancreatic islets. ovaries, and Steroid hormones, on the other hand, enter the testes. They are also synthesized in diffusely cells themselves (..... p. 290). Once they bind to scattemiendocrinecellsofthe CNS, in Ccells of eytosolic receptor proteins, steroid hormones the thyroid, and in the thymus. atria. kidneys, (as well as caldtriol, T1. and T.) are transported liver, gastrointestinal tract. etc. Paracrlne hor· to the cell nucleus, where they influence tranmones, i.e., those that affect nearby cells only scription (genomic action). A target cell can (tissue hormones or mediators; see below) are have different receptors for different horsecreted by cells widely distributed through- mones (e.g., insulin and glucagon) or different receptors for a single hormone (e.g., a1- and out the body. jh-adrenoceptors for epinephrine). Types of hormon1s. 1. Peptide hormones (-+A, dark blue areas) Hierarchy of hormones (-+A on p. 284f.). and glywproteln hormones (-+A, light blue The secretion of hormones Is often triggered areas) are hydrophilic hormones stored in by neural impulses from the CNS. The hysemtory granults and released by exocytosis poehalamus is the main neurohormonal conas required. Multiple hormones can be pro- trol center(-+ p.294 and 348). Hypothalamic duced from a single gene (-+e.g., POMC gene, neurons extend to the posterior pituitary (neup. 294) by variable splicing and posttrans- rohypophysis). The honnones are secreted either by the hypothalamus itself or by the lational modification(-+ p.Sff.). 2.Steroid hormones(-+A,yellow areas)and posterior pituitary. Hypothalamic hormones Cilldtr1ol are chemically related lipophilic also control hormone release from the anterior honnones metabolized from cholest:mll pituitary (adenohypophysis). Anterior pitui(->pp.306 and 310). They are not stored, but tary glandotropic hormones control peripheral are synthesized as needed. They leave their endocrine glands (-+A top, green areas), which cells probably via carriers of the OAT family release the end-hormone (-+A). The original signal can be amplified or modulated at these (-+p.168). 3, 'l)roslne derlvatlws (->A, orange areas) relay sites (..... p. 286~ Pituitary hormones. Hypothalamic horinclude (a) the hydrophilic catecholamines dopamine, epinephrine, and norepinephrine mones control anterior pituitary hormone (-+ p. 88) and (b) lipophilic thyroid honnones secretion by either stimulating or inhibiting hormone production. They are therefore called (T3, T4;-+ p. 300). The lipophilic hormones in (2) and (3b) are releasing hormones (RH, liberins) or release-intransported in the blood while bound to hibiting hormones (IH, statins), respectively plasma proteins. Corticosteroids are carried (-+A and table). Most anterior pituitary horbound to globulin and albumin, testosterone mones are glandotropic (-+p.294). The posteand estrogen to sex hormone-binding rior pituitary hormones are released by neuglobulin, and T3 and T4 to albumin and two ronal signals and are mainly aglandotropic (-+p.294). other plasma proteins(-+ p. 302). Hormone receptors. The receptors (docking Other endoatne hormones are secreted sites) for glycoprotein hormones, peptide hor- largely independent of the hypothalamicmones, and the c.Uecbolamines are trans- pituitary axis, e.g.. pancreatic hormones, paramembrane proteins (..... p. 14) that bind to their thyroid hormone (P'IH), caldtonin. caldtriol, specific hormone on the outer cell surface. al'lg'iotensin n, aldosterone (..... p. 198ft'.), eryMany of these hormones induce the release of thropoietin (-op.92), and gastrointestinal horintracellular SICOIId m1snnprs that transmit mones (-+ p. 248). Atrial natriuretic peptide the hormone signal inside the cell. cAMP, (ANP) is secreted from the heart atrium in .,.. cGMP, I~. DAG, ca1•, and NO function as secPituitary tumors, hyperthyroidism, hypothyroidism, hypercalcemia, hypocalcemia

Hormones (continued) ~ response to stretch stimuli (..... p.180), whereas the release of melatonin is subject to afferent neuron control (..... p. 352). Some of these hormones (e.g., angiotensin II) and tissue hormones or medliltors exert paraaine effects within endocrine and exocrine glands, the stomach wall, other organs, and on inflammatory processes. Bradykinin (->pp. 226 and 250), histamine (->pp.104 and 256), serotonin (5-hydroxytryptamine, ..... p. 106) and eicosanoids are members of this group. Elmsanolds. Prostaglandins (PG), thromboxane (TX), leukotrienes, and epoxyeicosatrienoates are eicosanoids (Greek e110001 = twenty (C atoms]) derived in humans from the fatty add iilradlidonic: ac:id (AA). (Prostaglandins derived from AA have the index number 2 ). AA occurs as an ester in the phospholipid layer of the cell membranes and is obtained from dietary sources (meat), synthesized from linoleic acid, an essential fatty acid, and released by diacylglycerol lipase (..... p. 290).

There are three pathways of eicosanoid synthesis from arachidonic acid (AA): 1. CydoWQI!Ienase pathway: Cyclooxygenase (COX)·1 and COX-2 convert AA into PGG,, which gives rise to PGH,, the primary substance of the biologically active compounds PGE,, PGD,, PGF2o. PGI, (prostacyclin) and TXA,. COX- 1 and 2 are inhibited by nonsteroidal anti-inflammatory drugs (e.g., aspirin). 2. UpWQI!Ienase pathway: Leukotrlene A.. Is synthesized from AA (via the Intermediate 5-H PETE= 5-hydroperoxyeicosatetraenoate) by way of 5-lipaxygenase (espedally In neutrophilic granulocytes). Leukotriene A.. is the parent substance of the leukotrienes C... D4 and ~- The significance of 12llpaxygenase (especially In platelets) Is not yet clear, but 15-lipaxylJenase is known to produce vasoactive lipoxins (LXA.. LXB.). 3. Cytochrome P45(J.epWQ~~~enase produces epaxyeicosatrienoates (EpETrE = EE).

283

PCD:z induces bronchoconstriction. PCI2 (prosblcydln), synthesized in the endothelium, is vasodilatory and inhibits platelet aggregation. ~. on the other hand, occurs in platelets, promotes platelet aggregation, and acts as a vasoconstrictor ( ..... p. 106). 11,12-EpETrE has a vasodilatory effect (= EDHF, ..... p. 226). Hormones (h.) of the hypotfliilamus and pituitary Niilme•

Abbrevlatlonfsynonyme

Hypothalamus The suffix "-liberin" denotes releasing h. (RH) or factor (RF); ·-stalin" is used for release-inhibiting h. (I H) or factors (IF) Corticotropin RH, CRH, CRF Corticoliberin Gonadoliberin Gonadotropin RH, GnRH, ICSH Prolactin IH, PIH, PIF, dopamine Prolactostatln Somatotropin RH, SRH, SRF, Somatoliberin GHRH,GRH Somatostatin • • Somatotropin (growth h.) IH, SIH Thyroliberin Thyrotropin RH, TRH, TRF Anterior lobe of the pltultilry Corticotropin Adrenocorticotropic h. (ACTH) Follltropln Follicle-stimulating h. (FSH) Lutropln Luteinizing h. (LH), Interstitial cell-stimulating h. (ICSH) Melanotropin a-Melanocyte-stimulating h. (a-MSH), a-melanocortln Somatotropin Somatotropic h. (STH), growth h. (GH) Thyrotropin Thyroid stimulating h. (TSH) Prolactin PRL, lactogenic (mammotropic) h.

Posterior lobe of the pituitilry Oxytocin Adiuretin Anti-diuretic h. ADH, (arginine-) vasopressin (AVP) • Names generally recommended by IUPAC-IUB Committee on Biochemical Nomenclature. • • Also synthesized in gastrointestinal organs, etc.

Typical effects of elmsilnolds: PCQ dilates the bronchial and vascular musculature (and keeps the lumen of the fetal ductus arteriosus and foramen ovale open; ..... p. 232 ), stimulates intestinal and uterine contractions, protects the gastric mucosa (..... p. 256), inhibits lipolysis, increases the glomerular filtration rate (GFR), plays a role in fever development ( ..... p. 236), sensitizes nociceptive nerve endings (pain), and increases the permeability of blood vessels (inflammation). Dliibetes melllbls ;md Insipidus, mngenltal iidrenill hyperpliislil, dw;uflsm iind giantism

..... .....

284

c

Plate 11.2 Hormones A. The hormones (simplified overview excklding tissue hormones) - - - - - - - -

0

Hypothalamus

~

..

"8

ICI.

~ "1:11 c

G~

"'XI 6

..

E

PIH (• dopamine)

Prolactin (PRL)

TRH

TSH

0

::t:

........

---+

.,....

Somatostatin (SIH) GH-RH (•SRH)

ltJI;oid gland ( licle cells)

LiYI!r

5TH (-GH) Anglotenslnogen (liver)

GloiTli!I'UI;rzone

Fascicular zone Reticular zone

Axoplasmlc transport lr.

ADH Axoplasmlc transport ..

-------------------------

Oxytocin Adrenal medulla Kidneys

Stimulates .........

I ~::.. 1

lnhibits.......,e

Stem~. etL 1

Irs~

I

Affects Secreb!s

Effect

, ~

, ,•

~ ~

B i!0 E :I .c

.

....c

Paracrtne:

6

Pancreas Dcells A cells Bcels Parathyroid gl;nd

::I

Thyroid, etc.:

Ccells

J

Plate 11 .3 Hormones

285

c 0

:e

Functions (limpllfiN)

Encl-honnorw

.. ::II

~

"8

Testosterone

~

~

~

~

Estrogens Gestagens ( esterone)

~

c

Ill

"'cGl

.. :z: 0

E

~

~ ~

)

Thyroxin (T.) -l- Delodlnlziltlon Triiodothyronine (T3)

0

......

Somatomedlns (IGF)

•I Angiotensin II ~

Mineralomrtlcoids

~

Glucocorticoids

~

Androgens

~

Epinephrine (norepinephrine)

=I

Erythropoietin Calcitrlol

= ~

~

Somatostatin (SIH) Glurnon lnsUlO Parathyroid hormone Caldtnnln (CT)

t/

Antagonistic


"'

::::E

!5

iI

] E

.D

.:

i

j

::::E

0

~

~

1!1 c: "CI_! .!I

i-

~ c:~ .... ~ .E

286

Humoral Signals: Control and Effects Hormones and other humoral signals function

to provide t.edbKk control, a mechanism in

......

which the response to a signal feeds back on the signal generator (e.g., endocrine gland). The speed at which control measures are implemented depends on the rate at which the signal substance is broken down- the quicker the degradation process, the faster and more flexible the control. In negiltlw teedback control, the response to a feedback signal opposes the original signal. In the example shown in A1, a rise in plasma cortisol in response to the release of corticoliberin (corticotropin-releasing hormone, CRH) from the hypothalamus leads to down regulation of the signal cascade "CRH => Acrn => adrenal cortex,· resulting in a decrease in cortisol secretion. In shorter feedback loops, Acni can also negatively feed back on the hypothalamus (--> A2), and cortisol, the end-hormone, can negatively feed back on the anterior pituitary (--> A3). In some cases, the metaboUc parameter regulated by a hormone (e.g., plasma glucose concentration) rather than the hormone itself represents the feedback signal In the example (-+B), glucagon increases blood glucose levels (while insulin decreases them), which in turn inhibits the secretion of glucagon (and stimulates that of insulin~ Neuronal signals can also serve as feedback (neuroendocrine feedbaclc) used, for example, to regulate plasma osmolality (-+p.178). In positive feedback control, the response to the feedback amplifies the original signal and heightens the ~rail response (e.g., in outoaine regulation; see below). The higher hormone not only controls the synthesis and excretion of the end-hormone, but also controls the growth of the peripheral endocttn• gland. If, for example, the end-hormone concentration in the blood is too low despite maximum synthesis and secretion of the existing endocrine cells, the gland will enlarge ID increase end-hormone production. This type of compensatory hypertrophy is observed for instance in goiter development (-+ p. 300) and can also occur after surgical excision of part of the gland.

Thenpeutlc .d"*'lstmion of a llormone (e.g., cortisone, a cortisol substitute) has a similar effect on higher hormone secretion (ACTH and CRH In the example) as that of the end-hormone (cortisol in the example) normally secreted by the peripheral gland (adrenal cortex In this case). Long-term administration of an end-hormone would therefore lead to Inhibition and atrophy of the endocrine gland or cells that normally produce that hormone. This is known as CDrnpei1Htory atrophy.

A rebound e11ect can occur if secretion of the higher hormone (e.g., ACTH) is temporarily elevated ~r discontinlliltion of end-hormone administration. The principal functions of endocrine hormones, paracrine hormones, and other humoral transmitter substances are to control and regulate: • enzyme activity by altering the conformation (allosterimt) or inhibiting/stimulating the synthesis of the enzyme (induction); • transport processes, e.g~ by changing the rate of insertion and synthesis of ion channels/ carriers or by changing their opening probability or affinity; • growth (see above), i.e~ increasing the rate of mitosis (proliferation), "programmed cell death" (apoptosi.f) or through cell differentiation or dedifferentiation; • secretion of other hormones. Regulation can occur via endocrine pathways (e.g., Acni-mediated cortisol secretion; -.AS~ a short portal vein-like circuit within the organ (e.g., effect of CRH on .AC1ll secretion,--> A4), or the effect of cortisol from the adrenal cortex on the synthesis of epinephrine in the adrenal medulla, (->A&), or via paracrine pathways (e.g., the effect of somatostatin, SIH, on the secretion of insulin and glucagon; --> B). Cells that have receptors for their own humoral signals transmit autocr1I"MI slgMis that function to: • exert negative feedback coniTDl on a target cell, e.g., to discontinue secretion of a transmitter (e.g~ norepinephrine; --> p. 88); • coordinare cells of the same type (e.g., in growth); • exert positive feedback control on the secreting cell or to cells of the same type. These mechanisms serve to amplify weak signals as is observed in the eicosanoid secretion or in T cell monoclonal expansion(--> p.lOtff.).

Compensatory hypertrophy (e.g., goiter) and atrophy (e.g., cortisone therapy)

Plate 11.4 Humoral Signals: Control and Effects

287

A. Regulation of cartf10l•nd eplnephrfne cancentratfonsln pll11n11 - - - - - - ,

I I

......

288

.,.... .,....

Intracellular Transmission of Signals from Extracellular Messengers Hormones, neurotransmitters (-+ pp. 59 and 98), cytokines and chemokines (..... p. 94ff.) act as messenger substances (first messengers) that are transported to their respective target cells by extracellular pathways. The target cell has a high-affinity binding site (receptor) for its speciJic messenger substance. CilycOfll'*ln and peptide messengers as well as a~tec:hot.mlnes bind to cell surface receptors on the target ceiL Binding of the messenger to its receptor (with certain exceptions, e.g., insulin and prolactin; ..... p. 292) triggers certain protein- protein interactions (and sometimes protein-phospholipid interactions). This leads to the release of secondill'Y messenger substances (s•concl messengers) that forward the signal within the cell. cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositol 1.4,5-ttisphosphate (IPJ), 1,2-diacylglycerol (DAG) and Ca2• are such second messengers. Since the molecular structure of the recep!Dr ensures that the effect of the first messenger will be spedfK, multiple first messengers can use the same second messenger. Moreover, the intracellular concentration of the second messenger can be raised by one messenger and lowered by another. In many cases, different types of receptors exist for a single first messenger. cAMP as a Second Messenger

G,-Ktlvatlng messengers. ACTH, adenosine (A... and Aze rec.), antldluretk hormone • vasopressin ~2

rec.). epinephrine and norepinephrine (~~- . ~•• lhadrenoceptcrs), calcitonin, CGRP, CRH, dopamine (01 and Ds rec.), FSH, glucagon, histamine (H2 rec.), oxytocin, many prostaglandins (OP, IP, EP2, and EP• rec.), serotonin - 5-hydroxytryptamine (5-HT. and 5-HT7 rec), secre~. and VlP activate G, proteins, thereby raising cAMP levels. TRH and TSH induce partial actiwtion. c;....ctlvatlng messengers. Some of the above messenger substances also activate G; proteins (thereby luwerfng cAMP levels) using a different binding receptor. Amyicholine (M2 and M4 rec.), adenosine (A! and A3 rec.), epinephrine and norepinephrine (az-adrenoceptors), angiotensin II, chemokines, dopamine (02, D3, and 04 rec.), GABA (GABAa rec.), glutamate (mGW2-4 and mGWihl rec.), melatonin, neuropeptlde V, opiolds, serotonin - 5-hydroxytryptamine (5-HTr rec.), somatostatin, and various other substances activate Gr proteins.

Eth!cts of cAMP. cAMP activates type A protein kinases (PKA • protein kinase A) which then activate other proteins (usually enzymes and membrane proteins, but sometimes the receptor itself) by phosphorylation (-+ A4 ~ The specific response of the cell depends on the type of protein phosphorylated, which is determined by the type of protein kina.ses present in the target cell. Phosphorylation converts the proteins from an inactive to an active form or vice versa. Hepatic glycogenolysis, for Instance, Is dually In-

For a cAM~medlated response to occur, the creased by cAMP and PKA. Glycogen synthase catacell membrane must contain stimulatory (G,) lyzing glycogen synthesis is Inactivated by phosphoor inhibitory (Gt) c; proteins (guanyl nu- rylation whereas glycogen phosphorylase stimulatcleotide-binding proteins) (-+Al). These G ing glycogenolysis Is activated by cAMP-mediated phosphorylation. proteins consist of three subunits-alpha (as or 111), beta (j3), and gamma (y)-and are therefore Signal transdudton comprises the entire sigheterotrimers. Guanosine diphosphate (GOP) is llilling pathway from the time the first mesboWld to the a-subunits of an inactive senger binds to the cell to the occurrence of the G protein. Once the first messenger (M) binds cellular effect, during which time the signal to the receptor(rec.), the M-rec. complex con- can be (a) modified by other signals and jugates w ith the C.-GOP (or G;-GOP) molecule (b)amplified by many powers of ten. A single (-+ A2). GOP is then replaced by cytosolic Gil', adenyiate cyclase molecule can produce and the fly-subunit and the M-rec. complex numerous cAMP and PKA molecules, which in dissociate from the a-subunit if Mg1 • is pres-- tum can phosphorylate an enormous number ent (-+ Al). a.-GTP or 111-GTP remain as the of enzyme molecules. The interposition of final products. Adenylate cydMe on the inside more kinases can lead to the formation of long of the cell membrane is activated by kinase cascades that additionally amplify the a s-GTP (cytosolic cAMP concentmtion rises) original signal while receiving further regula.,.. and inhibited by at-GTP (rAMP concentmtion tory signals. fulls; -+ Al). Honnone receptor defects, hormone therapy, phosphodiesterase Inhibitors (e.g., slldenafll citrate)

Plate 11.5 G Proteins and cAMP

289

A. cAMP • second m e s s e n g e r - - - - - - - - - - ---;:= = = =:::;] Deedllldon: fxlroa!llubr spact ~ Fll'5t mwenger

/M:"S .Messenger (M)

Stimulatory ~enger ~ e.g., eplnephrlne

(II adrw~oceptnrs)

~ \..

lnhlb~ messenge

blnd5to

e.g., epinephrine

receptor (R)

(a2 ad-enDDI!ptDr:)

R.

Ct/1 mernbrcrnt

cAMP

1

-

Ad~;e

.......

M-Rmmplex binds to G protein

2

Retum

Adenylate

to rnact!Ye

cyclase

,...,...

__[J') R. 3

4

'

a-GTPinfluences adenylirtE cyclase

stab!

0 ----1

/ R!

290

Intracellular Transmission of Signals from Extracellular Messengers (continued) .,.. Deactivation of the signaling casc:.ade (->A, light panel) is induced by the a-subunit in that its GTP molecule splits off GOP and P1 after reacting with its GTPase (->AS), and the subunit subsequently binds to the py subunits to again form the trimeric G protein. Phosphodiesterase also converts cAMP into inactive 5'-AMP (-+ M, A&), and phosphatases dephosphorylate the protein previously phosphorylated by protein kinase A (.... A4). Another way to inactivate a receptor in the presence of high messenger concentrations is to make the receptor insensitive by phosphorylating it (desensitization).

.,.... .,....

Cholera toxin Inhibits the GTPase, thereby blocking Its deactiwting effect on adenylate cyclase (-> A5). This results in extremely high lev!!ls of intracellular cAMP. When occurring In Intestinal cells, this can lead to severe diarrhea (-+ p. 276). Pertussis (whooping mug h) toxin and forskolln also lead to an increase in the cytosollc cAMP concentration. Pertussis toxin does this by Inhibiting G, protein and thereby blockIng Its inhibitory effect on adenylate cyclase, while forskolln directly activates adenylate cyclase. Theophylline and caffeiM inhibit the c~ of cAMP to 5'-AMP, which extends the life span of cAMP and prolongs the effect of the messenger.

Certain 1on ~nels are regulated by G,, G;. and other G proteins (C..) with or without the aid of adenylate cyclase. some Ca2• channels are activated by G. proteins and inactivated by Go proteins, whereas some 1C' channels are activated by Go proteins and (the py subunits of) c;, proteins (.... p. 87 B). c.r in olfactory receptors, transdudn in retinal rods (->p.370ff.), and u-gustcludn in gustatory sensors are also members of the G protein family (.... p. 360). IP3 and DAG •• Semnd Meaengers As in the case of G, proteins, once the frrst messenger using this transduction pathway binds to its receptor outside the cell, the aq subunit dissociates from the heterotrimeric c. prob!ln and activates phospholipasec-p (PLC-1\) on the inside ofthe cell membrane (-+ 81). PLC-fi converts phosphatidylinositol 4,5-bisphosphate (M), to lnosltDI1,4,5-trlsphosphate (iPl) and 1, :Z-cllacylglycerol (Do\G).IP. and DAG function as parallel second messengers with different actions that are exerted either independently or jointly (-+ 81 ).

IPs is a hydrophilic molecule carried via the cytosol to ea2• stores within the cell (mainly in the endoplasmic reticulum). IP1 binds there to (a2+ channels to open them (-+ 82), leading to an effiux of Ca2' from the intracellular stnres into the cytosol In the cytosol, Ca2' acts as a thinf messenger that regulates various cell functions, e.g., by interacting with the cAMP signaling chain. Many Ca1'-related activities are mediated by calmodulin. a calcium-binding protein (-+ p. 74). 1,2-DAC is a lipophilic molecule that remains in the cell membrane and has two main functions: • DAG is broken down by diacylglycerol lipase to yield arochfdonfc add, a precursor of eicosanoids (.... 83 and p. 283 ). • DAG activates protein kinase C (PKC). PKC is Ca2+-dependent (hence the "C") because the ea2+ released by IP1 (see above) is needed to transfer PKC from the cytosol to the intracellular side of the cell membrane (-+ 84). Thus activated PKC phosphorylates the serine or threonine residues of many proteins. PKC triggers a series of other phosphorylation reac-

tions (high signal amplification) that ultimately lead to the p/losphorylatlon of MAP kinase (mitogen-activated protein kinase). It enters the cell nucleus and activates flit. I, a gene-regulating protein. NF-KB, another gen~regulatlng protein, Is also released In response to PKC phosphorylation. In addition, PKC activates No'/H' ontiport"m, thereby raising the cellular pH-a stimulus that triggers many other cellular reactions. IP. 1nd DAG actlvltlng m1ssengers include acetylcholine (M 1 and M3 chollnoceptors), antidiuretic hormone - wsopressln (V1 rec.), epinephrine and norepinephrine (a1-adrenoceptor), bradykinin, CCK, endothelin, gastrin, glutamate (mGLU1 and mGLU5 rec.), GRP, histamine (H1 rec.), leukotrienes, neurotensin, oxytocin and various prostaglandins (FP, TP, and Ep1 rec.), serotonin • 5-hydroxytryptamine (5-HT> rec.), tachykinln, and tlvornboxane Az. TRH and TSH induce partial activation. DNctivltion of the signaling cascade can also be achieved through le/f-inactiYOtion of the G

proteins involved (GTP cleavage) and phosphatase(see above) as well as by degradationofiP3. .,..

Receptor density and affinity abnormalities, cholera toxin, pertussis toxin, effects of theophylline

Plate 11.6 DAG, IP,, Tyrosine Klnases

:Z91

Cell membrane PIP:! Fhospho-

llpaseC-~

1

Cytosol

IP,

ea>+ stores

2 J

-

4

+-'

~In

Elcosanolds

1 Protein

\

T 1f

.)t

C.ll'lllpon!ill N~rons. exocrine and endoaine pancreas, platElets, liwr, adrenal m!Ull. leukocytes,~~.

m.

'ii

membl'ilne

E

alpha helbc

I

I!!

o

Tlilns-

CytDsolic domains

A

Tyrosine kinase h1

Ina~ monomers

~SH2clorNin 2 Target proteins bind to SH2domalns

292

Intracellular Transmission of Signals from Extracellular Messengers (continued) ~ Enzyme-Llnlr.t!cl Cell Surface ReceptDrs for Messenger Subsbnces

.... ....

These (G protEin-independent) receptors. together with their cytosolic domains, act as enzymes that are activated when a messenger binds to the receptor's extracellular domain. There are five dasses of these receptors: 1, Receptor guanylyl cyclases convert GI'P into the second messenger cGMP, which activates prorein kinase G (PKG; see below). The ANP belongs to this dass. 2. Recepmr tyrosine klnases (-+C), phosphorylate protEins (of same or different type) at the OH group of their tyrosyl residues. The receptors for insulin and various growth fuctors (GF) such as e.g~ E[epidermal]GF, PD[platelet-derived]GF, N[nerve)GF. F[fibroblast]GF, H[hepatocyte]GF, and l[insulinlike)GF-1 belong to this dass of receptors. Signals ~rding first mtsSenger binding (e.g.• EGF and PDGF) are often transferred Inside the cell via binding of two receptors(clmerlzatlon; Cla ~ Clb) and subsequent mutual phosphorylation of their cytosollc domain (autuphosphorylatlon, -+ Clb). The receptor for certain hormon~s.like insulin and IGF·T, Is from the beginning a heterotetramer (a2~2) that undel"!loes autophospllorylatlon before phospllorylating another protein (insulin tm!piDr substro~T . IRS-1) that In tum activates Intracellular target proteins containing SH2 d01mins (-+ C2).

3. RK..,tor sertne/threonlne lclnases, which like the TGF-/J m:eptor, function similar to leioases in Group 2, the only difference being that they phosphorylate serine or threonine residues of the target protEin instead of tyrosine residues (as with PKC; see above). 4. Tyrosine ldnase-assodated recaptors are those where the receptor works in combination with non-receptor tyrosine kinases (chiefly proteins of the Src family) that phosphorylate the target protein. The receptors for sm. prolacdn, erythropoietin. and numerous cyrokines belong to this group. 5. bceptor tyrosine phosphmses remove phosphate groups from tyrosine residues. The CD45 receptor involved in T cell activation belongs to this group.

hormones in that they induce a spedfic ceU response with the difference being that they activate a different type of signaling cascade in the cell. They are lipid-soluble substances that freely penetrate the cell membrane. Stllrold hormones bind to their respective cytoplasmic receptor protein in the target cell (-4 D). This binding leads to the dissociation of inhibitory proteins (e.g., heat shock protein, HSP) from the receptors. The hormone-receptor protml complex (H-R complex) then migrates to the ceO nudeus (tronslocation), where it activates (Induces) or inhibits the transcription ofcertain genes. The resulting increase or decrease in synthesis of the respective protein (e.g., AlPs; ..... p. 194) is responsible for the actual cell response(-+ D). Trfiodothyronlne (T1; -+p.300ff.) and caldb1ol (-+ p. 308) bind to their respective receptor proteins in the cell nudeus (nuclear receptors). These receptors are horrnone-arowted transcription fac:trJrs. Those of calcitriol can induce the transcription of calbindin, which plays an important role in cytosolic C".\2• transport (-+ p.276). Recent research indicates that steroid hormones and caldtriol also regulate cell function by non-genomic control mechanisms. Nrtrk Oldde as a Transmitter Subsbnce

In nitrogenergic neurons and endothelial tissues, nlb1c (mon)oxlde (NO) is released by cal+JcaJmodulin-mediated activation of neuronal or endothelial nitric oxide synthase (NOS) (-+E). Although NO has a half-life of only a few seconds, it diffuses into neighboring cells (e.g., from endothelium to vascular myocytes) so quickly that it activates cytoplasmic guanylyl cyclase, which converts GTP into cQII> (-+E). Acting as a second messenger, cGMP activates protein kinase G (PKG), which In tum decreases the cytosolic ca2• concentration [Ca2+)1by blocking CaH secretion from the endoplasmic reticulum via !RAG (IP1 receptor-associated cGMP kinase substratE). This leads to vasodilatation (e.g., in coronary artEries).

Hormones with llntnlcellul;lr Receptors Steroid hormones (-. p.284tr., yellow areas), cakitriol, and thyroid hormones are like other

Type 2 diabetes mellitus, erectile dysfundlon, steroid hormone therapy

Plate 11.7 steroid Honnones. NO

:Z93

D. Mode of illdlon of steroid honnones - - - - - - - - - - - - - - - - ,

ECF

-

Cell response

ProtEin

kinaJe

[Ac~J""~,:-~

NO

NO synthase 411!E;-----"'7'"----":;.....- Arginine

r ,NADPH

guanylate

cyclase

cGMP

Ce/12

(e.g., Vi1K1llar myocyte)

Citrulline U/11

(e.g., endothelial eel~

294

Hypothalamic-Pituitary System In the hypot~lamus (1) humoral signals from the periphery (e.g., from circulating cortisol) can be converted to efferent neuronal signals. and (2) afferent neuronal signals can be converted to endocrine messengers (neuroucretion). The first c-Is possible l>ecause the hypothalamus Is situated near drcumventrlcular organs Mice the organum vasculosum laminae m-minalis (OVLT), the subfomlcal organ, the median eminence of the hypothalamus, and the neurohypophysis. Since there is no blood-brain barrier there, hydrophilic peptide hormones can also enter.

.,.... .,....

Thl! hypothalamus is closely connected to other parts of the CNS (..... p. 348). It controls many autonomous regulatory functions and its neuropeptides Influence higher brain functions. The hypothalamus is related to the sleeping- waking rhythm (-+p. 352) and to psychogenic factnrs. Sttess, for example, stimulates the release of cortisol (via CRH, ACIH) and can lead to the cessation of hormone-controlled menstruation (amenorrhea). rHurosecretlon. Hypothalamic neurons synthesize hormones, incorporate them in granules that are transported to the ends of the axons (axoplasmic trunsport, -+ p. 46), and secrete them into the bloodstream. In this way, oxytocin and ADH are carried from magnocellular hypothalamic nuclei tD the neurohypophysis, and RHs and IHs (and ADH) reach the median eminence of the hypothalamus (..... A). The action potenriol-triggered exocytotic release of the hormoneslniD the bloodstream is mediated by ca2• Influx into the nerve endings (-+p. 54ff.). Oxytocin (• ocytocin) and antidiuretic hormona (ADH) are two posterior pituitary hormones that enter the systemic circulation directly. ADH induces water retention in the renal collecting ducts {Vz-rec.; -+ p. 174) and induces vasoconstriction (endothelial V1 rec.) by stimulating the secretion of endothelin-1 (-+p.224ff.). ADH-bearing neurons also secrete ADH intn the portal venous circulation (see below). The ADH and CRH molecules regulate the secretion of ACill by the adenohypophysis. Oxytocin promotes uterine contractions, milk ejection and also influences social behavior (-+ p.322).

Releasing hormones (RH) or ltbertns that stimulate hormone release from the adenohypophysis (GnRH, TRH, SRH, CRH; -+p.284ff.) are secreted by hypothalamic neurons into a kind of portal venous system and travel only a short distance to the anterior lobe (-+A). Once in its vascular network. they trigger the release of anterior pituitary hormones into the systemic circulation (-+ A). Some anterior pituitary hormones are regulated by release-Inhibiting hormones (IH) or st.tlns, such as SIH and PIH • dopamine. Peripheral hormones, ADH (see above), and various neurotransmitters such as neuropeptide Y (NPY), norepinephrine (NE), doJ)amine, VIP, and opioids also help to regulate anterior pituitary functions.

From the anterior plbllbiry, the four glandotroptc hormones (ACill, TSH, FSH, and lll). and the aglandotroplc hormones (prolactin and GH) are secreted (-+A). The secretion of growth hormone (CH = somatotropic hormone, STH) is subject to control by GH-RH, SIH, and JGF-1. GH stimulates protein synthesis (anabolic action) and skeletal growth with the aid of somatomedins (growth factDrs formed in the liver). which play a role in sulfate uptake by cartilage. SomatDmedin C = insulin like growth factnr-1 (JGF-1) inhibits the release of GH by the anterior pituitary via negative feedback control. GH has lipolytic and glycogenolytic actions that are independent of somatnmedin activity. Pro-oplomelanocortln (POMC) is a peptide precursor not only of ACill, but (inside or outside the anterior pituitary) also of ~-endor­ phin and a-melanocyte-stimulating hormone (a-MSH = a-melanocortin). ~-endorphin has analgesic effects in the CNS and immunomodulatnry effects, while a -MSH in the hypothalamus helps tD regulate the body weight (-+ p. 242} and stimulates peripheral melanocytes.

Pituitary tumors and lesions, eRects of morphine and barbltul"iltes, amenorrhea, acromegaly

Plate 11.8 Hypotltalamlc-Pitultary System

295

A. Hypothalam~ltultary hormone secretion (schematic) - - - - - - - . . . ,

15

tl:II ~a. I "a

c

Ill

"'c

Ill

..:z:cc E

......

,......-"'---o-

Axoplasmic transport by neurosecretory nerve cells

Release of RHs, IHs, ADH, NE, NPY and other transmitters

+RH Induce release of .1. anterior pituitary

' hormones IH inhibit their

release

Anll!llar plblbry

hoiiiiiiM!i ACTH PRL STH LH TSH

o-MSH

FSH

~endorphin

ADH, CDI)'tocin

RH • Relooalng hunnon!S IH -

(~)nhlbltfng honnanes

296

Carbohydrate Metabolism and Pancreatic Hormones Glucose is the central energy carrier of the human metabolism. The brain and red blood cells are fully glucose-dependent. The plasma gluC also activat~ 24-hyd r~

Rickets, osteoporosis, arrhythmias, goiter surgery, nephrocalcinosis, paresthesia

D. Hormonal regulation of the blood caz• concentration - - - - - - - - - - - - - - - - - - - - - - - - - - , Sl!ru m caZ+ {lonlzl!d) Serum c.aZ+ (Ionized)

. ,,_,,,. '

falls below no1111al

'

1

'

'

......_

..- " '

___ ~ ~T

rises~ no1111al

,#

,l

'

'--nN\a ~

0 -....._.

Thyroid gkmd fCallsJ

I

,.

Inactive

~

8 ___. P1li

~- ~

--8 "1:1

"'

_dj r.

cr• absorption

'i

rf

.. .j:o.

~

!r c 3

In~ c¥- e~~Cretlon (Dec:reased a:mlon}

Serum cr• {Ionized) retums tD nonnil

____ _j

L ___ _

• 1 mmol ca" •2 mEq ca" •40 mg ca>'"

~ StimulatEs

ro.-

~ lmlblts

Serum cr• (Ionized) retums tD no1111al

~ No sllmula!lon

--t1 No lmlblllon ~Semllon, abmrpllon

r3

II

i"'

II'

w

11 Honnones and Reproduction

s

308

.,.... .,....

calcium, Phosphate, and Magnesium Metabolism (continued) .,. Target Of'!PR5. Calcittiol's primary target is the gut, but it also acts on the bone, kidn~. p/Gcenttl, mammary glands, hair follicles. skin. etc. It binds with its nuclear receptor and induces the expression of caldum-binding protein (calbindin) and Ca2' -ATPase (--> p.38). Calcitriol also has genomic effects. Caldttiol increases the intestinal absorption ofboth Mgl+ and Co;,. (__. D4) and promotes minemlizution of the bone, but an eX£eSs of alcltrtolleads to decalcification of the bone, an effect heightened by J7Jlf. Caldtriol also inCil!ases the transport ofCa2 ' and phosphate at the kidney (-+p. 190), placenta, and mammary glands. In transitory hypocalmmla, tht! bones act as a temporary Cfil' buffer (-+D) until the Ca 2' deflctt has been balanced by a calcttriol-mediated increase in ca>• absorption from the gut. If too little calcitriol is available, skeletal demlnerall>atlon will lead to osteom.ladll In adults and rickets in children. Vlumin D cMflclendes are caused by inadequate dietary Intake, reduced absorption (fat maldlgestlon), lnsuffklent UV light exposure, and/or reduced 1-ahydroxylation (renal lnsuff~eiency). Skelml demineralization mostly occurs due to the prolonged Increase in parathyroid hormone secretion associated with chronic hypocal~ia (rompemotory hyperporcztlyyrold/$m).

Rlcbt, osteoponosls, arrllyttlmlas, goiter surgery, nephnocaldnosls, pa...sthesla

Plate 11.15 Pllosphate Homeostasis

309

E. Phosphat~! ml!tabollllll - - - - - - - - - - - - - - - - - - - - , Diet

......

!') In seNm flllll

~seNmln~

below normal C0.8nnDI/l

':::....... / ...~'

/

rx.l

In serum

~

PTH J Bowel absorption

and tubular resorption

~ Pi

I

..

1101111ill

~>1.4nnDI/l

I

e \ ~

lnpla$ma

f PTH

I

~

Renal eMretlon

Pt

~ /

tl :: \. _....:;,~

310

..... .....

Biosynthesis of Steroid Hormones Cholesterol is the precursor of steroid hormones (..... A). Ololesterol is mainly synthesized in the liver. It arises from acetylcoenzyme A (acetyl- M·:---....;.;N;eg.=.;~;a;tf; .l;.l;!.;f.=ba eed=dc;;...._ __ 5

"'\ E ne

I

r1ne stlmuli!W

Angiotensin II

-

B. Orcadlan rhythm of ACTH and cortisol secretion----------...,

Mean

- - Short-tenn

flucluattons

12:00 p.m.

6:00p.m.

12:00 a.m.

6:00a.m.

12:00 p.m. Time af day

314

Oogenesis and the Menstrual Cycle Oogenesis. The development of the female gametes (ova) extends from the oogonium stage to the primary oocyte stage (in the primordial follicle), starting long before birth. Oogenesis therefore occurs much sooner than the cornsponding stages of spermatogenesis (~ p. 324). The fetal phase of oogenesis Is completed by the first week of gestation: these oocytes remain latent until puberty. In the sexually matwe female, a fert"izable ovum develops In the graaflan follicles approximately rNery 28d~.

......

Menstru.. cyde. After the start of sexual maturation, a woman starts to secrete the following hormones in a cyclic (approximately) 28-day rhythm (-+Al, A2). Gonadoliberin (•gonadotropin-releasing hormone, GnRH) and dopamine (PIH) are secreted by the hypothalamus. Follide-stimukJting hormone (FSH), luteinizing hormone (IR), and prokJctin (PRJ.) are relei!Sed by the anterior pituitary. Progtstmme. esrrogrns (chiefly estradiol, E2). and inhibin are secreted by the ovaries. GnRH controls the pulsatile secretion of FSH and lH (-+ p. 316), which in turn regulate the secretion of estradiol and progesterone. The female sex functions are controlled by the periodic release of hormones, the purpose of which is to produce a fertilizable egg in the ovaries each month (-+A4) and produce an environment suitable for sperm reception (!mitization) and impl.lntation of the fertilized ovum (nidation) (-+ A5). This cyclic activity is reflected by the monthly menses (menstruation) which, by definition, marks the start of the menstrual cycle. Pubertylslnltlated by the start ofGnRH secretion for which binding ofthe hormoneklsspepttnto its receptor (KiSS-1) is a prerequisite. Girls in Central Europe usually have their first menstrual period (me1111rche) around the age of 13. By about age 40, the cycle becomes increasingly irregular oYer a period of up to 10 years (clmKterk) as the end of the reproductive period nears. The last menses (menopMIII!) generally occurs around the age of48-52.

The length of the menstrual cytle varies from 21 - 35 days. The second half of the cycle (IutHI phase • secretory phase) usually lasts 14days, while the frrst half(follicular phase • proliferatiV!! phase) lasts 7-21 days. Ovulation separates the two phases (-+A). If the cycle length varies by more than 2-3 days, ovulation generally does not occur. Such anovulatory

cydes account fur 20S of all cycles in healthy females.

In addition to general changes in the body and mood, the following changes occur in the ovaries, uterus, and cervix during the menstrual cycle (-+A): Day 1: Start of menstruation (lasting about 2-6days). Days 1-14 (variable): The follculw phase starts on the first day of menstruation. The endometrium thickens to become prepared for the implantation of the fertilized ovum during the luteal phase (-+ A5), and about 20 ovarian follicles mature under the influence of FSH. One of these becomes the dominant foUicle, which produces increasing quantities of estrogens (-+A4and p.316). The small cervical os is blocked by a viscous mucous plug. Day14 (variable): Ovulation. The amount of esrrogrns produced by the follicle increases rapidly between day 12 and 13 (-+ A2). The increased secretion of IR in response to higher levels of estrogen leads to ovulation (-+ A1, A4; see also p. 316). The basal body temperature (measured on an empty stomach before rising in the morning) rises about OSC around 1-2 days later and remains elevated until the end of the cycle (~ Al). This temperature rise generally indicates that ovulation has occurred. During ovulation, the cervical mucus is less viscous (it can be stretched into long threadsspinnbarlceit) and the cervical os opens slightly to allow the sperm to enter. Days 14-28: The luteal phase is characterized by the development of a corpus luteum (-+ M), which secretes progesterone (-+ A2); an increase in mucoid secretion from the uterine gl.lnds also occurs (-+ A5). The endometrium is most responsive to progesterone around the 22nd day of the cycle, which is when nidation should occur if the ovum has been fertilized. Otherwise, progesterone and estrogens now inhibit GnRH secretion (-+ p. 316), resulting in degeneration of the corpus luteum. The subsequent rapid decrease in the plasma concentrations of estrogens and progesterone (-+ A2) results in constriction of endometrial blood vessels and ischemia. This ultimately leads to the breakdown and discharge of the uterine lining and to bleeding. i.e., menstruation (..... A5}.

Family planning, suppression of ovulation, hormone deficiencies (menopause, anorexia)

Plate 11.18 Menstrual Cycle

315

15

tl:II ~a. I

Ovulllfon

1

~[ ~

"a

c

Ill

"'c

Ill

D

..:z:cc

1

E

2

......

ng/ml ng/ml

l

.,6

t:

£o

0,4

0.3 ~ 0.2

Jo·:

3 Basal body temperaturt

4 Ovi'lrian follicle di!Wiopment

Follicle

Dominant

~~ctlon

folllcl~

Rupture affulllde {owiCitlon)

Corpus luteum

Degenel'iltlng OOI'P'JS luteum

:====:;::::===::i::==;:::~

316

Hormonal Control of the Menstrual Cycle In sexually mature women, gonadoliberin (gon.dotropln-...luslng hormone, Cn-RH) is

secreted in 1-minute pulses every 60-90min in response to signals from various neurotransmitters, such as kisspepr:in. This, in turn, induces the pulsatile secretion of FSH and U:l from the anterior pituitary. If the rhythm of GnRH secretion is much faster or continuous, less FSH and U:l will be secreted, which can result in infertility. The U:l : FSH secretion ratio changes during the course of the menstrual cycle. Their release must be therefore subject to additional factors besides GnRH.

..... .....

The secretion of LH and FSH Is. for example, subject to centn1l nervous etrec:ts (psychogenic factors, stnm) mediated by various tnnsmltters circulating in the portal blood In the hypothalamic region, e.g., norepinephrine (NE) and neuropeptide Y (NPY) as well as by ovarian hormones, i.e., by estrogens (estrone. estradiol, estriol. etc.). progesterone and inhibin. Ovarian honnones affect GnRH secretion indirectly by stimulating ~ntral nerve cells that activate GnRH-secretlng neurons by way of neurotransmitters such as norepinephrine and NPY and inhibit GnRH secretion by way of GABA and opioids.

Toward the end of tfle IutHI p'-e (-> p. 315 A1). FSH production again increases. In the Hrty folkul.- phllte (-oA1), FSH induces the proliferation of the s!nltum granulosum in about 20 follicles and stimulates the secretion of aromatase In their granulosa cells. Aromatase catalyzes the conversion of the androgens testosterone and androstenedione to estradiol (E2) and estrone (E,) (-> p.311 A. steps r and o). Estrogens are synthesized in theca reUs and absorbed by granulosa cells. Although relatively small amounts of U:l are secreted (..... A1 and p. 315 At). this is enough to activate theca cell-based enzymes (17~-hydroxy­ steroid dehydrogenase and C17/C20-lyase) that help to produce the androgens needed for estrogen synthesis. The follicle-based estrogens increase their own FSH receptor density. The follicle with the highest estrogen content is therefore the most sensitive to FSH. This loop has a self-amplifying effect, and the follicle in question is selected as the dominant follide around the 6th day of the cycle (..... A2). In the mkl-folkular p~Mw, estrogens restrict FSH and LH secretion (via negative feedback control and with the aid of lnhtbin; ..... A2) but later stimulate U:l receptor production in granulosa

cells. These cells now also start to produce progesterone (start of luteinization), which is absorbed by the theca cells (..... A3) and used as precursor for further increase in androgen synthesis (-> p. 311 A, stepsf and 1). lnhlbln and estrogens secreted by the dominant follcle Increasingly inhibit FSH secretion, thereby

decreasing the estrogen production In other fo llicles. This leads to an androgen build-up in and apoptosis of the unselected follicles.

In the late follicular phas1, increasing quantities of IJf and FSH are released (..... A3 ), causing a sharp rise in their plasma concentrations. The FSH peak occurring around day 13 of the cycle induces the first meiotic division of the ovum. Estrogens Increase the U:l secretion (mainly via the hypothalamus), resulting in the increased production of androgens and estrogens (positive.feedback) and a rapid rise in the U:l concentration (lH surge). The lH Jlfilk occurs around day 14 (-> A2). The follicle ruptures and discharges its ovum about 10 hours later(ovulation~ Ovulation does not take place if the U:l surge does not occur or is too slow. Pregnancy is not possible in the absence of ovulation. LutHI p'-e (-+ M). LH, FSH, and estrogens transform the ovarian follicle into a corpus luteum. It actively secretes large quantities of progesmrone (progestational hormone), marking the beginning of the luteal phase (..... A). Estrogens and progesterone now inhibit the secretion of FSH and U:l directly and indirectly (e.g., through inhibition of Gn-RH; see above), causing a rapid drop in their plasma concentration. This negative feedback leads to a marked drop in the plasma concentration of estrogens and progesterone towards the end of the menstrual cycle (approximately day 26), thereby triggering the menses (-+p. 315 A2). FSH secretion starts to rise just before the start of menstruation (..... M). The I'll (see alsop. 319~ Combined administration of estrogens and gestagens during the first half of the menstrual cycle prevents ovulation. Since ovulation does not occur, pregnancy cannot take place. Most contraceptives work according to this principle.

Infertility, menstrual cycle abnormalities, suppression of ovulation, signs of pregnancy

Plate 11.19 Honnonal Control of the Menstrual Cycle

317

-

3 Late

follicular phase, ovulation

Day14:

LH peak

Estrogens Progesterone

!

~

Uterus. rtc.

OVUlation

'

318

...... ......

Estrogens, Progesterone Estrogens (E) are steroid hormones with 18 • Fertiliution. In the female body, estrogens carbon atoms. Estrogens are primarily synthe- prepare the sperm to penetrate and fertilize sized from the 17-ketnsteroid androstene- the ovum (capadtatlon) and regulate the dione, but testosterone can also be a precursor speed at which the owm travels in the fal(..... p. 311 A). The ovaries, (granulosa and theca lopian tube. cells~ plocenta (..... p.320), adrenal cortex, and • ~I effects of estrogen. During Leydig's cells (interstitial cells) of the testes puberty, estrogens stimulate breast develop(..... p. 32A) are the physiological sites of estro- ment, induce changes in the vagina and in the gen syntt.sls.. In some tar~ ceUs for testo- distribution of subcutaneous fat, and (together sterone, it must first be converted to estradiol with androg.ms) stimulate the growth of pubic and axillary hair. to become active. Estndlol (~) is the most potent estrogen Antihormone can p. 232), the p!K.nu produces most of the hormones needed during pregnancy. ovarian hormones also play a role, especially at the start of pregnancy(-oA~

...... ......

Plaonbll hormoMS. The primary hormones produced by the placenta are human chorionic: gonadotropin (hCCi), corticotropin-releasing hormone (CRH), estrogens, progesl:mlne, human placental lactogen (hPL • human chorionic somatomammotropin, HCS), and pro-opiomelanocortin (POMC; -op.294). hCG is the predominant hormone during the first trimester of pregnancy (3-month period calculated from the beginning of the last menses). Maternal concentrations of hPL and CRH-controlled estrogens rise sharply during the third trimester (-+B). Placental hormones are distributed to mother and fetus. Because of the close connection between maternal, fetal and placental hormone synthesis, they are jointly referred to as the ~I unit (--+A). H111m1n dlorlonlc goMC!otropln (hCC) (a) stimulates the synthesis of steroids like DHEA and DHEA-S by the fetal adrenal cortex (see below); (b) suppresses follicle maturation in the maternal ovaries; and (c) maintains the production of progesterone and estrogen in thecorpusluteum (-+A1)untilthe6thweekof gestation, i.e.. until the placenta is able to produce suffident quantities of the hormones. Pregnancy tests. Most tests are based on the fact that hCG is d~ctable In th~ urin~ about 6-8 days after conception. Since the levels of estrogen and prog~st~ron~ gr~atly lncreas~ during pregnancy (see table on p. 31 B). larger quantities of these hormones and their metabolites estriol and pregnanediol are excreted in the urine. Therefore, their concentrations can also b~ measured to ~t for pregnancy.

sterone sulfate (DHEA-S). DHEA and DHEA-S pass to the p!KHU, where they are used for estrogen synthesis. Progesterone is converted to testostmJne in the testes of the male fetus. Human piKent;~IIKmgen (hPl) ~~steadily durilg pregnancy. IJcie prolactin (--+ p. 322). hPl stimulates mammary enlargement and lactogenesis in particular and, Ike GH (--+ p. 294}, stimulates physal growth and development in general. hPl also seems to Increase maternal plasma glucose con· centration.

Corticotropin-releasing honnone (CRH) secreted by the placenta seems to play a key role in the hormonal regulation af birth. The plasma levels of maternal CRH increase exponentially from the 12th week of gestation on. This rise is more rapid in premature births and slower in post-term births. ln other words, the rate at which the CRH concentration rises seems to determine the duration of the pregnancy. Placental CRH stimulates the release of ACIH by the fetal pituitary, resulting in increased cortisol production in the adult zone ofFAC; this again stimulates the release of CRH (positive feedback). CRH also stimulates lung development and the production ofDHEA and DHEA-S in the fetal zone of FN:.. The maternal utrogen concentration rises sharply towards the end of the pregnancy, thereby counteracting the actions of progesterone, including its pregnancy-sustaining effect. Estrogens induce oxytocin rectptors (-op.322), a 1-adrenoceptors (-+ p. 88ff.), and gap junctions in the uterine musculature (-+ p.16ff.), and uterine cells are depolarized. All these effects (-+ p. 323 B) increase the responsiveness of the uterine musculature. The simultaneous increase in progesterone synthesis triggers the production of collagenases that soften the taut cervix. Stretch receptors in the uterus respond to the increase in size and movement of the fetus. Nerve fibers relay these signals to the hypothalamus, which responds by secreting larger quantities of axytodn which, in turn, increases uterine contractions (positive feedback~ The gap junctions conduct the spontaneous impulses from individual pacemaker cells in the fundus across the entire myometrium at a rate of approximately 2 cm{s.

In contrast to other endocrine organs, the placenta has to receive the appropriate precursors (cholesterol or androgens, --> p. 310) from the maternal and fetal adrenal cortex, respectively, before it can synthesize progesterone and estrogen (..... A2). The fetal adrenal cortex (F.AC) is sometimes larger than the kidneys and consists of a [rtal zone and an adult zone. The placenta ukes up cholesterol and pregnenolone and uses them to synthesize progesterone. It is transported to the fetal zone of the FN'., where it is converted to dehydroepiandrosterone (DHEA) and dehydroepiandroPregnancy test, preeclampsia, placental failure, depression, endometriosis

Plate 11.20 Hormonal Control of Pregnancy and Birth

321 c

Cl

2 LatEr pregnancy: Steroid hormone synthesis in placenta

Mother

Malht!r

CHW

Adrenal mriElr

AtJrmal CDitPX

ll:II

-a

ea.

&!

-a

c

Ill Ill

Ill

cg

~

g

:1:

DHEA DHEAS

......

DHEA DHEM

DHEA DHE.Ai Steroid honnones: P - prog~rone; DHEA(-5) - dehydroeplilndrosterone (sulfa~~::); E- estrogens

B. Honnone concentrations in plasma during pregnancy - - - - - - - - . . ,

;;;

f.. E

j

~

a

E

fd

E

.5 c

s 0

c

el c

a Wl!ek

Trfmester

4

8

12

16

20 2

24

28

32 3

36

40

322

.,.... .,....

Prolactin and OXytocin Prolactin Prolactin (• PRL.lactotropk hormone, LTII) is a peptide hormone consisting of 199 amino acids (23 kDa) produced in the mammotropic cells of the anterior pituitary. Function. In women, prolactin (together with estrogens, progesterone. glucocortkoids, and insulin) stimulates breast en/a~~t and diffn'entiation during pregnancy and lactogenesis after parturition. In breast-feeding, stimulation of the nerve endings in the nipples by the suckling infant stimulates the central secretion of prolactin (lactation reflex). When the mother stops breast-feeding, the prolactin levels drop, leading to the rapid stoppage of milk production. PRL also suppresses ovulation as it inhibits the pulsatile FSH and LH secretion. Some women utilize the anti-ovulatory effect of nursing as a natural method of birth contro~ which Is often but not always effective. Regulation. The secretion ofPRL is inhibited by dopamiM (prolactostatin • PIH) and SIH and stimulated especially by thyroliberin (lllH) (~p.284). Prolactin increases the hypothalamic secretion of PIH in both men and women (negative feedback control). Conversely, estradiol (E2) and progesterone inhibit PIH secretion (indirectly via transmitters, as observed with GnRH; see above). Consequently, prolactin secretion rises significantly during the second half of the menstrual cycle and during pregnancy.

Function during childbirth. Oxytocin derives its name from its effect on uterine motllty during parturition. In late pregnancy, ACIH production in the fetal anterior pituitary lobe increases, leading to a rise in estrogen secretion and progesterone antagonism in the placenta (..... p. 320), with a resulting rise in the estrogen:progesterone ratio in maternal blood (-+B). Uterine contractility increases because more gap junctions, which promote conduction from pacemalrer cells In the fundus, and oxytocin receptors form in the uterus. This is aided by increased prostQglandin secretion. With the onset of labor the baby presses on the cervix, and stretching of the cervix is signaled to the hypothalamus, which increases oxytocin secretion (-+B). This in tum increases uterine contractions (positive feedback; feJXUson reflex). Oxytocin is metabolized rapidly by oxytocinase, so that the contractions are interrupted roughly every 2 minutes and mother and baby can have a short "breather.• Oxytocin also expels the placlfltl, constricts uteri~~~!

vessels, and Increases postnatal lochia dltcharge. In dinical obstetrics, aocytDdn is gJwn to induce labor. Other functions. Oxytocin is also important in bn!ut-fMdlng. The lactation reflex increases

release of oxytocin as well as PRL (-+C), which triggers milk ejection. Recent research has shown that neurons project from the hypothalamus to several nglons of the b111ln where they release oxytocin (~B), for example, the stria terminalis, the Hyperproladlnemra. Stress and certain drugs In- anterior cingulum, the nucleus accumbens, hibit tfle secretion of PIH, causing an increase in pro- and suprachiasmatic nucleus, the amygdaloid lactin secretion. Hypothyroidism (-+ p. 300) and a pmlactlnoma In the anterior lobe oflfle pituitary can also body, the hippocampus, and the brain stem lead to hyperprolactlnemla, because the associated (A 2-8). These projections control nprodutincrease in TRH stimulates the release af prolactin. tlon and preservation of the species in the Hyperprolactinemia inhibits ovulation and leads to widest sense. Physical caresses increase oxyga/octolrllfo,l.e., the secretion of milk Irrespective of tocin secretion, which has been nicknamed the pregnancy, and amenorrhea. "love hormone•; orgasm increases secretion threefold. Oxytocin improves pC}'todn rraptor grne Galactorrhea, prol11ctlnoma, autism spectrum disorders

Plate 11.21

Prolactin. Oxytocin

323

A. Effects of oxytocin rn the b r a i n - - - - - - - - - - - - - - - , Recollection of

Oxytocin improves:

(a~ allfltendly) faces 4

Soclil confidence Recognition of social signals (e.g. eyes, t.lce)

..7 - -..

'

~ ""' PosiiMH8ilt11ons of fathers to their small children

•

Couple bonding beh;Mor

...... 324567

B. Control ofub!rlne motor actlvtty clurfng blrtfl ----------~ MDI2moJ blood

1

Prostaglandin ~ Oxytocin secretion

Produdlon of n!CI!ptors ~ lnaused ~-1:1 udtability --.~.... on

-

1i

J

OMopment of gap functions Increased

contractility

'M

Impulse

Oll'lduction -

:f

!

Contraction

!

U!f\lle p.374). lbe potential of slowly adapting sensors becomes proportional to stimulus intensity (Psensors or tonic sensors). Fastadapting sensors respond only at the onset and end of a stimulus. lbey sense differential changes in the stimulus intensity (Dsensors or phasic sensors). PDsensors have both characteristics. Central processing. In a f!fst phase, inhibitory and stimulatory impulses conducted to the CNS are integrated-e.g., to increase the tontra5t of stimuli (..... D; see also p. 376). In this case, stimulatory impulses originating from adjacent sensors are attenuated in the process (lotmJI inhibition).In a second step, a sensory impression of the stimuli (e.g., "green" or "sweet") takes form in low-level areas of the sensory cortex. This is the first step of subjective sensory physiology. Consciousness is a prerequisite for this process. Sensory impressions are followed by their interpretation. lbe result of it is called perteptlon, which is based on experience and reason, and Is subject to individual interpretation. lbe impression "green; for example, can evoke the perception '"There is a tree• or '"This is a meadow.• Other lmportMJt conatpts of sensory physiology: Absolute threshold (-->pp.362ff., 374 and 384), difference threshold (--> pp.360ff~ 374 and 390), spatial and temporal summation (-->pp. 56 and 374). receptive field (..... p.376), habituation, and sensitization. 1be latter two mechanisms play an important role in learning processes(--> p. 356).

Demyelination, multiple sclerosis, neuritis, sensory abnormalities

Plate 12.2 Stimulus Reception and Processing A. Reception, perception and transmission ofl'nformatlon - - - - - - - - - - , CamfDURW55 1

10 -lO'blb/s

®

~

m

Environment RMI!ptlan

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Transmlsslan

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ld'bits/s

331

7

10 bltsfs

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j

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] 1:

B. Stimulus processing and lnfonnation coding - - - - - - - - - - - - - ,

a

.. N

C. SUmulwi, Rm501' and Klian -----, pob!ntial relatlonshiP5

i- ' Jf il / .bl7': Stimulus

5en$0r I)OU'ntial

D. Cantrilitlng - - - - - - - - - - , Centril

contrasting

332

....N

Sensory Functions of the Skin 5omatovlsceral sensibility is the collective frequency (--o B3 ). These acceleration sensors term for all sensory input from receptors or also play a role in proprioception (-+ p. 334). sensors of the body (as opposed to the sensory Raolutlon. RA and SA I sensors are densely organs of the head). It includes the areas of distributed in the mouth, lips, and fingertips, proprioception (--o p. 334), nocirepnon (--o p. especially in the index and middle finger (about 100/cm2 ). They can distinguish closely 336), and skin or swface sensitivity. adjacent stimuli as separate, I.e., each afferent The sense of touch (taction) is essential for perception offonn, shape, and spatial natur'l! of axon has a narraw receptive field. Since the sigobjects (stereognosis). Tactile sensors are lo- nals do not conve~ as they travel to the CNS, cated predominantly in the palm. especially in the ability of these sensors in the mouth, lips, the fingertips, and in the tongue and oral cav- and fmgertips to distinguish between two ity. Stereognostic perception of an object re- closely adjacent tactile stimuli, i.e., their resoquires that the CNS integrate signals from ad- lution, Is very high. jacent receptors Into a spatial pattern and The spatial threshold for two-point dlscr1mlnacoordinate them with t1dlle motor function. tlon, i.e., the distance at which two simultaneous Mech1nos•nsors. Hairless areas of the skin stimuli can be perceived as separate, is used as a contain the following mechanosensors (-+A), measure of tactile resolution. The spatial thresholds which are afferently innervated by myelinated are roughly 1 mm on the fingers, lips, and tip of the tongue, 4 mm on the palm of the hand, 15 mm on nerve fibers of class II/A~ (-+ p. 53 C): • The spindle-shaped Ruffini's corpuscle the ann, and over 60 mm on the back. SA II receptors and plldnl1n ClOI'puscles have a (-+A3) partly encapsulates the afferent axon branches. This unit Is a slowly adapting (SA) broad rtceptive field (the tlti!ct function of SA II receptors Is not known). PaclnlAS), which low as compared to the much higher densities respond to bending of the hairs, assume these in the mouth and lips. (That is why the lips or functions in hairy areas of the skin. cheeks are used for temperature testing.) • Pacinian corpusdes (-+ M) are innervated Different sensors are responsible for thermoceptlon by a centrally situated axon. They adapt l'I!J)I at temperatures exa!edlng 4s•c. These hut senrapidly and therefore respond to changes in lOIS a~ also !Ked for the perc~n of pungent substances sudlas cupsolcln, the actllle oonstltuent of pressure change velocity, i.e., to accelmlnon hot chili peppers. Stimulation of VR1 receptnrs 2 (d p/dtl), and sense high-frequency vibration (vaniloid recqJtnrtype 1)formpsoidn mediates the (t00-400Hz; indentation depths o,.- Ia ond Uaffrrolt:s ~.---~ Y~

335

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•

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?; ~=-

~

z•

Iu• ... N

Reflex contrilctlon of skeletill muscle

II:J bring mwc:le bad; II:J initial length

From l!lltensor

lnbmeuron

,...._ Inhibitory ,...._ Stfmuliltory

336

1.. -a c

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z

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....N

Noclception and Pain Pain is an unpleasant sensory experience associated with discomfort. It is protective insofar as it signals that the body is being threatened by an injury (noxa). Nociception is the perception of noxae via nocisensors, neural conduction. and central processing. The pain that is ultimately felt is a subjective experience. Pain can also occur without stimulation of nocisensors, and excitation of nocisensors does not always evoke pain. All body tissues except the brain and liver contain sensors for pain. i.e~ nodsensors or nodceptors (-+ A). Nocisensors are bead-like endings of peripheral axons, the somata of which are located in dorsal root ganglia and in nuclei of the trigeminal nerve. Most of these fibers are slowly conducting C fibers (< 1 mfs): the rest are myelinated A6 fibers (5-30 m/s; fiber types described on p. 53 C). When an Injury occurs, one first senses sharp "fast pain" (All fibers) before feeling the dull "slow pain" (C fibers), which is f~t long~ and over a broader

area. Although most noclsensors adapt, the pain can last for days. The reason for this is not entirely de;u. Most nocisensors are polymoclal ~ (C fibers) activated by mechanical stimuli, chemical mediators of lnftammation, and high-intensity heat

cold stimuli. The ifis common ullimocbll nodconsist of thtnnol nodsensors (All fibers), mechanlcol noclsensors (All fibers), and "dormont" nodsensors. Thermal nocisensors are activated by extremely hot (> 4S' C) or cold (< S' C) stimuli (-+ p. 332). Dormant nodsensors are chiefly located in internal organs and are •awa~ned" after prolonged exposure (sensitization) to a stimulus, e.g., inflammation. Nodsensors can be inhibited by opioids (desensiUatlon) and stimulated by bradykinin, ATP, and K+ released in response to inflammation or prostaglandin E2 (sensltl2iltlon; -+A). Endogenous opioids (e.g., dynorphin. enkephalin, endorphin) and exogenous opioids (e.g., morphine) as well as inhibitors of prostaglandin synthesis (e.g. acetylsalicyclic add (aspirin); ...... p.283) are therefore able to alleviate pain (analgesic action). or

~

1""-IIIIMtory sensltlutlon (e.g., sunbool} lowers the threshold for noxious stinnuM,ieading to excessive

sensitivity (hypevlgesia) and additional pain resulting from non-noxious stimuli to the skin (aRodynio), e.g., touch or warm water (37'C). Once the nocisensors art stimulated, they start to release neuropeptkks such as substance P or CGRP (calcitonin

gene-related peptide) that cause Inflammation of the surrounding vessels (neurogtnk Inflammation).

Projected pain. Damage to nociceptive fibers caustS pain (neurogtnlc or neuropathic) that Is often projected to and perceived as amlng from the periphery. A prolapsed disk compressing a spinal ntrve can, for example, cause ltg pain. Nociceptive flbers can be blocked by cold or local anesthesia. Noc:keptlve tracts (-+ Cl ). The central axons of

nociceptive somatic neurons and nociceptive afTerents of internal organs end on neurons of the dorsal horn of the spinal cord. In many cases, they terminate on the same neurons as the skin afferents. ~rred pain (-+ B). Convergence of somatic and ~visceral nociceptive afferents Is probably the main

cause of referred pain. In this type of pain, noxious visceral stimuli cause a perception of pain in certain skin areascalled Head'none1. Thatfor the heart, for example, is located mainly in the chest region. Myocardlilllschemlills therefore perceived as pain on the surfiiO! of the chest wall (angina pectoris) and often also In the left arm and upper abdominal region. In the spinal cord, the nociceptive afferents cross to the opposite side (decussation) and are conducted in the tracts oftM anterobit.ral funiculus-mainly in the spinothalamic tractand continue centriillly via the brain stem where they join nociceptive afferents from the head (mainly trigeminal nerve) to the thalamus (-+ Cl ). From the ventrolateral thalamus, sensory aspects of pain are projected to 51 and 52 areas of the cortex. Tracts from the medial thalamic nuclei project to the limbic system and other centers. Components of pilln. l'illn has a sensory rompon~ Including the conscious perception of sltt, duration, and Intensity of pain; a motor compon~ (e.g., defensive posture and withdrawal reflex; -+ p. 338}, an autooamic component (e.g., tachycardia), and an a(fKtM! component (e.g., aversion). In addition, pain assessmenb based on the memory of a previous pain experience can lead to piiln-reJ.led behavior (e.g., moaning). In the thalamus and spinal cord, nociception

can be lnhl»>ted via descending tracts with the aid of various transmitters (mainly opioids). The nuclei of these tracts (-+ C2, blue) are located in the brain smn and are mainly activated via the nociceptive spinoreticular tract (negative feedback loop).

Inflammiltlon, Head's zones, phantom pain, peripheral and central pain relief

Plate 12.5 Nodceptlon and Pain A. Noc:la!pUon - - - - - - - - ,

B. Wen'l!d pllln - - - - - - - - ,

Sensitization via bradykinin, prostaglandin E2, serotonin Acute

nCIICil

337

II "'r:: II

1"'

!!!

Ill

E

!

iTT

Desensltfzadon via opioids, SIH, gala nin, etc.

C. Ascending and descending tracts for nodceptton - - - - - - - - - - - , 2 Descending nociceptive tracts 1 Ascending nodc:eptive tracts (mainly inhibitDry)

(After R. F. Sdlm~

... N

338

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z

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... N

Polysynaptic Reflexes Unlike proprioceptive reflexes (~ p. 334), polysynaptic reflexes are activated by sensor.; that are spatially separate from the effector organ. This type of reflex is called polysynaptic, since the reflex arc involves many synapses in series. This results in a relatively long reflex time. The intensity of the response is dependent on the duration and intensity of stimulus, which is temporally and spatially summated in the CNS (-+ p. 56). Example: itching sensation in nose ~ sneezing. The response spreads when the stimulus intensity increases {e.g., coughing ~choking cough). Protective reflexes (e.g., withdrawal reflex, corneal and lacrimal reflexes, coughing and sneezing), nulril:ion reflexes (e.g~ swallowing, sucking reflexes), locomotor reflexes, and the various autonomic reflexes are polysynaptic reflexes. Certain reflexes, e.g., plantar reflex, cremasteric reflex, and abdominal reflex, are used as diagnostic tests. Wlthdr.w~ reflex(~A). &Dmple: A painful stimulus in the sole of the right foot (e.g., stepping on a tack) leads to flexion of all joints of that leg (flexion reflex~ Nociceptive afferents (-+ p. 336) are conducted via stimulatory interneurons (-+ Al) in the spinal cord to motoneurons of ipsilateral jle1eors and via inhibitory interneurons (-+A2) to motoneurons of ipsilateral e1etemorr (-+ Al), leading to their relaxation; this is called antagonistic inhibition. One part of the response is the crossed extensor nflu, which promotes the withdrawal from the injurious stimulus by increasing the distance between the nociceptive stimulus (e.g., the tack) and the nocisensor and helps to support the body. It consists of contraction of extensor muscles (-+AS) and relaxation of the flexor muscles in the contralateral leg (..... A4, Ali). Nociceptive afferents are also conducted to other segments of the spinal cord (ascending and descending; -+A7, AS) because different extensors and flexors are innervated by different segments. A noxious stimulus can also trigger flexion of the ipsilateral arm and extension of the contralateral arm (double crossed eKm~Sor rejle1e). The noxious stimulus produces the perception of pain in the brain (~ p. 337).

Unlike monosynaptk stretch reflexes, polysynaptic reflexes occur through the co-activation of« and y motDneurons (-+ p.334). The reflex 1!1Cdtability of a motoneurons is largely controlled by supraspinal mnt.rs via multiple intemeurons (-+p.342). The brain can therefore shorten the refii!1C time of spinal cord reflexes when a n01eious stimulus is anticipated. Supraspinal lesions or inb!rruption of descending tracts (e.g., in ~raplegics) can ltad to exaggeration of reflexes (hyperreflexlll) and stereotyplc reflexes. The absence of reflexes (a...tlull) corresponds to specific disorders of the spinal cxml or peripheral nerve.

Synaptic Inhibition GABA ( y-aminobutyric acid) and glycine (-+ p. 59ff.) function as Inhibitory tl'llnsmlttl!rs in the spinal cord. Presynaptic Inhibition (-+ B) occurs frequently in the CNS, for 1!1Cample, at synapses between type Ia afferents and a motoneurons, and involves axoaKonic synapses of GABAergic interneurons at presynaptic nerve endings. GABA exerts inhibitory effects at the nerve endings by increasing the membrane conductance to a- (GAI!Iv. receptors) and K' (GABAa receptors) and by decreasing the conductance to Cal+ (GABAa receptor.;). This decreases the release of transmitters from the nerve ending of the target neuron (--. 82), thereby lowering the amplitude of its postsynaptic EPSP (-+p.54). The purpose of presynaptic inhibition is to reduce certain influences on the motoneuron without reducing the overall excitability of the cell. In postsynaptic Inhibition (-+C), an inhibitory interneuron increases the membrane conductance of the postsynaptic neuron to a- or K', espedally near the axon hillock, thereby short-circuiting the depolarizing electrical currents from excitatory EPSPs (-+ p. 56ff.). The interneuron responsible for postsynaptic inhibition is either activated by feedback from axonal collaterals of the target neurons (I"I!CUIHI'It Inhibition of motoneurons via glydnergic Renshaw cells;-+ C1 ) or is directly activated by another neuron via feed-forward control (~ C2). Inhibition of the ipsilateral1!1Ctensor (-.A2, A3) in the flexor reflex is an 1!1Cample of.feed-forward inhibition.

Diagnostic polysynaptic reflexes, 1rellexla, hyperreflexia, spasUclty, spinal cord lesions

Plate 12.6 Polysynaptk Reflexes, Synaptic Inhibition

~

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+--

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339

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4

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--< !i11m.l111D1y lnllrn......, --< Inhibitory nwmeurcn B.

Presym~ptlc Inhibition

1 Uninhibited

Nociception in right foot

-----,

e. g. lrJ a{ftmtt

~

Inhibitory inm'llfiNon

C. P'astsynaptlc Inhibition - - - - - - ,

1 Feedbildl: inhibition

Toilgonlst

To antilgonlst

(e.g., flexor)

(e.g.,l!lltensor)

340

Central Conduction of Sensory Input The posterior funiculus-lemniscus system (-+ C. green) is the principal route by which the

... N

somatosensory cortex S1 (postcentral gyrus) receives sensory Input from skin sensors and propriosensors. Messages from the skin (supeljidal sensibility) and locomotnr system (proprioceptive .sensibility) reach the spinal cord via the dorsal roots. Part of these primarily affe~nt fibers project in trads of the posll?rior fUniculus without synapses to the posll?rior fUnicular nuclei of the caudal medulla oblongata (nuclei cunl!atus and gracilis). The tracts of the posterior funiculi exhibit a somatotopic arrangement, I.e., the further cranial the origin of thl! fibers the mo~ lateral their location. At the medial lemniscus, the secondary afferent somatosensory fibers cross to the contralateral side (decussate) and continue to the posterolateral ventral nucleus (PLVN) of the th•l•mus, where they are also somatotopically arranged. The secondary afferent trigeminal fibers (trigeminal lemniscus) end in the posreromtdial 11t11tral nucleus (PMVN) of the thalamus. The tertiary afferent somatosensory fibers end at the quaternary somatosensory neurons in the soJMt:osensoly cortex Sl. The main function of the posterior funiculus-lemniscus pathway is to relay information about tactill! stimuU (pressure, touch, vibration) and joint position and movement (proprioception) to the brain cortex via its predominantly rapidly conducting fibers with a high degree of spatial and temporal resolution. As in the motor cortex (--+p.343B), each body part !s assigned to a corresponding projection area in the som•tosensory cortex 51 (--+A) following a somatotopic arrangtntent (-->B). Three features of the organization of Sl are (1) that onl! hemisphere of the brain receives the information from the contralateral side of the body (tracts decussate in the medial lemn!.scus; -+ C); (2)that most neurons in Sl receive afferent signals from tactile sensors in the fingers and mouth (--+p.332); and (3)that the afferent signals are processed in columns of the cortex (-+ p. 351 A) that are activated by specific types of stimuU (e.g., touch). .AntercHteral spinothalamic po~thw.y (--> C; violet). Afferent signals from nocisensors, thermosensors, and the second part of pres-

sure and touch afferent neurons are already relayed (partly via intemeurons) at various levels of the spinal cord. The secondary neurons cross to the opposite side at the corresponding segment of the spinal cord, form the lateral and anterior spinothalamic tract in the anterolateral funiculus, and project to the thalamus (PLVN). The tertiary afferent fibers then reach the somatosl!nsory corti!X Sl. Descending trKts (from the cortex) can inhibit the Dow of sensory input to the cortex at all relay stations (spinal cord, medulla oblongata, thalamus). The main function of these tracts is to modify the receptive field and adjust stimulus thresholds. When impulses from different sources are conducted in a common afferent, they also help to suppress unimportant sensory input and selectively process more! important and interesting sl!nsory modalities and stimuli (e!.g., eavesdropping). Hemlplegr.. (-->D) Brown-S«~uord syndrome occurs due IXl hemisection of the spillill oord, resulting in ipsilateral paralysis and loss of various functions below the lesion. The Injured side exhibits motor poro/ysis (initially flaccid, lab!r spastic) and loss of tactile sensation (e.g., impaired two-point discrimination, --+ p. 332). An additional loss of pain and temperature sensation ocrurs on the contralab!ral side (dissodE). The sensory input described above as well as the input from the sensory organs are specific, whereas the reticular activating system (RAS) !s an unspecific system. The RAS is a complex processing and integrating system of cells of the micu/arformation of the brainstem. These cells receive sensory input from all sensory organs and ascending spinal cord pathways (e.g., eyes, ears, surface sensitivity, nodception), basal ganglia, etc. Cholinergic and adrenergic output from the RAS is conducted along descending pathways to the spinal cord and along ascending "unspecific" thalamic nucll!i and "unspecific" thalamocortical tracts to almost all cortical regions (-+ p. 351 A), the limbic system, and the hypothalamus. The ascending RAS or ARAS controls the state of consciousness and the degree of wakefulness (arousal activity; -+ p. 354).

Neural and spinal cord lesions. dlssodatecl disorder of sensation, paresthesia, anesthesia, hypesthesl•, dysesthesia

Plate 12.7 Central Condudlon of Sensory Input A. Sensory mnters of thl! brain - - - - - - , I'llmary

pro]ectlon ireil forhei!lfng

341

II "'r:: II

Pri'!lary projection areil for body surface

"' 1 Ill

Primary

projection area

for vision

E

! ... N

Loss of l;lctfle

sensation Mator

paralysis

StiJte of mnscklusness Autonomic functions

Mldllla oblongmu

from much senson and propriosenson

b== From nocisenson and thennosensors

Affl!ct

342

... N

Movement Coordinated muscular movements (walking, grasping. throwing, etc.) are functionally dependent on the postural motor system, which is responsible for maintaining upright posture, balance, and spatial integration of body movement Since control of postural motor function and muscle coordination requires the simultaneous and uninterrupted flow of sensory impuls~ from the periphery, this is also referred to as sensortmotor function. « motoneurons in the anterior horn of the spinal cord and in cranial nerve nuclei are the terminal tracts for skeletal muscle activation. Only certain parts of the corticospinal tract and type Ia afferents connect to a motoneurons monosynaptically. Other afferents from the periphery (propriosensors, nocisensors, mechanosensors), other spinal cord segments, the motor cortex, cerebellum, and motor centers of the brain stem connect to a motoneurons via hundreds of inhibitory and stimulatory interneurons per motoneuron. Volunbuy motor funcdon. Voluntary movement requires a series of actions: decision to move ~ programming (recall of stored subprograms)~ command to move~ execution of movement (-+A1-4). Feedback from alferents (r~afferents) from motor subsYstems and information from the periphery is constantly integrated in the process. This allows for adjustments before and while executing voluntary movement

The neuronal activity associated with the first two phases of voluntary movement activates numerous motor areas of the cortex. This electrical brain activIty Is reflected as a negative cortlall readiness potential, which can best be measured in association areas and the wrtex. The more complex the movement, the higher the readiness potential and the earlier Its onset (roughly 0.3-3 s). The motor cortwx consists of three main areas (-+ C, top; -+ see p.329E for area numbers): (a)primarymotorarea, M1 (area4); (b)premotor area, PMA (lateral area 6); and (c)supplementory motor area, SMA (medial area 6). The motor areas of the cortex exhibit somatotopic organization with respect to the target muscles of their fibers (shown for M1 in B) and their mutual connections. Cortical afferents. The cortex receives motor input from (a) the body periphery (via

thalamus~ Sl(-+ p. 341 A) ~ sensory association cortex~ PMA); (b) the basal ganglia (via thalamus~ M1, PMA, SMA(-+ A2) ~ prefrontal association cortex); (c) the cerebellum (via thalamus ~ M1, PMA; ~ A2); and (d) sensory and posterior parietal areas of the corh!x (areas 1-3 and 5-7, respectively). Cortic:al efferenb. (->C, D, E, F) Motor output from the cortex is mainly projected to (a) the spinal cord, (b) subcortical motor centers (see below and p.344), and (c) the contralateral cortex via commissural pathways. The pyramldlll tr1ct includes the corticospinal !Tact and part of the corticobulbar !Tact. Over 90% of the pyramidal tract consists of thin fibers, but little is known about their function. The thick, rapidly conducting corticospinal tr.tct (-+C) projects to the spinal cord from areas4and6andfromareas1-3 of the sensory cortex. Some of the fibers connect monosynaptically to a and y motoneurons responsible for fmger movement (precision grasping). The majority synapse with interneurons of the spinal cord, where they influence input from peripheral alferents as well as motor output (via Renshaw's cells) and thereby spinal reflexes.

Function of the Bual Ganglia

Circuitry. The basal ganglia are part of multiple parallel corticocortic:al signal loops. Associative loops arising in the frontal and limbic cortex play a role in mental activities such as assessment of sensory information, adaptation of behavior to emotional context, motivation, and long-term action planning. The function of the ske/etomotor and oculomotor loops (see below) is to coordinate and control the velocity of movement sequences. Efferent projections of the basal ganglia control thalamocortical signal conduction by (a) attenuating the inhibition (disinhibiting effect, direct mode) of the thalamic motor nuclei and the superior colliculus, respectively, or (b) by intensifying their inhibition (indirect mode). The principal Input tD the basal g.-gilAcom~ from the putamen and caudate nucleus, which are collectively referred to as the strtabnn. Neurons of the striatum are activated by tracts from the entire con.x and use glutamate as their transmitter (-+D). Once activated,

Cerebral hemormage and IKhemla, spinal shock, spasticity, clasp-knife effect

~

Plate 12.8 Movement I A. Events from decision to mcwe to uecutlon of mOVI!ml!nt

C. Descending motor tracts - - - - - . ~ M 1 (area4)

SMA

(an:a~ ,-----:-._~ 51AreaS (areasl-3) medial) ( ·· and 7 PMA

(area6, lateral)

.' /

1

~ Tl;octstll

• Stl1alum (sam• II) • n,iamus (som• II) ·Rod nudous (x)

·Pons .Qiw, ·~111L1r

fontllliGn (somnl

« ond T ,_,uron• and Interneuron•

B. Somatotopic organiDtlon of primary motor am (M1) of tlw mrtl!x

343

II

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344

1.. -a c

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Movement (continued) ~ neurons of the striatum release an inhibitorytransmitter(GABA) and a co-transmittereither substance P(SP)orenkephalin (Enk•• ~ D and~ p. 59). The prindpal output of the ~I gangb runs through the pars reticularis of the substantia nigra (SNr) and the pars intema of the globus pallidus (CiPI), both of which are inhibited by SP/GABAergic neurons of the striatum(~D).

Both SNr and GPI inhibit (by GABA) the ventrolateral thalamus wtth a high level of spontaneous activity. Activation of the striatum therefore ltads to disinhibition of the thalllmus by this direct pathwil)'. If, however, enkephalin/GABA-releasing neurons of the striatum are activated, then they inhibit the pars extema of the globus pallldus (CPe) which, In turn, inhibits (by GABA) the subthokrmic nucleus. The subthalamic nucleus induces glutamatergic activation of SNr and GPI. The ultimate effect of this lndlred pathwil)' is lncn~~~sed th1lamlc Inhibition. Since the thalamus projects to the motor and prefrontal cortex. a corticothalamocorUcalloop that influences skeletal muscle movement (sbletomotor loop) via the pufDm61 runs through the basal ganglia. An oallomotor loop projects through the caudate oockus, pars reticula lis and superior coliculus and is involved in the control of eye movement (-+ pp. 364 and 382). Des'CEnding tnxts from the SNr project to the tectum and peduncular nucleus of the pans. The fact that the pars compocto of 1M substuntia nigra (SNc) showers the entire striatum with dopamine (dopaminergk neurons) is of pathophysiological Importance (-+D). On the one hand, dopamine binds to 01 receptors (rising cAMP levels), thereby activating SP/GABAergic neurons of the striatum; this is the direct route (see above). On the ather hand, dopamine also reacts wtth 02 receptors (decreasing cAMP levels), thereby inhibiting enkephalln/GABAerglc neurons: this Is the Indirect route. These eth!cts of dopamine are essential far nonnal striatum function. Degeneration of more than 70:1\ of the dapaminergic neurons of the pars compacta results In l!lfCeSSI~ Inhibition of the motor areas of the thabmus, thereby impairing voluntary motor function. This occurs in Parkinson disease and can be due to genetic predisposition, trauma (e.g., boxlng), cerebral infection and other causes. The characteristic symptoms of disease include ~ of movement (olrlntslo), slowness of movement (bradyldnesia), a festinating gait, small handwriting (micrognlphio), masldike facial expression, muscular hypertonia (rigidity), bent pasture, and a lmnor of resting muscles ("money-counting" movement of thumb and fingers).

Function of the Cerebellum The cerebellum contains as many neurons as the rest of the brain combined. It is an important control~ for motor function that has afferent and efferent connections to the cortex and periphery A3, top right). jasmine blooms and wine contain several dozens and hundreds of odorants, re5peetively, so their overall scent is a more complex perception (Integrated In the minencephalon). Olfactofy padlway (-+ A2). Axons of (ca. UJl) same-type sensors distributed over the olfactory epithelium synapse to dendrites of their respective mitral ails and bristle ails within the glomeruli of the olfactory bulb. The glomeruli therefore function as convergence

centers that integrate and relay signals from the same sensor type. Their respective sensor protein also determines which glomerulus newly formed sensor axons will connect to. Periglomerular ceUs and granular reUs connect and inhibit mitral and bristle cells(-+ A2~ Mitral cells act on the same reciprocal synapses (->A."+/-") in reverse direction to activate the periglomerular cells and granular cells which, on the other hand, are inhibited by efferents from the primary olfactory cortex and contralateral anterior olfactory nucleus (--. A:Z, violet tracts). These connections enable the cells to inhibit themselves or nearby cells (contrast), or they can be dislnhibited by higher centers. The signals of the axons of mitral aUs (1) reach the anterior olfactory nucleus. Its neurons cross over (in the anterior commissure) to the mitral cells of the contralateral bulb and (2) form the olfactory tract projecting to the primary olfactory corte1t (prepiriform cortex, olfactory tubercle, cortical amygdaloid nucleus). The olfactory input processed there is relayed to the hypothalamus, limbic system (see alsop. 348). and reticular formation ; it is also relayed to the neocortex (iiiSU/a, orbitofrontal area) either directly or by way of the thalamus. Tbi'Hholds. It takes only 4 x ut·15 g of methylmercaptan (in garlic) per liter of air to trigger the vague sensation of smell (peruption or absolute threshold). The odor can be properly identified when 2 x to-u g{L is present (identification threshold). Such thresholds are affected by air temperature and humidity; those for other substances can be 1010 times higher. The relative intensity differential threshold .6.1/1 (0.25) is relatively high ( ..... p.374). Adaptotion to smell is sensor-dependent (desensitization) and neuronal (-->C). The sense of smell has various functions. Pleasant smells trigger the secretion of saliva and gastric juices, whereas unpleasant smells warn of potentially spoiled food. Body odor permits hygiene control (sweat, excrement), conveys social information (e.g., family, enemy; ..... p.348), and influences sexual behavior. Other aromas influence the emotional state.

Conductive hyposmla (tumor, foreign body), skull base flilcture, anosmia, parosmia

Plate 12. 18 Sense of Smell A. OlfactDry pathway and olfactory sensor spedfldty - - - - - - - - - - - ,

1 Nasal cavity

363

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5 (NII!r [llgel•nd Elcmln et al)

364

Sense of Balance Anatomy. Each of the three semk'lrcul¥ ~Is (-+ Al) Is located in a plane at about right angles to the others. The ampulla of each canal contains a structure caned the crlstrl ompullaris (-+ A2). It contains hair cells (secondary sensory cells), the dlla and villi of which project Into a gelatInous membrane called the cvpulo (-+ A2). Each hair cell has a long ldnocilium and ca. 80 stereovilli of variable length. Their tips are connected to longer adjacent dlra vfa the "ttp /Inks" (-+ Al). ridg~like

... N

S.mlc:traMrcanals. When the cilia and villi are in a resting state, the hair cells release a transmitter (glutamate) that triggers the firing of action potentials (AP) in the nerve fibers of the vestibular ganglion. When the head is turned, the semicircular canal automatically moves with it. but endolymph in the canal moves more sluggishly due to inertia. A brief pre.ssure dijJerence thus develops between the two sides of the cupula. The resultant vaulting of the cupula causes the stereovilli to bend (..... A2) and shear against each other, thereby changing the cation conductance of the hair cell membrane. Bending of the stereovilli toward the ldnocilium increases conductivity and allows the influx of K' and Na• along a high electrochemical gradient between the endolymph and hair cell interior (see also p. 386). Thus, the hair cell becomes depolarized, Ca,. channels open, more glutamate is released, and the AP frequency increases. The reverse occurs when the cilia and stereovilli bend in the other direction (away from the ldnocilium). The semicircular canals function to detect angular (rotational) accelerations of the head in all planes (rotation, nodding, tilting sideways). Since normal head movements take less than 03 s (acceleration ~ deceleration), stimulation of the semicircular canals usually reflects the rotational velocity. The pressure difference across the cupula disappears when the body rotates for longer periods of time. Deceleration of the rotation causes a pressure gradient in the opposite direction. While bending of the cilia and villi Increases the AP frequency at the start of rotation, it decreases during deceleration. Abrupt cessation of the rotation leads to vertigo and nysggmus (see below).

The SKaJie and utrtde contain maallae (..... A1, M) with ldnocilia and stereovilli that project into a gelatinous membrane (-+ A4) with high density (- 3.0) calcite crystals called staiD-

conia, staroliths or otoliths. They displace the membrane and thereby bend the embedded cilia and villi (-+A4) due to changes in the direction of gravity, e.g., when the head position deviates from the perpendicular axis. The maculae respond also to other linear (translational) accelerations or decelerations, e.g., ofa car or an elevator. Central connections. The bipolar neurons of the vestibular ganglion synapse with the vtStibular nuclei (-+A. B). Important tracts extend from there to the contralateral side and to ocular muscle nuclei, cerebellum (-+p.344), moroneurons of the skeletal muscles, and to the postcentral gyrus (conscious spatial orientation). Vestibular reflexes (a) maintain the balance of the body (postural motor function. -+ p.346) and (b) keep the visual field In focus despite changes in head and body position (oculomororconlrol,-+ Band p.382). EJtomp1e (_..C): If a support holding a test subject Is

tilted, the activated vestibular organ prompts the subject to extend the ann and thigh on the declining side and to bend the arm on the Inclining side to maintain balance (-+ C2). The patient with an Impaired equilibrium organ fails to respond appropriately and topples over(-+ C3).

Since the vestibular organ cannOI: determine whether the head alone or the entire body is moving (sense of movement) or has changed position (postural sense), the vestibular nuclei must also receive and process visual information and that from propriosensors in the neck muscles. Efferent fibers project bilaterally to the eye muscle nuclei, and any change in head position is immediately corrected by opposing eye movement(-+ B). This vestibulo-ocular reflex maintains spatial orientation. estibular organ function can be assessed by testing oculomotor control. Secondary or postl1ltototy nystagmus occurs after abrupt cessation of prolonged

rotation of the head around the vertical axis (e.g., in

an office chair) due to activation of the horizontal semicircular canals. It is characterized by slow hor· lzontal movement of the eyes in the direction of rota· tlon and rapid return movement. Rightward rotation leads to left nystagmus and vice Vl!rsa (-+ p. 382). Ca· loric stimulation of the horimntal semicircular canal by lnstlllng cold (30 'C) or warm water (44 •q In the auditory canal leads to mloric: nystugmus. This method can be used for unilateral testing.

Damage to semicircular canals or maculae (lsdlemla, Meniere's disease}, nystagmus, dizziness

366

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Eye Structure, Tear Fluid, Aqueous Humor Ught entering the eye must pass through the cornea, aqueous humor. lens, and vitreous body, which are collectively called the optlcilll appiililtus, before reaching the retina and its light-sensitive pbotnsensors (--+A). This produces a reduced and inwrse image of the visual field on the retina. All parts of the apparatus must be transparent and have a stable shape and smooth surface to produce an undistortl!d image, which is the main purpose of tear ftuld in the case of the cornea. Tears are secreted by lacrimal glands located in the top outer portion of the orbit and their mode of production is similar to that of saliva (-+ p. 250). Tears are distributed by reflex blinking and then pass through the lacrimal puncta and lacrimal canaliculi (or ducts) of the upper and lower eyelid into the lacrimal sac and finally drain into the nasal sinuses by way of the nasolacrimal duct. Tear fluid improves the optical characteristics of the cornea by smoothing uneven surfaces, washing away dust, protecting it from caustic vapors and chemicals, and protects it from drying out. Tears lubricate tbe eyelid movement and contain lysozyme and immunoglobulin A (-+pp.98ff. and 246), which help ward off infections. In addition, tears are a well known mode of expressing emotions. The entry of light into the eye is regulated by the Iris (-+A; p. 375C1), which contains annular and radial smooth muscle fibers. Cllolinergic activation of the sphincter muscle of the pupil leads to pupil contraction (miosis), and adrenergic activation of the dilator muscle of the pupil results in pupil dilatation (mydriasis). The bulbus(eyeball) maintains its shape due to its tough outer coat or sclera (-+ C) and In· traoculilr pn1s.sure which is normally 10- 21 mmHg above the atmospheric pressure. The drainage of aqueous humor must balance its production to maintain a constant ocular pressure(-+ C). Aqueous humor is produced in the ciliary process ofthe posterior ocular chamber with the aid of carbonic anhydrase and active ion transport. It flows through the pupil into the anterior ocular chamber and drains into the venous system by way of the trabecular meshwork and Schlemm's canal. Aqueous humor is renewed once every hour or so.

c:;~a.

Obstruction of humor drainage can

oca. clue to chronic obllb!ratlon of the trabecular meshwork (open-angle glaucoma) or due to acute block of the anterior angle (angle-

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Conduction of Sound, Sound Sensors Sound waves are transmitted to the organ of hearing via the external ear and the auditory canal, which terminates at the tympanic membrune or eardrum. The sound waves are conducted through the air (air conduction) and set the eardrum in vibration. These are transmitted via the auditory ossides of the tympanic cavity(middle ear) to the membrane of the IMll window(-.A 1,2), where the inremal or inner ear (labyrinth) begins. In the middle ear, the malleus, incus, and stapes conduct the vibrations of the tympanic membrane to the oval window. This ensures that the sound is conducted from the low wave impedance in air to the high impedance in fluid with as little loss of energy as possible. This Impedance adaptation occurs at f + - 'b mole ca>+ or 1 mole ea>+ • 2 Eq ca>•, The osmole (Osm) is also derived from the mole (see below). Elec:tr1cal Units Electrical current is the flow of charged particles, e.g., of electrons through a wire or of ions through a c;ell membrane. The number of partides moving per unit time is measured in amperes (A). Electrical current cannot occur unless there is an elec:tr1cal potenUal difference, in short also called "potential," voltage, or tension. Batteries and generators are used to create such potentials. Most electrical potentials in the body are generated by ionic; flow (..... p. 32). The volt(V) is the SI unit of electrical potential(-+ Table 1 ). How much electrical current flows at a given potential depends on the amount of elec:trlcal resistance, as is described in Ohm's law

(voltage • current-resistance). The unit of electrical resistance is ohm (C) (-+ Table 1 ). Conductivity is the reciprocal of resistance (1/C) and is expressed in siemens (S), where S = c-1• In membrane physiology, resistance is related to the membrane surface area (C · m2 ). The reciprocal of this defines the membrane c::onduc;tance to a given ion: c-t. m-2 - s. m-2 (-+ p.32). Electrical work or energy is expressed in joules ()) or watt seconds (Ws ), whereas electrical power is expressed in watts (W). The electrical capacitance of a capacitor, e.g., a cell membrane, is the ratio of charge (C) to potential (V); it is expressed in farads (F) (-+ Tilble 1, p.395). Dlred curTent {DC) always flows In one direction, whereas the direction of flow ofilltematlng current (AC) constantly changes. The frequency of one cyde of change per unit time Is expressed In hertz (Hz). Mains current is generally 60Hz in the USA and 50 Hz in Europe.

Temperature Kelvin (K) is the SI unit of temperature. The lowest possible temperature is 0 K, or absolure zero. The Celsius or cenUgrilde scale is derived from the Kelvin scale. The temperature in degrees celsius ('C) can easily be converted intoK: •c =K-273.15 In the USA, temperatures are normally given in degrees Fahrenheit {'F). Conversions between Fahrenheit and Celsius are made as follows: "F • {9/5 ·"C)+ 32 ·c = ("F -32)· 5/9 Some important Kelvin, Celsius, and Fahrenheit temperature equivalents:

•c

'F

Freezing point of water +273

0

+32

Room temperature

2025

68-77

K

293298

Body core temperature 310

37

98.6

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373

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212

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Na• +a-. Both of these ions are osmotically active. When a substance that dissociates is dissolved in 1 kg of water, the ideal osmolality equals the molality times the number of dissociation products, e.g., 1 mmol NaCI/kg H20 • 2 mOsmfkg H.20. Electrolytes weaker than NaCI do not dissociate completely. Therefore, their degree of electrolytic dissociation must be considered. These rules apply only to ideal solutions, i.e., those that are extremely dilute. As mentioned above, bodily ftuids are nonldeal (or real) solutions because their real osmolality is lower than the ideal osmolality. The real osmolality is calculated by multiplying the ideal osmolality by the osmotic coefficient (g). The osmotic coefficient is concentration-dependent and amounts to, for example, approximately 0.926 for NaCL with an (ideal) osmolality of 300 mOsm/kg H20. The real osmolality of this NaCI solution thus amounts to 0.926 · 300 = 278 mOsmfkg H20. Solutions with a real osmolality equal to that of plasma (-290mOsmfkgH20) are said to be isosmolal. Those whose osmolality is higher or lower than that of plasma are hyperosmolal or hyposmolal. Osmolality and Tonicity Each osmotically active partide in solution (cf. real osmolality) exerts an osmotic pressure (:n) as described by van't Hoff's equation: [13.2[ where R is the universal gas constant (8.314 J · K-1 . osm-1 ). Tis the absolute temperature inK, and c.... is the real osmolality in Osm . (m3

Hzo)-1 • mOsm · (LH20)-1• If two solutions of different osmolality (h.c...,) are separated by a water-permeable selective membrane, h.c.,sm will exert an osmotic pressure difference (M) across the membrane in steady state if the membrane is less permeable to the solutes than to water. In this case, the selectivity of the membrane, or its relative impermeability to the solutes, is described by the reflection coefficient (o), which is assigned a value between 1 (impermeable) and 0 (as permeable as water). The reftection coefficient of a semipenneable membrane is o = 1. By combining nn't Hoff's and Staverman's equations, the osmotic pressure difference (h.:n:) can be calculated as follows: [13.3[ Equation 13.3 shows that a solution with the same osmolality as plasma will exert the same osmotic pressure on a membrane in steady state (i.e., the solution and plasma will be isotonic) only if o = l.ln other words, the membrane must be strictly semipermeable. Isotonicity, or equality of osmotic pressure, exists between plasma and the cytosol of red blood cells (and other cells of the body) in steady state. When the red cells are mixed in a urea solution with an osmolality of 290 mosmfkg H20. isotonicity does not prevail after urea (a < 1) starts to diffuse into the red cells. The interior of the red blood cells therefore becomes hypertonic, and water is drawn inside the cell due to osmosis ( ..... p. 24). As a result, the erythrocytes continuously swell until they burst. An osmotic gradient resulting in the subsequent Dow of water therefore occurs in all parts ofthe body in which dissolved partides pass through water-permeable cell membranes or cell layers. This occurs, for example, when Na• and a- pass through the epithelium of the small intl!stine or proximal renal tubule. The extent of this water Dow or volume flow jv (m3. s-1 ) is dependent on the hydraulic conductivity k (m·s-1 -Pa-1 ) of the membrane (i.e., its permeability to water), the area A of passage (m2), and the pressure difference, which, in this case, is equivalent to the osmotic pressure difference 6.:n (Pa): jv•k·A·An [m3 -s-1 [

[13.4[

399

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body fluids weight242 regulato!}' mechanism 242, 294 Bohr effect 136 equation, dead space 120, 121 A Boiling point, water 397 Bomb calorimeter 240 Bone 304, 306 break down 304 calcitonin effect 306 calcitriol effect 306 conduction, sound 386 estrogen effects 318 growth 318 marrow 92, 94, 98 Fe homeostasis 94 megakaryocytes 106 preprocessed precursor cells 98 metabolism 304 disorders 188 mineralization 306 I'IH effect 304 Botulinum toxin 60 Bowel flora 246 Bowman's capsule 156 Bradycardia, sinus 212 Bradykinesia 344 Bradykinin 196, 220, 226, 283, 336 coronaty vasodilatation 222 saliva!}' glands 250 second messenger 290 Bradypnea 114 Brain 328 ff. anatomy 328 blood flow 198 regulation 224 cortex afferents 342 area 1 327 E. 342, 343 C area 2 327 E. 342, 343 C area 3 327 E. 342, 343 area 4 327 E. 342, 343 C area 5 327 E. 342, 343 C area 6 347 E, 342, 343 area 7 327 E. 342, 343 C area 22 327 E,392 area 44327 E. 392 area 45327 E, 392 area Ml342, 343 area PM 342, 343 C area S1 336, 340, 341 A

c c

c

420 Brain (cont.) ~a S2 336,341

A ~a SMA 342, 343 C asssociation are.ils 346, 356 auditory 390 Brodman's areas 329 E columns3SO corticocortlcal s!Jnal loops 342 cortical alferents 342 efferenu 342 ul~cture 350 motor 342, 346 motosensory 392 neuron.ill drcultry 350 orbitofrontal area 362 organization 350 potenti.ills 350 prefrontal association 342 premotor area (PMA) 342 prepiriform 362 primary motor arN (MI) 342 pyramidal cells 350 scarring360 sensory assodation 342 input340 supplementary motor area (SMA)342 ~ath, diagnosis 350 derived growth factor (BDGF) 360 glucose deficit 256 glutamate, transmitter 356 hemisphere, dominant 358 metabolism 296 nerve cells 360, 362, 381 stem (- also medulla oblongata, pons, and midbrain) 328,336 motor centers 342, 346 survival time, anaxla 138 visu.ill areas 346, 376, 378, 380 BrNthllli capadty, maximum (MBC)124

&t126 ras (- also Oa and O>a) 112 mechanics 114 Breast 318, 319 development 320 estroren efRct 318 ~teroneefRct319

prol.ilctin effect 319 enlarrement 320 r-ling319 iodine302 Brightness ch.ilnnel, visU.ill pathways378 Bristle cell, olfactory bulb 362 Broca's are;~ 392 Brodmann's miiP 328 Bronchi392 epithelium 116

Bronchi ( mnt.J innervation 8311. Bronchial mucus 116 tree 198 Bronchiectasis 36 Bronchitis 36, 124 Brown fat 235, 302 Brown-s&juanl syndrome 340 Brunner's glands 258 Brush border 9 f., 162, 166 intestinal mucosa 258 renal tubule 152 stomach, parietal cells 255 BSC (bumetanide-sensitive cotransporter) 170 NH.+ reabsorption 185 BSEP (bile salt export pump) 262,

264 Bll'S (body temperature pressure

saturated) 118 a-BTX (a-bungarotoxin) 50

Buffer 132, 146, 148, 150, 152, 400f. base148 blood 146 concrntration 146, 150 total154 capadty 146, 148 closed systrm 148 ~402B

hemoglobin 132, 136 non-bicarbon.ilte 134, 148, 152 open system 148 titration curve 402 Bulb, ocular 366 Bumetanlde 182 Bundle of His 204 Bundle-branch 212 block212 a-bungarotoxin (a-BTX) 60 Bunsen solubility coefficient 134 Bunte glass burette 120 Bumlng230 Butanol~ble iodine (BEl) 302 Bytr330

c c (submultiple of a unit) 389 C17}C20-Iyase 316 C cells, thyroid gland 306 "C, conversion to 'F 397 ca>+ (-+ also calcium) 38,238, 276 .iibsorpdoo.lntestine 276, 292, 304,306 antagonists 206 A11'ase 17 A, 17 82, 26, 38, 188, 306 heart206

CJil+(cont.) muscle 58 ren.iil 188

billana304 calmodulln-~ndent protein

kinase II 36, 54 cell regul.iltion 38 ch.ilnnels 38, 56, 188, 370 activation 290 ~adrenoceptors 88 hair cells 364 heart muscle 67 83, 69 D, 206 inhibition 88, 290 muscle 56 photosensors 370 regulation 38 ren.ill188 ryanodine-sensitive 206 voltase-gated 206 clotting process 106 complead 304 concentration 54 cytosolic 38, 70, 250 .ildJene!Jic transmission 88 electromechanical coupling 55, 206 epinephrine 91 B exocytnsis 30 extracellular 38, 50 heart206 intracellular 38, 290 muscle 67B smooth 74, 758 norepinephrine 91 B oscillations 38 photosensors 372, 374 muscle fibers 66, 68, 206 neurons 356, 360 serum304 conductance, GABAa receptors 338 daily requirement 238, 304 darkness-induced 372 deficiency 304 equilibrium potential48 excretion 188, 304 exocytosls 30 fat absorption 266 fetal304 free 188, 304 hormone rele.ilse 294 intake304 intestinal absorption 276, 304, 306 intracellular stores 38 Ionized 188, 304 light sensors 374 metabolism 188, 304 milk304 muscle contraction 54 ff

421

ca>+ (cont) /3 Na+ antiport 38 plasma 188, 304 pregnancy 304 prorein bound 188, 302, 304, 306 reabsorption, renal164, 188 paracellular 182 renal excretion 188 saliva 250 sensors 38, 306 kidney188 serum304 smooth muscle 74 solubility 304 store, intracellular 10.38 IP~ 290 myocard206 skeletal muscle 64 third messenger 290 transport, regulation of tubular 188 trigger effect 66 urine 304, 188 Ca2 +and Mg'+ sensor (CaSR) 190 CaBP (calcium-binding protein) 276, 292, 306 Cabrera circle (ECG) 210 Caffeine 290 Caisson disease 142 Cajal cells 254, 258 C~al's horizontal cells, retina 366,376 cal (calorie). unit 396 Calbindin 188, 276, 292, 308 Calcidiol (25-0H-cholecalcit"erol) 166,306 Calciferol238, 306 1,25-{0H)>-calciferol-+ calcitriol Calciol ( • cholecalciferol • vitamin D) 274. 306 Calcitonin 36, 37 C2, 288, 300, 304,306 gene-related peptide (CGRP) 226, 248, 324, 336 Calcitriol (1,25-(0H)a -+ 188 electrolytes 165 D fractional (FE) 160 f. w 150,184 titratable acid 188 HCO! 146, 152 Mgl+ 188 organic substances 165 D, 166,168 phosphate 186 f. steroid hormones 310 urobilinogen 264 water 162, 165 D, 172 glucocorticoid effect 312 extraction fraction 160 filtration 156, 160 amount of a substances 166 dissolved substances 162 equilibrium 160 fraction (FF) 160 pressure, effective 160, 412 function 156 ff. glomerular filtration rate (GFR) 158 glucocorticoid effect 312 glomerulotubular balance glomerulus 156 rr. glucocorticoid effect 312 glutaminase 186 glutamine 186 W+-ATPase 184,193 84 W -All'ase 184 H+ -excretion 150, 184 H+ -secretion 184 handling of amino acids 166 angiotensin 166 cal+ 188, 306 diuretics 164 drugs 164

Kidney (cont.) glucose 166 glucuronides 164 glutathione 166 W152, 184 HCD,- 150, 184 K+ 164, 192 ff. lactate 166 Na+ 164, 170,180 oxalate 166 peptides 166 phosphate 186, 188, 304, 306 proteins 166 urea 174 uric acid 164, 166 inulin clearance 160, 162 juxtaglomerular apparatus 196 juxtamedullary nephrons 158 K+ channels 170 homeostasis 192 Kidney loss 182 loop of Henle 172 Ca1 +-reabsorption 188 Mg'+ reabsorption 188 Na+ transport 170 water permeability 174 medulla 158 medullary blood flow 174, 182 metabolism 158, 296 Mg'+ sensors 188 Na+ channels 182 Na+ -K• -An>ase 162, 164, 170 function 162 nephron types 156, 174 0, consumption 158 PAH clearance 158 pH homeostasis 150, 184 plasma flow 158 potential, transeplthelial164, 170 protein transcytosis 166 P'lH effect 188 reabsorption ca>+ 182,304

c1-11o electrolytes 165 D fractional162 D-glucose 166 HCD,-184 K• 192 Mg'+ 182 Na•170 collecting duct 194 driving force 164 organic substances 165 D, 166 phosphate 188 PTI:I effect 306 water 162, 172 renal failure 150, 186 vitamin D 306

438 Kidney loss (cont) renin 196 se!Rtion 164 K+ 182, 192 orpnic subst.lJJas 168 solvent drag 170 structure 156 tight junctions 162 tnnsport processes 162 ff. 163 B,C tubuloglomerular feedback (TGF) 182 ultrafiltrate 162 UrN 174 Killer cells, mtur.a198, 100 T killer cells 102 Kilo- (multiple of a unit) 395 Kilowatt hour (kWh~ conversion into Sl unit 396 Kinase cascades 288 Kinesia252 Kinesin 46, 62, 66 Kinesin-2 motors 36 Kininogen 106, 226, 250 high-molecular-weiaht (HMK) 106 salivary gland 250 Kinocilium364 Kisspeptin 316 Klotbo 44, 188 Knee jerk reflex 334 Kohlrausch's fold 278 Kohlrausch breu 374 Korotkow sounds 218 Korsalroff syndrome 358 Krebs cycle-+ citrate cycle Krogh's diffusion coefficient 22, 126,410 Krogh's cylinder model138 Kuplfer cells 100, 246 kWh (kilowatt hour), unit 396

L !A.bla minora, alands 326 IA.byrinth 386 basal, tubulus epithelium 162 IA.byrinth reflexes, tonic 346 IA.criiiW tm1liculi 366 glands 366 sac366 IA.ctacidosi$ 76, 80 l.actase272 Lactate 76, 77 82, 78, 150, 184, 296 concentration In plasma 80 gluconeogenesis from 296 musde metabolism 76 myocard metabolism 222 physical work 80 renal reabsorption 164, 166 vagina318

uaatlon 306 relle!x 319 lactic acid-o lactate uaogenesis 319, 320 uaose272 l.amellipodia 30 L-amina adds -+ amino acids Ulldolt rings 371 A l.angerhans cells 100 Language 356, 358, 392 Ullosterol310 uplace's law 124, 200, 214, 222, 412 Large intestine 246, 278 Larynx392 testosterone 324 Literal geniculate body 378, 380 lemniscus 390 signal flow, retina 376 l.ateralization, sound 386 utency, hearing 390 Law of mass actions 401 Laxati~s 276 LCCS (limited capadty control system)356 LCAT (lecithin cholesterol ;K)'l transferase) 268 lDL (low density lipoproteins) 268,270,318 estrogen effect 318 receplllrs 268, 270 L-dopa88 Learning 356 Lecithin 14, 262, 266 bile262 cholesterol ;K)'l transferase (LCAT)268 Left axis (heart) 210 Lemniscus, medlal340 trigeminalis 340 Length, units 394 Lens 366, 368 Leptin 242, 244 receptors 242, 348 Leucine238 Insulin release 296 Leu-fltkephalin 248 Leukocytes 92 interferon secretion 100 Leukotriene 282, 283 allergy104 second messenger 290 Lewl5's response 226 Leydig cells 318, 324 LFA 1 (lymphocyte functionassociated antigen1 ) 102 Ui --+ lutropin UiRH - gonadolibmn liberins282 libido324 lids366 lifespan, maximum 44

Uaht. adithelial potential (LPTP) 190 Luminous intensity, unit 394 Lumirhodopsin 370 Lung(--+ also pulmonary) 112, 114, 116, 118 add base balance 146ff. alveolar contact time 149 B blood flow 112, 128, 198 fetus 232,231 B bronchial, obstruction 126 capadty, total (TCL) 118, 119 A capillaries 112 blood pressure 128 disease, obstructive 124 restrictive 124 edema 124, 126, 128, 140, 152, 182,220 fetal232 function test, dynamic 118, 124 gas exchange 126ff. hypoxic vasoconstriction 128 inflation 124 iron 116, 117A2 O:z diffusion capadty 22 opening pressure 124 perfusion--+ lung, blood flow128 stretch receptors 140

Lung(cont.) surface tension 124 total capacity (TO.) 118 ventilation/perfusion ratio 128 wlumes118ff. measurement 118 If. Lung and thorax compliance 122, 124 pressure-volume relationship 122 Lusitropism 88, 204, 206 Luteal phase 314, 316 Luteinization 316 Luteinizing hormone (LH) --+ lutropin releasing hormone (LTil)--+ gonadollberin Luteotropic hormone (LTH)--+ prolactin Luteotropin (LTH)--+ prolactin Lutropin 283, 294, 310, 324 menstrual cyde 314 peak316 receptor, cells of Leydig 324 secretion, pulsatile 314 cymph flow 220, 221 B intestinal246, 268 nodes 92, 100 ~sels258

cymphocyte function-associated antigen 1 (!.FA1 ) 102 cymphocytes 92, 98 B-98, 102 activation 102 donal selection 102 differentiation 102 donal deletion 98 expansion 98 selection 98 intraepithelial (IEL) 246 naive 98 T-98 •armed" 98, 100 CD4102 CD8102 cytotnxic cells 102 donal expansion 102 selection 102 differentiation 102 naive100 T helper cells 102 THl cells 102 T"' cells 102 T killer cells 98, 102, 246 receptor 102 cymphocytOpoiesis 92 Lymphokine, cortisol312 Lysine 184, 238, 272 intestinal absorption 272 J¥sis, bacterial 98 Lysosomes 12, 14, 26f., 28,300

Lysozyme 98, 100, 246 renal reabsorption 166 saliva 250 tears 366

M ~ (submultiple of a unit) 395 M (multiple of a unit) 395 m (submultiple of a unit) 395 M line, muscle 64 o,-Macroglobulins 110 Macrophages 30, 98, 100, 102, 236,264 activation 100 breakdown of red blood cells 92 hemoglobin degradation 264 immune defense 98, 100 iron metabolism 94 migration 30 respiratory tract 116 Macula densa 156, 182, 196 Maculae364 Magnesium-+ MgZ+ Magnetoencephalography (MEG) 350 Maintenance heat 78 Major histocompatibility complex (MHC) 100, 102 Malabsorption, folic add 94 Maldigestion, enzyme defidt 260 Malplghian bodi6 156 Malleus 386 Maltase 272 Maltose 260, 272 Maltotriose 260, 212 Mammary glands 306 Mammotropic hormone --+ prolactin Manganese (Mn) 238 MannitoL osmotic diuresis 182 Mannose-6-phosphate 12, 14 Mannose-binding protein (MBP) 100 MAO (monoamine oxidase) 90 MAP kinase (mitogen-activated protein kinase) 290 MaiXination 98 Masking, sound 384 Masklike facial expression 344 Mass, units 396 Mass actions, law 401 Mass concentration 398 Mass movement, large intestine 278 Mast cells 110, 270 illlergyt04 Maturation, influence of thyroid hormones 302 sexual314, 324

440 Matrix, extracellular 14 Maximal breathing capacity (MBC)124 Maimum diastolic po~ntial (MDP)204 MBC (nwtim;al breathing capacity) 124 MBP (mannose-binding protein) 100 M cells, mucosal epithelium 246 MCH (mean corpuscular hemoglobin) 92 r. 93 c MCHC (m~ corpusamr hemoglobin concentration) 92, 93C MCV (mean corpuscular volume) 92,93C MDR1 (multiclrus resistance protein 1)264 MDR3264 Measles98 Mechano-electric transduction (•MET)388 Mechanosensors, skin 332, 334 Medial&eniculate body 390 Mediators 282 Medications, bile excretion 262 Medulla, ;adn!na) 286

oblongata 140, 328, 340 cimilatory •center" 226 r!Jythm generator, respiration140 vomiting cen~r 252 MEG (magnetoencephalography) 350

Mega- (multiple or a unit) 395 Megalcacyocyt:es 92, 106, 108 Meiosis324 Meiotic division, spermatDcyte 324 first, ovum 316 second, ovum 326 Meissner's corpusdes 332 Meissner's plexus (plexus submucous) 258 a-Melanocortin (• a-MSH • amelanotropin) 242, 283, 294 Melanocortin receptOr (MC4 receptor) 242 Melanocytes 294 Melanocyte-stimulating hormone -+ melanottOPin a-Melanocyte-stimulating hormone (a -MSH) 242, 283, 294 Melanopsin 352, 370 Melanotropln (a -MSH) 242,283, 294 release-inhibiting factor-+ melanostatin releasing honnone-+ melanoliberin

Melatonin 352 second messenger 288, 290 Membrane basolateral170, 192 capacity, neM! 52 conductance 32 fractional32 electric properties 46, 56 function2 permeability for K• so, 192 influence of cyclic AMP 288 for Na• so, 60, 170 postsynaptic 46, 54 potential32, 48, 52 pbotosensors 376 renal tubule 164 smooth musde 74 presynaptic 46, 54 proteins, glycosylation 12 synthesis 12 structure 14 transport 16ff. active 26f. carrier-mediated 22f. intracellular 16 nonionic22 paracellular 18 passive20 potential. driving force 22,

32 Memory356 immunological 98 knowledge 356 loss356 motoric344 shnrt-term 356,390 Menaquinone (vitamin K.) 274 Menarche 314 Menopause 314, 318 Menses 294, 314f. Menstrual cycle 236, 314, 316, 319 body temperature 236, 314 hormonal control316 interactions 316 Menstruation 294, 314 f. Mercapturic acid 264 Merlcrl's cells 332 Merosin64 Mesencephalon 328 Mesentery 258 Messenger, first(.... ;also hormones) 282, 288 nllonudeic add-+ mRNA second 282, 288 substances 280 third282 MET (- Mechano electric transduction) 388 MET channels 388

Metabolic allcal011is, 150 rate 238, 240 basal (BMR) 238 total238 syndrome 242 Metabolism, amino acids 166 bone 184, 306 carbohydra~ 296, 312 enellY 76, 298 glucose 296, 312 heart222 iron94 lipids 268, 296 musde268 Metarhodopsin 1370 Metarhodopsin 11370, 374 phosphorylation 372 Metastasizatlon 30 Metenkephalin 248 Methane, intestine 278 Methemoglobin (MetHb) 136 reductase 136 Methionine 184, 238 Methotreu~ 274 5-Methyltet:rahydrofolic acid 274 Methopyrapone 310 Metopyrone 310 Mgl• 188, 276, 288 absorption, intestine 276 inhibition or ca•• channels, 54 CNS356 channel (TRPMS. transient receptor potential melastat!n) 190 excretion, ren;aJ 188 functions 304 hormonal control304 metabolism 304 plasma concentration 188 renal reabsorption 164, 182, 188 sensors, kidney 188 mGW-receptors, second messenger 288, 290 MJS0•262 MHC (major histocompatibility romplexrs) tOO MHC proteins 100, 102 MI (cortex area) 342 Micelle, bile 262 intestine 266, 274 Michaelis constant 28 Michaelis-Men~n constant (K.o) 28, 166, 405 f, 410 kinetics 28, 166, 405 (, 410 renal glucose transport 166 Micro- (submultiple or a uolt) 395

Microfilaments 14, 16 Microglia 100, 360 Micrography 344 a,-Microglobulin, ren;al reabsorption 166

441 fl:l-Miaoglobulln. renal reabsorption 166 Micron, conversion into Sl unit 394 Microphone potentials 388 microRNA (miRNA) 8 Microtubules 14, 36 Micturition 83 ff.• 156 Middle ear 386 MIF-+ melanostatin Migrating motor complex (MMC)

254 Migrating wave 388 Migration 30 phagocytes 98 MIH-+ melanostatin Mile, conversion into SI unit 394 Milk 266, 274, 304 (al+ 304 ejection 294, 319 fat266 human, lipase 266 lactation reflex 319 oxytocin 319 production 319 prolactin 319 sugar (lactose) 272 Milli [submultiple of a unit) 395 Mineralocorticoids (-+ also aldosterone) 194,312 production 310 Minetals. intake 238 intestinal absorption 276 nutrition 238 Miniature endplate current 60, 61 B2 Minipill319 Miosis 366, 380 f. miRNA (mlcroRNA) 8 MIT (monoiodotyrosine residue) 300 Mitochondria 12, 302 critical o, pressure 138 skeletal muscle 62, 67 A structure and function 12 effect 302 thermal balance 234 Mitochondrial DNA (mtDNA) 8 Mitral cells, olfactory bulb 362 valves 202 MLCK (myosin light chain kinase) 38 MMC (migrating motor complex) 254 mmHg, conversion into Sl unit 396 Mobilfenin 94 Modification, posttranscriptional 10 posttranslational12, 282 Mol, unit396f. Molality 396 ff.

r,rr.

Molarity 396ff. Mole, unit 396 f. Molecular layer 344, 346 "weight", unlt396f. Molybdenum (Mo) 238 2-Monoacylglycerol 260, 266 Monoamine oxidase (MAO) 90 Monoaminergic pathways system348 Monocytes 92, 98, too Monoiodotyrosine residue (MIT) 300 Mononuclear phagocytotic sys. tern (MPS) 100 Monosaccharides (-+ also glucose)272 Monooxygenases 264 MonoSYnaptic stretch reflex 334 Morning siclcness 252 Morphine 336 tubular transport 168 Moss fiber, cerebellum 346 Motilin254 esophagus 252 interdigestive motility 248 secretion 248 Motility, molecular basis 62 Motion parallax 382 siclcness 252 Motivation, limbic system 348 Motor activity 6011., 334ff~ 342 basal ganglia 342 cerebellum 344 f. influence on cin:ulation 78 pyramidal tract 342 voluntary motor function 342 postural motor control 346 apbasia392 cortex 34211. end-plate 60 function. control center 344 supportive 344 neuron 46, 62 a-338,342 y- 334,338 paralysis 340 proteins 62, 66 system342 unit62, 70 recruitment 62 types 52 Mouth-to-mouth resuscitation 116 Movement, sense of 364 MPS (mononuclear phagocytotic system) 100 MRF-+ melanoliberin MRH-+ melanoliberin mRNA (messenger ribonucleic add)8 MRP2 (multi-drug-resistance protein type 2)168, 264

MSH -+ also melanotropin a-MSH (a-melanocyte-stimulating hormone) 242, 283, 294 mtDNA (mitochondrial DNA) 8 Mucoviscidosis 260 Mucus 116, 250, 258 bronchial116 cervical os 314 intestine 256, 258, 278 neck cells (MNC). stomach 254 saliva250 stomach256 transport 36 MOller's maneuver 122 Multidrug resistance protein 1 (MORt )168, 264 3 (MDR3)264 Multi organ failure 230 Muramidase -+ lysozyme Muscarine 86 Muscle 46, 48, 50, 60 If., 62, 63 A, 268 abdominal 114 activity, heat production 236 ATP76 afterloaded contraction 70 cardiac 50, 204 ff. dliary366 contractile machinery 64 ff. contraction 70 afterloaded 70, 214 auxotonic 70ff. isometric 70 isotonic 70 role of ea•• 68 dllator366 energy supply 76, 268, 297 extensibility 70 titin 72 fatigue 80 fiber64ff, force-velocity diagram 72 hypertrophy 80 inspiratory 114 intercostal114 length-force curve 72 length. regulation 334 mechanical features 70 metabolism 296 middle ear 386 multi-unit type 74 Muscle myofibrlls 64 0. extraction 76 pump216 puporectal278 refiexes334 relaxants 60 respiratory 114, 140 resting length 72 force 72 tension curve 70 single-unit type 74

44:Z Muscle myoflbriiJ (cont) short-tenn high performance 76 slreleU160 ff. smootb74 action potenti1l 63 A caklesmon 74 contraction 74 Ms-I'I!CI!ptDrs 86 softening effect of AlP 68 soreness 80 spindle334 sphincter 366 stapedius 386 stiffness 80 striated(-+ also skeletal muscle, heart muscle) 63 ff. contraction. molecular mechanism 66 cyde68 summation of excitation 70 tension. reiiJ)atlon 334 tensor tympani 386 tone70 typeS of contractions 70 weakness60

Muscular dystrophies 64 Musculus bulbocavemous 326 ischiocav.!IDOUS 326 Myasthenia gnvis 124 Myto~ immune defense 100 Mydriasis 366 M)'elin 46, 52 sheath. nerVI! fibers 46, 52 M)'elopoiesls 92 M)'elosis, funicular 274 Myenteric plexus 258 Myocard .... heart Myocardial function 202 If. infarction 210, 230 metabolism 222 0. consumption 222 oxygen supply 222 Myofibrils64 Myosenic tonus 74 Myoglobin 62, 76, 94, 136 Myometrium -+ uterus Myopalladin 64 Myopia368 Myosin 62, 64 light chain kinue (MLCK) 38 smooth muscle 74 Myosinl30 Myosin-1162, 64 striated muscle 64 rr. smooth muscle 74 Myoam~66

N n (submultiple of a unit) 395 N (newton). unit 396 N (nitrogen). balance 238 N2 dissolved in p~sma 142 role in diving 142 toxldty142 Na• 60, 166, 170, 180, 194, 196, 272,400 absorpdon In intestine 276 antiport curier 26 f. balance, effect of aldosterone 194 bicarbonate cotransporter 3 (=NBC3)184 body content, total180 channels 50, 60, 182, 276, 370 activation 50 collecting duct 170, 192 conductance 50 action potential 50 epithelial (ENaC) 192 inactivation 50 Intestine 276 kidney 170, 182 photosensors 370 resting potential 50 wl~-gated, heart 204 Osymport carrier 26 cona:ntration. cytosolic 26, 48 co-transport 272 distribution 97 excretion. renal 170 feces276 JW antiport carrier (- Na +/If+ exchanger, NHE) 26, 28, 170, 184, 186, 260 exchange carrier .... Na• I H+ antiport carrier kidney 184

PKC290 stomach. parietal ceUs 256 inHux. motor end plate 60 intake, hypertension 228 renal reabsorption 164 handling 170 retention 228 glycyrrhicinic acid 312 saliva 250 symport carrier 26 r. amino acids 212 bile salts 262 a- 28, 110. 182. zso glucose 164(, 272 HC(h- (hNBC} 170, 184 Intestine 276 iodide (NIS) 300 phosphate (NaPi) 188 vitamins 274 transport 48, 170, 180, 280 paracellulu 250 tubular reabsorption 170

Na•-ca•• antiport carrier 38, 206 kidney 188, 194 myocard206 photoseruors 372 Na+-2 a--K• cutransport 250 inhibition 182 kidney 170 saliva 250 Na+-2CI'-K• symporter, parietal celb256 Na•-2ct--K+ carrier (NKCCI) 36, 260

Na•-K•-AlPase (-+ alsoATPase) 26, 28, 50, 192, 256, 302 car~ alycosldes 26, 206 electrogenicity 50 hyperpolarizing afterpotential 50 heart muscle 206 ouabain26 phosphorylation 26 renal collectinS duct 192 tubule 162, 164, 170 resting potential 48 salt reabsorption. intestine 276 ston2ach. parietal cells 256 TsfT• effect 302 transport cycle 26 NaPi-2a (phosphate carrier) 188 Na+-taurochol1te cotransporting polypeptide (NTCP) 262 NaCI. homeostasis 180 disturbances 182 regulation 180 deficiency 180 excess, counter reiiJ)adon 180 hypertension 228 n:absorption, salivaty glands 250 sense of taste 360 uptake 180 NADH41C Nal't (Na•-phosphate symport carrier) 188 nano- (submultiple of a unit) 395 Narcolepsy 356 Natriuretic honnone 180 Natural killer cells 98, 100 Nausea 252, 346 NBC (- Na• -bicarbonate cotransporter) 184, 260 Near point, eye 340, 368 sightedness 368 vision366 response 381, 382 Nebulin64 Neaosis 102 Neclc reflex. tonic 346

Nemaline myopathy 64 Neocerebellum 344 Neostigmine 60 Nephrine156

443 Nephrocaldn 188 Nephron 156, 158 cortical158 juxt.lmedullary 158 sections 156 structure 156 transport processes 162 Nemst equation 32, 48, 410 Nerve(.... also neuron and nervus) 82, 88, 328 antidromic conduction 52 cell46 cholinergic 82, 86 conduction velodty 52 endings, free, smell 362 fiber46,52 diameter 46, 53 C myelinated 46, 52 unmyelinated 46, 52 fibersla334 Ib334 Iia334 glossopharyngeal140 neurosecretory 294 optical366 pelvic splanchnic 326 stimulation 54 structure 46 trigeminal336, 340, 362, 381 Nerve growth factor (NGF) 46, 292,360 NeiVOUS System 46 autonomic 82 If., 85/86 A. 86, 280 centers82 cotrarumitter 90 innervation, organs 82 peripheral280 central280, 328 enteric 248, 280 somatic280 Nervus opticus 366, 381 vagus 140, 256, 262, 392 Net diffusion 20 Neurit46 Neuroendocrine system 280ff., 294ff. Neurofibrils 46 Neurofilaments 14 Neurogenic tonus 74 Neurohypophysis 282, 294 Neuron(-+ also nerve) 46,54 A6336 adrenergic 82 If, 348 axolemma46 axon46 axon hillock 46 axonal transport 46 ca>+ conductance 48 choUnergic 82 If. Cl--conductance 48 collateral$ 46 conduction velocity 52, 53 c

Nfilron (cont.) cortex area 350 dendrites 46 diameter 53 C dopaminergic 344, 348 GABAergic344 glutamatergic 344 Ia- 334, 338, 342 lb- 334 ll-334 intestinal258 internal longitudinal resistance 52 membrane capacity 52 a-motor338 y-motor338 motoric 342, 346 neurosecretory 294 nitrogenergic 292 parasympathetic 82, 86 postganglionic 82, 86 preganglionic 82, 86 sensoric 330 If. serotoninergic 348 soma46 summation, spatial 56 temporal 56 structure 46, 47A1 sympathetic 82, 86, 88 terminal buttons 46 action potential 52 transmission, electrotonic 52 visceral afferent 82, 248, 280 Neuropeptide Y (NPY) 88, 90, 242, 294, 316 cotrarumltter 88 receptor types 59 F second messenger 59 F, 288 Neurosecretion 294 Neurotensin 59 F second messenger 290 Neurotransmitter 46, 54, 56, 59 F, 248,280 autonomic nervous system 8211. excitatory 56 exocytosis54 function46 Inhibitory 56 ionotropic 34, 59 F metabotropic 34, 59 F release 54 re-uptalce 56 termination of action 58 E Neurotubuli 46 Newborn 93 D, 98, 124, 136, 144, 232, 236, 264, 302, 321 distress syndrome 124 respiratory syndrome (NRDS) 124 Newton (N), unit 396 Nexin36

NF-xB (necrosis factor) 290 NGF (nerve growth factor) 46, 292,360 Nih 22, 164, 184, 188 diffusion 22 production 186 renal cellular secretion 164, 184f. renal excretion 184 secretion, renal tubular 186 transpotter 186 NH.,+ 153 B2, 184ff. excretion 186 If, nonionic transport 184 production 186 NHE3--+ Na+ fH+ Antiport carrier 260 Niacin, intestinal absorption 274 Niacinamide 238 Nickel (Ni) 238 Nicotine 86 Nidation 314, 319 NIDDM (non-insulin dependent diabetes mellitus) 298 Nieman-Pick Cl-lilce protein 1 270 Night blindness 238, 372, 374 Nipples, erection 326 NIS (2 Na• -1--symport carrier) 300 Nitric oxide-+ NO synthase (NOS) 86, 292 Nitrogen .... Nand Nz NICCCl (Na+-20--K+ symporter) 26 NM-receptors 86 N..-receptors 86 NO 78, 98, 222, 224, 226, 252, 292 coronary vasodilatation 222 erection 326 immune defense 98 synthase 86, 292 Nociception 336, 338, 340 afferents 336 tract336 Nocisensors 336, 340 Nodal point, ~ 368 Nodes ofRanvier46, 52 Noise suppression, auditory pathway390 Non-bicarbonate buffers 134, 146, 148, 152 f. Non-ionic diffusion 22, 164, 186 Norepinephrine(-+ also catecholarnines) 56, 82, 88, 206, 242, 250, 282, 294, 316 adrenal medulla 90 cerebral cortex 350 coronary vasodilatation 222 extraneuronal uptake 90 heart206 inactivation 90

444 NorepWphrint ( cont) insulin secretion 296 inll!stinal tract 248 neurons348 pbeochromo) 134, 136 fetus 232, 231 A lnftuence on COl binding curve 134 solubility coefficient 136 in pl,uma 134 supply, fetus 232 myocard222 therapy 144 toxicity 142. 144 diving144 transport In blood 136 uptake, exercise 78 maximum 76, 80, 81 C endurance athlet 81 C OAT carriers 282 OATl (organic anion transporter type 1) 168,282 Obeslty242 Ocdudins18 OCT (orpnic cation transporter) 168 Ocular chamber 366 musde, nuclei 364 pressure, intem11338 Oculomotor control344, 347, 364 Ocytodn ~ Oxytocin

Odorant molecules 362 OFF-bipolar Celis 376 fitold (central) 376 ganglion cells 376, 380 OH--Ions 146ff. Ohm (0), unit 397 Ohm's law 32, 122, 200 ion transport 32,410 circulation 200, 410 ventilation 122 Oil-and-water putition coefficient20

445 Olfactory epithelium 362 pathway362 sensor cells, primary 362 sensors36 tract362 Oligodendrocytes 46, 360 Oligopeptides, digestion 272 renal handling 166 Oligosaccharides 272 Oliguria 112 shock230 Olive inferior 346 superior 390 Oncotic pressure 24, 98, 160, 174, 220,400 influence on capillary fluid exchange 220, 401 plasma 160 One-half maximum velocity constant (KM) 28 ON-bipolar cells 376 field (central) 376 ganglion cells 376, 380 Oocyte stage, primary 314 Oogenesis 314 Oogonia 314, 324 Open-probability, ion channels 34 Open system, thermodynamics 42 Opioids 288, 294 endogenous 336 exogenous 336 Gn-RH secretion 316 receptor types 59 F gastointestinal tract 248 second messenger 59 F, 288 Opponent color channel 378 Opsin, s. also scotopsin or photopsin Opsin 370, 372 transport 36 Opsonlzation 98, 100 Optic chiasm 380 nerve 380 lesion380 tract 376, 380 Optical apparatus 366 nerve 366 system, simple 368 Optokinetic nystagmus 382 ORCC (outwardly rectifying clchannel), pancreas duct 260 Orexigenlc effect 244 Orexin 242 Organ of balance 382 Corti386 Organelles 8 Organs, blood flow 197 A. 224, 226 fetus231 A transplanted 102

Organum vasculosum laminae terminalis (OVL11 294, 328, 348 Orgasm326 Orgasmic cuff 326 Ornithine 272 Orthopnea 114 Orthostasis 5 C. Sf., 216, 228 Orthostatic hypotension 194 reflex 7 E, 216, 228 Oscillation, unstable 6 Osmol399 Osmolality, blood pressure 96 unit399 urine 172, 182 Osmolarity 399 saliva250 unit399 Osmolytes, organic 178 Osmometer 399 Osmoregulation 178 Osmosensors 178, 286, 348 Osmosis 24 Osmotic coefficient 399 ff. diuresis 182, 186 effect on K• excretion 194 pressure 24, 399 colloidal96, 399 Ossicles, auditoiY 386 Osteoclasts 304, 306 Osteolysis, malignant 306 Osteomalacia 306 Osteoporosis 318 Otoliths364 ouabain 26, 180 Ounce, conversion into S! unit 396 OUter ear 386 OUtwardly rectifYing a- channel (ORCC), pancreas duct 260 Oval window 386, 388 Ovaries 268, 282, 310, 314, 324 HDL receptor 268 menstrual cycle 314 pregnancy 320 production, fertiliziable egg 314 testosterone production 324 Overshoot, action potential 50 Overtone 384 Overweight 238, 242 OVLT (organum vasculosum laminae terminalis) 178, 294, 328,348 Ovulation 314, 316, 318 antiovulatoiY effect 319 inhibitors 316 Ovum 314, 318 first meiotic division 316 second meiotic division 326 implantation 314, 319 Oxalate 106, 166, 168, 276

Oxalate (oont.) inhibition, blood clotting 106 renal secretion 166, 168 Oxidation, biological molecules 43 of glucose, aerobic 76 ~-oxidation 270 2-{IXOglutarate 186 ~-oxybutyric acid (298 Oxygen --+ Oz Oxygenation 136 Oxyntic cells --+ parietal cells Oxytocin 180, 283, 288, 294, 319, 320,322 receptors 59 F second messenger 59 F, 288, 290 social behavior 294, 322 uterus 320, 326

p P --+ progesterone P... (half saturation pressure) 136 PA (alveolar pressure) 114 p5344 P sensors 332 P (multiple of a unit) 395 p (submultiple of a unit) 395 P wave, ECG 208 Pa (Pascal), unit 396 Pacemaker 74, 254 cells, kidney 156 heart 204, 206, 212 artifidal212 tertia!)' 204 ventricular 204, 212 intestine, motility 258 potential, heart 204 stomach254 Pacinlan corpuscles 332 PAF (platelet-activating factor) 104,106 PAl:!--+ p-aminohippurate PAI-1 (plasminogen activator inhibitor) 108 pancreas 260 Pain 336, 338, 340 assessments 336 components 336 post-exercise muscle ache 81 D related behavior 336 Palaeocerebellum 344 Pallidum 328, 344 Pancreas 246, 260 cell types 296, 298 enzymes260 exocrine 260 gastrin release 266 hormones 296, 298 islets 282

446 Pancn!IIS (cont.) juice 260, 266 sonutDstatin 298 Pancreatic li~ 266 necrosis, acute 260 polypeptide (PP) 296

secretions 260 Pantothenic add 238 Papilla nervi optic! 366, 380 Para-aminohlppurate (PAH) 158, 168 Paraa!llin-1 190 Paracellular transport 162 Paraaine action of hormones 296 Paraflocculus 344 Parallel libel"$, cerebellum 346 Paralysis 66 dissociated 340 Paraplegia 338, 346 Parasites, defense aplnst 98 Parasympathetic fibers, aenitil tract226 heart 206 innervated ortans 86 gallJ)ia 82 If. nervous system, pstrolnrestin;al tract 248 saliva secretion 250 stimuli, salivary glands, blood flow226 Paralhonnone ..... paralhyrin Parathyrin (l'JH) 38, 39 0 , 188, 304 c;alcitriol306 chernlstty 304 deficiency 304 elfects304 innuence on c.a•• and phosphate excretion 188 regulation 304 ren;al c.a>+ reabsorption 188 Parathyroid alands, 282 304 honnone .... parathyrin Paravertebral ganglionic chain 82 Parkinson disease 344 Pariet;al cells, gastric 254, 256 Parotid glands 250 Pars recta, renal tubule 156 Partial pressure 18, 112, 126 Oilton law 112 Parvalbumin, muscle fibers 68 Pascal (Pa). unit 396 PAS doiiWns 352 Passivoe immunization 98 Patch-clamp technique 34 Pattern retOJnitlon receptOrs (PRRs) 100

Pause, compensatory212 post-extrasyStollc 212 PBI-+ iodine PCT (proximal co111/Qluted tubule) 172

PDGF (platelet~erived growth factor) 1116, 292 PD-Sensors 330, 332 Peak expiratory pressure 122 inspiratory pressure 122 Pendrin 184 Pendular movements. intestine motitity258 nystagmus 346 Penicillin, tubular secretion 164 Penis326 erection 292 REM sleep 352 Pepsin 252, 256, 272 Pepsinogrns 256, 272 PepTl (peptide transporter 1), intestine 272 PepT2, kidney 166 Peptidase 166, 256, 260, 272 Peptide(s), catabolism, renal 156 carrier PepTl 272 PepT2166 digestion 272 hormones 282, 288, 320 placenta 320 messenger 288 renal reabsorption 164, 166 handling 136 transmittEr 59 F Peptide-H• -symport carrier 28, 166,272 PER352 Perception, visual 330 color378 fonn332 shape332 spati.al nature 332 Perfusion, cerebm 198 pulmonary 126 imbalance 126, 128, 138 Performance limit 80 Periglomerular cells 362 Perilymph 386, 388 Perimeter 380 Peripheral resistance 200, 218 influence on heart function 218 Peristalsis 248 esophaius 252 intestine 258 large278 stomach254 ureter156 Permeability, ca>+ 86

a-48 coefficient (P) 22 K• 48,60,86

Na· 48, 60, 86 Peroxidase thyroid (TPO) 300 Peroxisomes 14 Perspiratio insensibilis 234

Perspiration 234 water losses 176 Pertussis toxin 290 Peta- (multiple of a unit) 395 ~·s patches 246 pH 146, 154, 400 blood 140, 146 buffer146 normal range 150 cerebrospinal ftuid 134. 140 clearance, esophaiuJ 252 erythrocytes 134 esophagus 252 homeostasis, kidney 184 role of liver 186 inftuence on diffusion 22 on protein bound c.a>+ 304 measurement 154 plasma134, 144, 146, 150 K• metabolism 192 saliv. 250 tubule lumen 184 urine164 Phagocytes 98 J>baaocytosis 12, 28, 100 Phase, wlnerabte, heart 212 Phenol red, tubular secretion 168 Phenprocournon 110 Phentolamine 88 Phenylalanine 238 Phenylephrine 91 B Phenylethanolamine-N-metbyltransferase 88 Pheochromocytoma 228 Phon384 Phosducln 372, 374 Phosphatase 290 alkal!ne264 Phosphate 146, 166, 185, 188, 304,306 absorption. intestine 276 blood buffer 146 calcium complex fanner 188 carriers 188 concentration, serum 304 delidency 188, 306 DNA8 excess188 excretion 186, 188, 306 w secretion 186 homeostasis 304 intake 304 intestinal absorption 306 metabolism 304 plasma304 ren;al reabsorption 166 solubility 304 Phosphatidylcholine (lecithin) 14,262,266 b!le262 inositol-4,5-bisphosphate (PIP,)290

447 Phosphatidylethanolamine 14 Phosphatidylserine 14 Phosphaturia 188 Phosphodiesterase 290, 370, 372 cGMP-specific 292 Phospholipase A, 260, 266, 336 Phospholipase qi (PI.Cjl) 39 Ct, 86, 88,290 Phospholipids 266, 268 blood clotting 105 lipoproteins 268 cell membrane 14 Phosphoric acid(--+ also phosphate) 150, 184 Phosphorylation 288 Photochemistry, eye 370 Photosensors 366, 368, 370 retinal distribution 370 sensor potential376 Photopic vision 370 Photopsin 372 Phyllochinone 274 Physical activity 76 ff. energy reserve 296 exercise capadty 80 core temperature 236 energy supply 238 heat production 234 measure 78 measurement 80 work 76ff., 150, 296 activation of the sympathetic nervous system 78 heat production 234 O:z consumption 78 threshold, aerobic 80 anaerobic 80 ventilation 78 respiratory control 78, 141 A5 unit396 Physiological integration 280 Phytin 276 Pico- (submultiple of a unit) 395 PIF --+ prolactostatin Pigmented epithelium 366 PIH (prolactin-release inhibiting hormone) --+ dopamine Pill, the 316 Pineal body (- pineal gland epiphysis) 352 Pinocytosis 28 PIP, (!nositol-4,5-b!sphnsphate) 290 Pirenzepine 86 Pituitary gland 294, 300 anterior 282, 294 influence of neurotransmitters 294 TSH secretion 300 TKH receptors 300 hormones 282

Pltultt:uy gland (cont) posterior 192, 282, 294 ADH secretion 180 hormone secretion 294 testosterone effect 324 pK. value 146, 148, 400f. PKA (protein kinase A - A kinase) 88,288 PKC (proteinldnase C) 38, 39 Ct, 74, 88,290 PKG (proteinldnase G) 292 PKK (prekallikrein) 106 Placenta 104, 232, 306, 318, 320 Placental barrier, function 320 hormones 320 immunoglobulins 96 transfusion 232 Plasma 92, 96 albumin96 cells98, 102 COa132 components 92, 96 factors 104 globulins 96 osmolality 96, 179 proteins 92, 96, 162, 166, 399 f. binding 24, 25 C. 92, 162 eaa+ 188, 304 blood puffer 146 function 92, 96, 399 f. types96 pH 134 thromboplastin antecedent (PTA) 106 volume 180 measurement 176 salt defidency 180 Plasmin 110 Plasminogen 110 Plasminogen activator inhibitor (PAI-l) 108 Plastidty of smooth muscle 74 pyramidal cells 350 Platelet(s) (-+also Thrombocytes) 92, 106, 108, 232 activating factor (PAF) 104, 106 activation 106 aggregation 106 inhibitors 110 derived growth factor (PDGF) 106,292 formation of 108 Platelet factor 4 108 PLC (Phospholipase C) 39 C1, 86, 88,290 Plethysmography 120 Pleura 114 pressure (P,J) 114 Plexus !Il)'l!ntericus (Auerbach) 248,258 submucous (Meissner) 248, 258

PMA (premotor area) 342 Pneumothorax 116 diving142 typeS 116 POdocytes, glomerulus 156 POikilothermy 234 POint,low76 POlkissen 196 POl~thylene glycol, intestine 276 POlypeptide, pancreatic 296 POlyribosomes 10 POlysaccharides, chemical structure 2378 digestion 272 POlysomes 10 POlysynaptic reflexes 338 POlyuria 172 POMC (pro-opiomelanocortin) 242,294 placenta 320 POund, conversion into Sl unit 396 POns 140, 328 eye movement 382 POntocerebellum 344 Porphyrin 136 Portal circulation 246, 262 hypothalamus 294 vein 220, 246 Partial thromboplastin time (PTT)409 Positive pressure ventilation continuous (CPPV) 116 intermittent (IPPV) Postcentral gyrus 340 Posterior funiculus, nudei 340 Postextrasystolk pause 212 Postsynaptic inhibition 338 membrane 46, 54 Posttranslational modification 10,12 Posttransscriptional modification 12 Postural control346 motor function 342, 344, 346,

364 system342 reflex346 labyrinthine 346 Posture 342, 346 maintaining 342 Potassium -+ K+ Potentia coeundi 324 Potential, action 50 52 unit397 difference 397 diffusion 48 electrochemical32 end-plate 60 equilibrium 48 excitatory postsynaptic (EPSP) 56,60,338 inhibitory pre5YDaptic (IPSP) 56,86,350

rr..

448 l'olrlllfa~ acdon (cont)

maximum diastolic. heart pacemakrr 204 readiness 342 rnting membrane 48 rew!rsal 51 B, 60 threshold 50, 52 tnnsepithellal 164, 192 lul'llen-neptive (lNTP) 170, 250,276

lumen-positive (LPTP) 170, 182, 188, 192 Potentials, microphone 388 Pound, conversion into Sl unit 396 Power, unit 396 Powers of ten, calculation with 402f. PP (pube pressure) 206, 218 PP (pancreatic polypeptide) 296 ppb (parts per billion), unit 398 ppm (parts per million), unit 398 P,t (pleural pressure) 114 PQ.interval, ECG 208 PQ. segment, ECG 208 Prader-Willi syndrome 242, 244 Pnzosin 91 B Prealbumin, thyroxin-binding ('tBPA) 302 Precapillary sphincter 200 Pregnancy 94, 274, 304, 306, 316, 318 CaH304 central venous pressure 216 hormone concentrations 318 hormonal control320, 348 nausea252 Rh system 104 tests 310, 320 vitamin D-bindlng protein 306 vomiting 252 Pregnanediol310, 319, 320 Pregnenolone 310, 319 17-0H310 Prebllikrein (PKK) 106 Preload, hNrt 214, 216 Preporential, heart 204 Preproinsulin 296 Presbyacusis 384, 388, 392 Presbyopia 368 Presentation of antigens 100 Pressure (unit) 396 Pressure arterial sensors 226 capillary220 central venous (CVP) 202, 216 colloidal osmotic 400 diuresis 180, 182 hydrostatic 220 ree~220

Internal ocular 366 intrapleural114 intrapulmonic 114

Pressure artmal smson (amt)

intrathoracic 114 oncotic 24, 220, 174, 400 peritubularcapillilrles 174 plasma 160 osmotic 24, 400 transmural200 transpulmonary 114 transthoracic 114 ventricular 202. 214 volume Clll'W!, hsrt 72 lung and thorax 122 wave, pube wave 202 Pressosensors, arterlal332 skin Prestin388 Presynaptic inhibition 338 membrane 46, 54 Prerectal region 381 Previtamln D 306 Primary, response, antigen contact 98 saliva 250 urine 172 Principal cells, kidney 170, 192 point, optical apparatus 368 PRL .... prolactin Proacalerln 106 Probenecid 168 Procarbaxypeptida2 260 Process. ciliary 366 Procollpase 260, 266 Proconllm:in 106 Procreative capacity 324 Proelastase 260 Progesterone 140, 310, 314, 316, 319,320 actions 306, 319, 320 chemistry 319 degradation 319 esophagus sphincter 252 menstrual cycle 314 17-0H- 310 placenta 320 plasma concentration 318 transport319 production 310, 319 respiration 140 secretion rate 319 Proglucagon 298 intestinal296 Proinsulin 294, 296 Prolactin 282, 283, 288, 294,319, 322,324 lactation reflex 319 menstrual cycle 314 receptor292 release inhibiting hormone .... prolactostatin 282ff., 294, 314,319 secretion, pulsatile 314 TRH effect 319

Prolactostatin (PIH • dopamine) 282 If., 294, 314, 319 Proliferition 286 lymphocyteS 98 Prollrerative phase, menstrual cycle314 Prollpase 260 Pro-opiomelanoaxtin (POMC) 242, 294, 320 Pro-phospholipase A2 266 Proponlo.W sensors 330, 332, 334 Proprioception 332, 334, 340 Proprlosensors 334, 342 neck346 Prostu:yclln (PGh) 110, 226, 282, 283 Prostaglandln(s) (PG) 170, 246, 248, 256, 282, 288, 290 autoregulation 224 Ea226, 336 rever 236 effects 283 F,.a- 226 retal circulation 232 H001- secretion, stomach 256 h (Prostacyclin) 110, 226, 282, 283

coronary vasodilatation 222 intestine 276 prostate 326 second messenger 288, 290 synthesis 283 inhibition 283, 336 uterus 320, 326 Prostate 324, 326 Protanomaly 378 Protanopia 378 Proteases, pancreatic juice 260, 272 Protective reflexes 252, 338 Protein etta s 110 Protein 162, 156, 238, 240 absorption, intestine 272 binding 24, 162 bound Iodine 300, 302 caloric equivalent 240 capillary permeability 220 catabolism. renal 156 chemical structure 239 B concentration in cerebrospinal fluid 152 digestion 260, 272 enzymes 256, 260 energy supply 240 filtrability, glomerulus 162 functional minimum 238 hormones 282 kinase A (PI