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(BQ) Part 1 book Review of medical physiology presents the following contents: Introduction, physiology of nerve and muscle cells, functions of the nervous system, endocrinology, metabolism and reproductive function.
Standard Atomic Weights Based on the assigned relative mass of C = 12 For the sake of completeness, all known elements are included in the list Several of those more recently discovered are represented only by the unstable isotopes In each case, the values in parentheses in the atomic weight column are the mass numbers of the most stable isotopes 12 Name Symbol Atomic No Atomic Weight Valence Name Symbol Atomic No Atomic Weight Valence Actinium Aluminum Americium Antimony (stibium) Argon Arsenic Astatine Barium Berkelium Beryllium Bismuth Boron Bromine Cadmium Calcium Californium Carbon Cerium Cesium Chlorine Chromium Cobalt Columbium (see Niobium) Copper Curium Dysprosium Einsteinium Erbium Europium Fermium Fluorine Francium Gadolinium Gallium Germanium Gold (aurum) Hafnium Helium Holmium Hydrogen Indium Iodine Iridium Iron (ferrum) Krypton Lanthanum Lawrencium Lead (plumbum) Lithium Lutetium Magnesium Manganese Mendelevium Ac Al Am Sb 89 13 95 51 227.028 26.9815 (243) 121.75 3,4,5,6 3,5 Hg 80 200.59 1,2 Ar As At Ba Bk Be Bi B Br Cd Ca Cf C Ce Cs Cl Cr Co 18 33 85 56 97 83 35 48 20 98 58 55 17 24 27 39.948 74.9216 (210) 137.33 (247) 9.0122 208.980 10.81 79.904 112.41 40.08 (251) 12.011 140.12 132.9054 35.453 51.996 58.9332 3,5 1,3,5,7 3,4 3,5 1,3,5,7 2 2,4 3,4 1,3,5,7 2,3,6 2,3 Mo Nd Ne Np Ni Nb 42 60 10 93 28 41 95.94 144.24 20.1179 237.0482 58.69 92.9064 3,4,6 4,5,6 2,3 3,5 N No Os O Pd P Pt Pu Po K 102 76 46 15 78 94 84 19 14.0067 (259) 190.2 15.9994 106.42 30.9738 195.08 (244) (209) 39.0983 3,5 2,3,4,8 2,4,6 3,5 2,4 3,4,5,6 Cu Cm Dy Es Er Eu Fm F Fr Gd Ga Ge Au 29 96 66 99 68 63 100 87 64 31 32 79 63.546 (247) 162.50 (252) 167.26 151.96 (257) 18.9984 (223) 157.25 69.72 72.59 196.967 1,2 3 2,3 1 2,3 1,3 Pr Pm Pa Ra Rn Re Rh Rb Ru Sm Sc Se Si Ag 59 61 91 88 86 75 45 37 44 62 21 34 14 47 140.908 (145) 231.0359 226.025 (222) 186.207 102.906 85.4678 101.07 150.36 44.9559 78.96 28.0855 107.868 3 3,4,6,8 2,3 2,4,6 Na 11 22.9898 Hf He Ho H In I Ir Fe 72 67 49 53 77 26 178.49 4.0026 164.930 1.0079 114.82 126.905 192.22 55.847 3 1,3,5,7 3,4 2,3 Sr S Ta Tc Te Tb Tl Th Tm Sn 38 16 73 43 52 65 81 90 69 50 87.62 32.06 180.9479 (98) 127.60 158.925 204.383 232.038 168.934 118.71 2,4,6 6,7 2,4,6 1,3 2,4 Kr La Lr Pb 36 57 103 82 83.80 138.906 (260) 207.2 2,4 Ti W 22 74 47.88 183.85 3,4 Li Lu Mg Mn Md 71 12 25 101 6.941 174.967 24.305 54.9380 2,3,4,6,7 (258) Mercury (hydrargyrum) Molybdenum Neodymium Neon Neptunium Nickel Niobium (columbium) Nitrogen Nobelium Osmium Oxygen Palladium Phosphorus Platinum Plutonium Polonium Potassium (kalium) Praseodymium Promethium Protactinium Radium Radon Rhenium Rhodium Rubidium Ruthenium Samarium Scandium Selenium Silicon Silver (argentum) Sodium (natrium) Strontium Sulfur Tantalum Technetium Tellurium Terbium Thallium Thorium Thulium Tin (stannum) Titanium Tungsten (wolfram) Uranium Vanadium Xenon Ytterbium Yttrium Zinc Zirconium U V Xe Yb Y Zn Zr 92 23 54 70 39 30 40 238.029 50.9415 131.29 173.04 88.9059 65.39 91.224 4,6 3,5 2,3 Modified and reproduced, with permission from Lide DR (editor-in-chief): CRC Handbook of Chemistry and Physics, 83rd ed CRC Press, 2002–2003 a LANGE medical book Review of Medical Physiology twenty-second edition William F Ganong, MD Jack and DeLoris Lange Professor of Physiology Emeritus University of California San Francisco Lange Medical Books/McGraw-Hill Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Deli San Juan Seoul Singapore Sydney Toronto Review of Medical Physiology, Twenty-Second Edition Copyright © 2005 by The McGraw-Hill Companies, Inc All rights reserved Printed in the United States of America Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written permission of the publisher Previous editions copyright © 2003, 2001 by The McGraw-Hill Companies, Inc.; copyright © 1999, 1997, 1995, 1993, 1991, by Appleton & Lange; copyright © 1963 through 1989 by Lange Medical Publications 1234567890 DOC/DOC 098765 ISBN 0-07-144040-2 ISSN 0892-1253 Notice Medicine is an ever-changing science As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required The author and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication However, in view of the possibility of human error or changes in medical sciences, neither the author nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work Readers are encouraged to confirm the information contained herein with other sources For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration This recommendation is of particular importance in connection with new or infrequently used drugs The book was set in Adobe Garamond by Rainbow Graphics The editors were Janet Foltin, Harriet Lebowitz, and Regina Y Brown The production supervisor was Catherine H Saggese The cover designer was Mary McKeon The art manager was Charissa Baker The index was prepared by Katherine Pitcoff RR Donnelley was printer and binder This book is printed on acid-free paper Contents Preface xi SECTION I INTRODUCTION 1 The General & Cellular Basis of Medical Physiology Introduction Transport Across Cell Membranes 28 General Principles The Capillary Wall 35 Functional Morphology of the Cell Intercellular Communication 36 Structure & Function of Homeostasis 48 DNA & RNA 18 Aging 48 Section I References 49 SECTION II PHYSIOLOGY OF NERVE & MUSCLE CELLS 51 Excitable Tissue: Nerve Introduction 51 Properties of Mixed Nerves 60 Nerve Cells 51 Nerve Fiber Types & Function 60 Excitation & Conduction 54 Neurotrophins 61 Ionic Basis of Excitation Neuroglia 63 & Conduction 58 51 Excitable Tissue: Muscle Introduction 65 Cardiac Muscle 78 Skeletal Muscle 65 Morphology 78 Morphology 65 Electrical Properties 78 Electrical Phenomena Mechanical Properties 78 & Ionic Fluxes 68 Metabolism 81 Contractile Responses 68 Pacemaker Tissue 81 Energy Sources & Metabolism 74 Smooth Muscle 82 Properties of Skeletal Muscles Morphology 82 in the Intact Organism 75 Visceral Smooth Muscle 82 Multi-Unit Smooth Muscle 84 65 Synaptic & Junctional Transmission Introduction 85 Principal Neurotransmitter Systems 94 Synaptic Transmission 85 Synaptic Plasticity & Learning 116 Functional Anatomy 85 Neuromuscular Transmission 116 Electrical Events in Postsynaptic Neuromuscular Junction 116 Neurons 88 Nerve Endings in Smooth & Cardiac Inhibition & Facilitation Muscle 118 at Synapses 91 Denervation Hypersensitivity 119 Chemical Transmission of Synaptic Activity 94 85 iii iv / CONTENTS Initiation of Impulses in Sense Organs 121 Introduction 121 Generation of Impulses in Different Nerves 123 Sense Organs & Receptors 121 “Coding” of Sensory Information 124 The Senses 121 Section II References 127 SECTION III FUNCTIONS OF THE NERVOUS SYSTEM 129 Reflexes 129 Introduction 129 Polysynaptic Reflexes: The Withdrawal Reflex 134 Monosynaptic Reflexes: General Properties of Reflexes 137 The Stretch Reflex 129 Cutaneous, Deep, & Visceral Sensation 138 Introduction 138 Temperature 142 Pathways 138 Pain 142 Touch 141 Other Sensations 147 Proprioception 142 Vision 148 Introduction 148 Responses in the Visual Pathways & Cortex 160 Anatomic Considerations 148 Color Vision 163 The Image-Forming Mechanism 152 Other Aspects of Visual Function 166 The Photoreceptor Mechanism 156 Eye Movements 168 Hearing & Equilibrium 171 Introduction 171 Hearing 176 Anatomic Considerations 171 Vestibular Function 183 Hair Cells 175 10 Smell & Taste 185 Introduction 185 Taste 188 Smell 185 Receptor Organs & Pathways 188 11 Alert Behavior, Sleep, & the Electrical Activity of the Brain 192 Introduction 192 Evoked Cortical Potentials 193 The Thalamus & the Cerebral The Electroencephalogram 194 Cortex 192 Physiologic Basis of the EEG, Consciousness, The Reticular Formation & the Reticular & Sleep 196 Activating System 192 12 Control of Posture & Movement 202 Introduction 202 Spinal Integration 207 General Principles 202 Medullary Components 210 Corticospinal & Corticobulbar Midbrain Components 211 System 203 Cortical Components 212 Anatomy & Function 203 Basal Ganglia 213 Posture-Regulating Systems 206 Cerebellum 217 CONTENTS / v 13 The Autonomic Nervous System 223 Introduction 223 Chemical Transmission at Autonomic Anatomic Organization of Autonomic Junctions 223 Outflow 223 Responses of Effector Organs to Autonomic Nerve Impulses 226 14 Central Regulation of Visceral Function 232 Introduction 232 Relation to Cyclic Phenomena 235 Medulla Oblongata 232 Hunger 235 Hypothalamus 233 Thirst 240 Anatomic Considerations 233 Control of Posterior Pituitary Secretion 242 Hypothalamic Function 234 Control of Anterior Pituitary Secretion 248 Relation to Autonomic Function 234 Temperature Regulation 251 Relation to Sleep 235 15 Neural Basis of Instinctual Behavior & Emotions 256 Introduction 256 Other Emotions 259 Anatomic Considerations 256 Motivation & Addiction 260 Limbic Functions 256 Brain Chemistry & Behavior 261 Sexual Behavior 257 16 “Higher Functions of the Nervous System”: Conditioned Reflexes, Learning, & Related Phenomena 266 Introduction 266 Learning & Memory 266 Methods 266 Functions of the Neocortex 272 Section III References 276 SECTION IV ENDOCRINOLOGY, METABOLISM, & REPRODUCTIVE FUNCTION 279 17 Energy Balance, Metabolism, & Nutrition 279 Introduction 279 Protein Metabolism 292 Energy Metabolism 279 Fat Metabolism 298 Intermediary Metabolism 282 Nutrition 311 Carbohydrate Metabolism 285 18 The Thyroid Gland 317 Introduction 317 Effects of Thyroid Hormones 323 Anatomic Considerations 317 Regulation of Thyroid Secretion 326 Formation & Secretion Clinical Correlates 328 of Thyroid Hormones 317 Transport & Metabolism of Thyroid Hormones 321 19 Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism 333 Introduction 333 Fate of Secreted Insulin 335 Islet Cell Structure 333 Effects of Insulin 336 Structure, Biosynthesis, & Secretion Mechanism of Action 338 of Insulin 334 Consequences of Insulin Deficiency 340 vi / CONTENTS Insulin Excess 344 Regulation of Insulin Secretion 345 Glucagon 348 Other Islet Cell Hormones 350 Effects of Other Hormones & Exercise on Carbohydrate Metabolism 351 Hypoglycemia & Diabetes Mellitus in Humans 353 20 The Adrenal Medulla & Adrenal Cortex 356 Introduction 356 Physiologic Effects of Adrenal Morphology 356 Glucocorticoids 369 Adrenal Medulla 358 Pharmacologic & Pathologic Effects Structure & Function of Medullary of Glucocorticoids 370 Hormones 358 Regulation of Glucocorticoid Regulation of Adrenal Medullary Secretion 372 Secretion 361 Effects of Mineralocorticoids 375 Adrenal Cortex 361 Regulation of Aldosterone Secretion 377 Structure & Biosynthesis of Role of Mineralocorticoids in the Adrenocortical Hormones 361 Regulation of Salt Balance 380 Transport, Metabolism, & Excretion Summary of the Effects of of Adrenocortical Hormones 366 Adrenocortical HyperEffects of Adrenal Androgens & Hypofunction in Humans 380 & Estrogens 368 21 Hormonal Control of Calcium Metabolism & the Physiology of Bone 382 Introduction 382 The Parathyroid Glands 390 Calcium & Phosphorus Metabolism 382 Calcitonin 393 Bone Physiology 383 Effects of Other Hormones & Humoral Agents on Vitamin D & the Calcium Metabolism 395 Hydroxycholecalciferols 387 22 The Pituitary Gland 396 Introduction 396 Physiology of Growth 404 Morphology 396 Pituitary Insufficiency 408 Intermediate-Lobe Hormones 397 Pituitary Hyperfunction in Humans 409 Growth Hormone 398 23 The Gonads: Development & Function of the Reproductive System 411 Introduction 411 Gametogenesis & Ejaculation 424 Sex Differentiation & Development 411 Endocrine Function of the Testes 428 Chromosomal Sex 411 Control of Testicular Function 431 Embryology of the Human Abnormalities of Testicular Function 433 Reproductive System 413 The Female Reproductive System 433 Aberrant Sexual Differentiation 414 The Menstrual Cycle 433 Puberty 418 Ovarian Hormones 438 Precocious & Delayed Puberty 420 Control of Ovarian Function 444 Menopause 421 Abnormalities of Ovarian Function 447 Pituitary Gonadotropins & Prolactin 421 Pregnancy 448 The Male Reproductive System 424 Lactation 451 Structure 424 CONTENTS / vii 24 Endocrine Functions of the Kidneys, Heart, & Pineal Gland 454 Introduction 454 Hormones of the Heart & Other Natriuretic The Renin-Angiotensin System 454 Factors 460 Erythropoietin 459 Pineal Gland 462 Section IV References 465 SECTION V GASTROINTESTINAL FUNCTION 467 25 Digestion & Absorption 467 Introduction 467 Lipids 473 Carbohydrates 467 Absorption of Water & Electrolytes 475 Proteins & Nucleic Acids 471 Absorption of Vitamins & Minerals 477 26 Regulation of Gastrointestinal Function 479 Introduction 479 Exocrine Portion of the Pancreas 497 General Considerations 479 Liver & Biliary System 498 Gastrointestinal Hormones 482 Small Intestine 504 Mouth & Esophagus 488 Colon 508 Stomach 491 Section V References 512 SECTION VI CIRCULATION 515 27 Circulating Body Fluids 515 Introduction 515 Red Blood Cells 532 Blood 515 Blood Types 537 Bone Marrow 515 Plasma 539 White Blood Cells 516 Hemostasis 540 Immunity 520 Lymph 546 Platelets 531 28 Origin of the Heartbeat & the Electrical Activity of the Heart 547 Introduction 547 Cardiac Arrhythmias 554 Origin & Spread of Cardiac Electrocardiographic Findings in Other Cardiac Excitation 547 & Systemic Diseases 561 The Electrocardiogram 549 29 The Heart as a Pump 565 Introduction 565 Cardiac Output 570 Mechanical Events of the Cardiac Cycle 565 30 Dynamics of Blood & Lymph Flow 577 Introduction 577 Capillary Circulation 590 Functional Morphology 577 Lymphatic Circulation & Interstitial Fluid Biophysical Considerations 581 Volume 593 Arterial & Arteriolar Circulation 587 Venous Circulation 595 31 Cardiovascular Regulatory Mechanisms 597 Introduction 597 Systemic Regulation by Hormones 600 Local Regulation 597 Systemic Regulation by the Nervous System 602 Substances Secreted by the Endothelium 598 viii / CONTENTS 32 Circulation Through Special Regions 611 Introduction 611 Brain Metabolism & Oxygen Cerebral Circulation 611 Requirements 619 Anatomic Considerations 611 Coronary Circulation 620 Cerebrospinal Fluid 612 Splanchnic Circulation 623 The Blood-Brain Barrier 614 Cutaneous Circulation 625 Cerebral Blood Flow & Placental & Fetal Circulation 627 Its Regulation 616 33 Cardiovascular Homeostasis in Health & Disease 630 Introduction 630 Inflammation & Wound Healing 635 Compensations for Gravitational Shock 636 Effects 630 Hypertension 641 Exercise 632 Heart Failure 643 Section VI References 644 SECTION VII RESPIRATION 647 34 Pulmonary Function 647 Introduction 647 Gas Exchange in the Lungs 660 Properties of Gases 647 Pulmonary Circulation 661 Anatomy of the Lungs 649 Other Functions of the Respiratory System 664 Mechanics of Respiration 650 35 Gas Transport Between the Lungs & the Tissues 666 Introduction 666 Carbon Dioxide Transport 669 Oxygen Transport 666 36 Regulation of Respiration 671 Introduction 671 Chemical Control of Breathing 672 Neural Control of Breathing 671 Nonchemical Influences on Respiration 678 Regulation of Respiratory Activity 672 37 Respiratory Adjustments in Health & Disease 681 Introduction 681 Hypercapnia & Hypocapnia 692 Effects of Exercise 681 Other Respiratory Abnormalities 692 Hypoxia 683 Diseases Affecting the Pulmonary Circulation 694 Hypoxic Hypoxia 684 Effects of Increased Barometric Pressure 694 Other Forms of Hypoxia 690 Artificial Respiration 695 Oxygen Treatment 691 Section VII References 697 SECTION VIII FORMATION & EXCRETION OF URINE 699 38 Renal Function & Micturition 699 Introduction 699 Tubular Function 708 Functional Anatomy 699 Water Excretion 713 Renal Circulation 702 Acidification of the Urine Glomerular Filtration 705 & Bicarbonate Excretion 720 452 / CHAPTER 23 Table 23–10 Composition of colostrum and milk (Units are weight per deciliter.) Human Colostrum Human Milk Cows’ Milk Water, g Lactose, g Protein, g Casein:lactalbumin ratio Fat, g Linoleic acid 5.3 2.7 88 6.8 1.2 1:2 88 5.0 3.3 3:1 2.9 Sodium, mg Potassium, mg Chloride, mg Calcium, mg Magnesium, mg Phosphorus, mg Iron, mg Vit A, µg Vit D, µg Thiamine, µg Riboflavin, µg Nicotinic acid, µg Ascorbic acid, mg 92 55 117 31 14 0.092 89 15 30 75 4.4a 3.8 8.3% of fat 15 55 43 33 15 0.15a 53 0.03a 16 43 172 4.3a 3.7 1.6% of fat 58 138 103 125 12 100 0.10a 34 0.06a 42 157 85 1.6a Component Reproduced, with permission, from Findlay ALR: Lactation Res Reprod (Nov) 1974;6(6) a Poor source Effect of Lactation on Menstrual Cycles Women who not nurse their infants usually have their first menstrual period weeks after delivery However, women who nurse regularly have amenorrhea for 25–30 weeks Nursing stimulates prolactin secretion, and evidence suggests that prolactin inhibits GnRH secretion, inhibits the action of GnRH on the pituitary, and antagonizes the action of gonadotropins on the ovaries Ovulation is inhibited, and the ovaries are inactive, so estrogen and progesterone output falls to low levels Consequently, only 5–10% of women become pregnant again during the suckling period, and nursing has long been known to be an important if only partly effective method of birth control Furthermore, almost 50% of the cycles in the first months after resumption of menses are anovulatory Chiari–Frommel Syndrome An interesting although rare condition is persistence of lactation (galactorrhea) and amenorrhea in women who not nurse after delivery This condition, called the Chiari–Frommel syndrome, may be associated with some genital atrophy and is due to persistent prolactin secretion without the secretion of the FSH and LH necessary to produce maturation of new follicles and ovulation A similar pattern of galactorrhea and amenorrhea with high circulating prolactin levels is seen in nonpregnant women with chromophobe pituitary tumors and in women in whom the pituitary stalk has been sectioned in treatment of cancer Initiation of Lactation After Delivery Gynecomastia The breasts enlarge during pregnancy in response to high circulating levels of estrogens, progesterone, prolactin, and possibly hCG Some milk is secreted into the ducts as early as the fifth month, but the amounts are small compared with the surge of milk secretion that follows delivery In most animals, milk is secreted within an hour after delivery, but in women it takes 1–3 days for the milk to “come in.” After expulsion of the placenta at parturition, the levels of circulating estrogens and progesterone abruptly decline The drop in circulating estrogen initiates lactation Prolactin and estrogen synergize in producing breast growth, but estrogen antagonizes the milk-producing effect of prolactin on the breast Indeed, in women who not wish to nurse their babies, estrogens may be administered to stop lactation Suckling not only evokes reflex oxytocin release and milk ejection; it also maintains and augments the secretion of milk because of the stimulation of prolactin secretion produced by suckling (see above) Breast development in the male is called gynecomastia It may be unilateral but is more commonly bilateral It is common, occurring in about 75% of newborns because of transplacental passage of maternal estrogens It also occurs in mild, transient form in 70% of normal boys at the time of puberty and in many men over the age of 50 It occurs in androgen resistance It is a complication of estrogen therapy and is seen in patients with estrogen-secreting tumors It is found in a wide variety of seemingly unrelated conditions, including eunuchoidism, hyperthyroidism, and cirrhosis of the liver Digitalis can produce it, apparently because cardiac glycosides are weakly estrogenic It can also be caused by many other drugs It has been seen in malnourished prisoners of war, but only after they were liberated and eating an adequate diet A feature common to many and perhaps all cases of gynecomastia is an increase in the plasma estrogen:androgen ratio due to either increased circulating estrogens or decreased circulating androgens THE GONADS: DEVELOPMENT & FUNCTION OF THE REPRODUCTIVE SYSTEM Hormones & Cancer About 35% of carcinomas of the breast in women of childbearing age are estrogen-dependent; their continued growth depends on the presence of estrogens in the circulation The tumors are not cured by decreasing estrogen secretion, but symptoms are dramatically relieved, and the tumor regresses for months or years before recurring Women with estrogen-dependent tumors often have a remission when their ovaries are removed Inhibition of the action of estrogens with tamoxifen also produces remissions, and inhibition of / 453 estrogen formation with drugs that inhibit aromatase (Figure 23–29) is even more effective Some carcinomas of the prostate are androgen-dependent and regress temporarily after the removal of the testes or treatment with GnRH agonists in doses that are sufficient to produce down-regulation of the GnRH receptors on gonadotropes and decrease LH secretion The formation of pituitary tumors after removal of the target endocrine glands controlled by pituitary tropic hormones is discussed in Chapter 22 Endocrine Functions of the Kidneys, Heart, & Pineal Gland 24 the amino terminal of prorenin, active renin contains 340 amino acid residues Prorenin has little if any biologic activity Some prorenin is converted to renin in the kidneys, and some is secreted Prorenin is secreted by other organs, including the ovaries After nephrectomy, the prorenin level in the circulation is usually only moderately reduced and may actually rise, but the active-renin level falls to essentially zero Thus, very little prorenin is converted to renin in the circulation, and active renin is a product primarily if not exclusively of the kidneys Prorenin is secreted constitutively, whereas active renin is formed in the secretory granules of the juxtaglomerular cells, the cells in the kidneys that produce renin (see below) Active renin has a half-life in the circulation of 80 minutes or less Its only known function is to split the decapeptide angiotensin I from the amino terminal end of angiotensinogen (renin substrate) INTRODUCTION The organs with endocrine functions include numerous structures in addition to the posterior, intermediate, and anterior lobes of the pituitary; the thyroid; the parathyroids; the pancreas; the cortex and medulla of the adrenal glands; and the gonads Hormones that stimulate or inhibit the secretion of anterior pituitary hormones are secreted by the hypothalamus (see Chapter 14), and a number of hormones are secreted by the mucosa of the gastrointestinal tract (see Chapter 26) Many different cells produce cytokines, interleukins, and growth factors (see Chapters 1, 22, and 27) The kidneys produce three hormones: 1,25-dihydroxycholecalciferol (see Chapter 21), renin, and erythropoietin Natriuretic peptides, substances secreted by the heart and other tissues, increase excretion of sodium by the kidneys, and an additional natriuretic hormone inhibits Na+–K+ ATPase The pineal gland secretes melatonin, and this indole probably has a timing function The endocrine functions of the kidneys, heart, and pineal gland are considered in this chapter Angiotensinogen Circulating angiotensinogen is found in the α2-globulin fraction of the plasma (Figure 24–1) It contains about 13% carbohydrate and is made up of 453 amino acid residues It is synthesized in the liver with a 32-amino-acid signal sequence that is removed in the endoplasmic reticulum Its circulating level is increased by glucocorticoids, thyroid hormones, estrogens, several cytokines, and angiotensin II THE RENIN–ANGIOTENSIN SYSTEM Renin The rise in blood pressure produced by injection of kidney extracts is due to renin, an acid protease secreted by the kidneys into the bloodstream This enzyme acts in concert with angiotensin-converting enzyme to form angiotensin II (Figure 24–1) It is a glycoprotein with a molecular weight of 37,326 in humans The molecule is made up of two lobes, or domains, between which the active site of the enzyme is located in a deep cleft Two aspartic acid residues, one at position 104 and one at position 292 (residue numbers from human preprorenin), are juxtaposed in the cleft and are essential for activity Thus, renin is an aspartyl protease Like other hormones, renin is synthesized as a large preprohormone Human preprorenin contains 406 amino acid residues The prorenin that remains after removal of a leader sequence of 23 amino acid residues from the amino terminal contains 383 amino acid residues, and after removal of the pro sequence from Angiotensin-Converting Enzyme & Angiotensin II Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxypeptidase that splits off histidyl-leucine from the physiologically inactive angiotensin I, forming the octapeptide angiotensin II (Figure 24–2) The same enzyme inactivates bradykinin (see Chapter 31) Increased tissue bradykinin produced when ACE is inhibited acts on B2 receptors to produce the cough that is an annoying side effect in up to 20% of patients treated with ACE inhibitors Most of the converting enzyme that forms angiotensin II in the circulation is located in 454 ENDOCRINE FUNCTIONS OF THE KIDNEYS, HEART, & PINEAL GLAND / 455 Angiotensinogen Renin Bradykinin Angiotensin I Angiotensin-converting enzyme Inactive metabolites Angiotensin II Various peptidases AT1 receptors AIII, AIV, others Figure 24–1 Formation and metabolism of circulating angiotensins endothelial cells Much of the conversion occurs as the blood passes through the lungs, but conversion also occurs in many other parts of the body ACE is an ectoenzyme that exists in two forms: a somatic form found throughout the body and a germinal form found solely in postmeiotic spermatogenic cells and spermatozoa (see Chapter 23) Both ACEs have a single transmembrane domain and a short cytoplasmic tail However, somatic ACE is a 170-kDa protein with two homologous extracellular domains, each containing an active site (Figure 24–3) Germinal ACE is a 90-kDa protein that has only one extracellular domain and active site Both enzymes are formed from a single gene However, the gene has two different promoters, producing two different mRNAs In male mice in which the ACE gene has been knocked out, blood pressure is lower than normal, but in females it is normal In addition, fertility is reduced in males but not in females AT2 receptors Inactive metabolites Metabolism of Angiotensin II Angiotensin II is metabolized rapidly, its half-life in the circulation in humans being 1–2 minutes It is metabolized by various peptidases An aminopeptidase removes the Asp residue from the amino terminal of the peptide The resulting heptapeptide has physiologic activity and is sometimes called angiotensin III (see below) Removal of a second amino terminal residue from angiotensin III produces the hexapeptide sometimes called angiotensin IV, which is also said to have some activity Most, if not all, of the other peptide fragments that are formed are inactive In addition, aminopeptidase can act on angiotensin I to produce (des-Asp1) angiotensin I, and this compound can be converted directly to angiotensin III by the action of ACE Angiotensin-metabolizing activity is found in red blood cells and many tissues In addition, angiotensin II appears to be removed Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-R Angiotensinogen Renin splits this bond Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Angiotensin I Angiotensin-converting enzyme splits this bond Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensin II Aminopeptidase splits this bond Angiotensin III Figure 24–2 Structure of the amino terminal end of angiotensinogen and angiotensins I, II, and III in humans R, remainder of protein After removal of a 24-amino-acid leader sequence, angiotensinogen contains 453 amino acid residues The structure of angiotensin II in dogs, rats, and many other mammals is the same as that in humans Bovine and ovine angiotensin II have valine instead of isoleucine at position 456 / CHAPTER 24 from the circulation by some sort of trapping mechanism in the vascular beds of tissues other than the lungs Renin is usually measured by incubating the sample to be assayed and measuring by immunoassay the amount of angiotensin I generated This measures the plasma renin activity (PRA) of the sample Deficiency of angiotensinogen as well as renin can cause low PRA values, and to avoid this problem, exogenous angiotensinogen is often added, so that plasma renin concentration (PRC) rather than PRA is measured The normal PRA in supine subjects eating a normal amount of sodium is approximately ng of angiotensin I generated per milliliter per hour The plasma angiotensin II concentration in such subjects is about 25 pg/mL (approximately 25 pmol/L) eight times as active as norepinephrine on a weight basis in normal individuals However, its pressor activity is decreased in Na+-depleted individuals and in patients with cirrhosis and some other diseases In these conditions, circulating angiotensin II is increased, and this down regulates the angiotensin receptors in vascular smooth muscle Consequently, there is less response to injected angiotensin II Angiotensin II also acts directly on the adrenal cortex to increase the secretion of aldosterone, and the renin–angiotensin system is a major regulator of aldosterone secretion (see Chapter 20) Additional actions of angiotensin II include facilitation of the release of norepinephrine by a direct action on postganglionic sympathetic neurons, contraction of mesangial cells with a resultant decrease in glomerular filtration rate (see Chapter 38), and a direct effect on the renal tubules to increase Na+ reabsorption Angiotensin II also acts on the brain to decrease the sensitivity of the baroreflex (see Chapter 31), and this potentiates the pressor effect of angiotensin II In addition, it acts on the brain to increase water intake (see Chapter 14) and increase the secretion of vasopressin and ACTH It does not penetrate the blood–brain barrier, but it triggers these responses by acting on the circumventricular organs, four small structures in the brain that are outside the blood–brain barrier (see Chapter 32) One of these structures, the area postrema, is primarily responsible for the pressor potentiation, whereas two of the others, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT), are responsible for the increase in water intake (dipsogenic effect) It is not certain which of the circumventricular organs are responsible for the increases in vasopressin and ACTH secretion Angiotensin III [(des-Asp1) angiotensin II] has about 40% of the pressor activity of angiotensin II but 100% of the aldosterone-stimulating activity It has been suggested that angiotensin III is the natural aldosterone-stimulating peptide, whereas angiotensin II is the blood-pressure-regulating peptide However, this appears not to be the case, and instead angiotensin III is simply a breakdown product with some biologic activity The same is probably true of angiotensin IV, though some investigators have argued that it has unique effects in the brain Actions of Angiotensins Tissue Renin–Angiotensin Systems Angiotensin I appears to function solely as the precursor of angiotensin II and does not have any other established action Angiotensin II—previously called hypertensin or angiotonin—produces arteriolar constriction and a rise in systolic and diastolic blood pressure It is one of the most potent vasoconstrictors known, being four to In addition to the system that generates circulating angiotensin II, many different tissues contain independent renin–angiotensin systems that generate angiotensin II, apparently for local use Components of the renin–angiotensin system are found in the walls of blood vessels and in the uterus, the placenta, and the fetal membranes Amniotic fluid has a high concentration of prorenin In Extracellular extension Zn2+ Zn2+ Amino terminal catalytic site Carboxyl terminal catalytic site NH2 Transmembrane domain Intracellular extension COOH Figure 24–3 Diagrammatic representation of the structure of the somatic form of angiotensin-converting enzyme Note the short cytoplasmic tail of the molecule and the two extracellular catalytic sites, each of which binds a zinc ion (Zn2+) (Reproduced, with permission, from Johnston CI: Tissue angiotensin-converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling Hypertension 1994;23:258 Copyright 1994 by The American Heart Association.) ENDOCRINE FUNCTIONS OF THE KIDNEYS, HEART, & PINEAL GLAND addition, tissue renin–angiotensin systems, or at least several components of the renin–angiotensin system, are present in the eyes, exocrine portion of the pancreas, heart, fat, adrenal cortex, testis, ovary, anterior and intermediate lobes of the pituitary, pineal, and brain Tissue renin contributes very little to the circulating renin pool, since plasma renin activity falls to undetectable levels after the kidneys are removed The functions of these tissue renin–angiotensin systems are unsettled, though evidence is accumulating that angiotensin II is a significant growth factor in the heart and blood vessels As noted in Chapter 33, ACE inhibitors or AT1 receptor blockers are now the treatment of choice for congestive heart failure, and part of their value may be due to inhibition of the growth effects of angiotensin II Angiotensin II Receptors There are at least two classes of angiotensin II receptors (Figure 24–1) AT1 receptors are serpentine receptors coupled by a G protein (Gq) to phospholipase C, and angiotensin II increases the cytosolic free Ca2+ level It also activates numerous tyrosine kinases In vascular smooth muscle, AT1 receptors are associated with caveolae (see Chapter 1), and AII increases production of caveolin-1, one of the three isoforms of the protein that is characteristic of caveolae In rodents, two different but closely related AT1 subtypes, AT1A and AT1B, are coded by two separate genes The AT1A subtype is found in blood vessel walls, the brain, and many other organs It mediates most of the known effects of an- / 457 giotensin II The AT1B subtype is found in the anterior pituitary and the adrenal cortex In humans, an AT1 receptor gene is present on chromosome There may be a second AT1 type, but it is still unsettled whether distinct AT1A and AT1B subtypes occur There are also AT2 receptors, which are coded in humans by a gene on the X chromosome Like the AT1 receptors, they have seven transmembrane domains, but their actions are different They act via a G protein to activate various phosphatases which in turn antagonize growth effects and open K+ channels In addition, AT2 receptor activation increases the production of NO and therefore increases intracellular cGMP The overall physiologic consequences of these second-messenger effects are unsettled AT2 receptors are more plentiful in fetal and neonatal life, but they persist in the brain and other organs in adults The AT1 receptors in the arterioles and the AT1 receptors in the adrenal cortex are regulated in opposite ways: an excess of angiotensin II down regulates the vascular receptors, but it up regulates the adrenocortical receptors, making the gland more sensitive to the aldosterone-stimulating effect of the peptide The Juxtaglomerular Apparatus The renin in kidney extracts and the bloodstream is produced by the juxtaglomerular cells (JG cells) These epithelioid cells are located in the media of the afferent arterioles as they enter the glomeruli (Figure 24–4) The membrane-lined secretory granules in them Glomerulus Lacis cells Renal nerves Macula densa Efferent arteriole Juxtaglomerular cells Afferent arteriole Figure 24–4 Left: Diagram of glomerulus, showing the juxtaglomerular apparatus Right: Phase contrast photomicrograph of afferent arteriole in an unstained, freeze-dried preparation of the kidney of a mouse Note the red blood cell in the lumen of the arteriole and the granulated juxtaglomerular cells in the wall (Courtesy of C Peil.) 458 / CHAPTER 24 have been shown to contain renin Renin is also found in agranular lacis cells that are located in the junction between the afferent and efferent arterioles, but its significance in this location is unknown At the point where the afferent arteriole enters the glomerulus and the efferent arteriole leaves it, the tubule of the nephron touches the arterioles of the glomerulus from which it arose At this location, which marks the start of the distal convolution, there is a modified region of tubular epithelium called the macula densa (Figure 24–4) The macula densa is in close proximity to the JG cells The lacis cells, the JG cells, and the macula densa constitute the juxtaglomerular apparatus Regulation of Renin Secretion Several different factors regulate renin secretion (Table 24–1), and the rate of renin secretion at any given time is determined by the summed activity of these factors One factor is an intrarenal baroreceptor mechanism that causes renin secretion to decrease when arteriolar pressure at the level of the JG cells increases and to increase when arteriolar pressure at this level falls Another renin-regulating sensor is in the macula densa Renin secretion is inversely proportional to the amount of Na+ and Cl– entering the distal renal tubules from the loop of Henle Presumably, these electrolytes enter the macula densa cells via the Na+–K+–2Cl– transporters in their apical membranes (see Chapter 38), and the increase in some fashion triggers a signal that decreases renin secretion in the juxtaglomerular cells in the adjacent afferent arterioles A possible mediator is NO, but the identity of the signal remains unsettled Renin secretion also varies inversely with the plasma K+ level, but the effect of K+ appears to be mediated by the changes it produces in Na+ and Cl– delivery to the macula densa Angiotensin II feeds back to inhibit renin secretion by a direct action on the JG cells Vasopressin also inhibits renin secretion in vitro and in vivo, although Table 24–1 Factors that affect renin secretion Stimulatory Increased sympathetic activity via renal nerves Increased circulating catecholamines Prostaglandins Inhibitory Increased Na+ and Cl− reabsorption across macula densa Increased afferent arteriolar pressure Angiotensin II Vasopressin there is some debate about whether its in vivo effect is direct or indirect Finally, increased activity of the sympathetic nervous system increases renin secretion The increase is mediated both by increased circulating catecholamines and by norepinephrine secreted by postganglionic renal sympathetic nerves The catecholamines act mainly on β1-adrenergic receptors on the JG cells and the increases in renin are mediated by increased intracellular cAMP The principal conditions that are associated with increased renin secretion in humans are listed in Table 24–2 Most of them decrease central venous pressure, and this triggers increased sympathetic activity as well as a potential decrease in renal arteriolar pressure Renal artery constriction and constriction of the aorta proximal to the renal arteries produce a decrease in renal arteriolar pressure Psychologic stimuli increase the activity of the renal nerves Pharmacologic Manipulation of the Renin–Angiotensin System It is now possible to inhibit the secretion or the effects of renin in a variety of ways Inhibitors of prostaglandin synthesis such as indomethacin and β-adrenergic blocking drugs such as propranolol reduce renin secretion The peptide pepstatin and newly developed renin inhibitors such as enalkiren prevent renin from generating angiotensin I Angiotensin-converting enzyme inhibitors (ACE inhibitors) such as captopril and enalapril prevent conversion of angiotensin I to angiotensin II Saralasin and several other analogs of angiotensin II are competitive inhibitors of the action of angiotensin II on both AT1 and AT2 receptors Losartan (DuP-753) selectively blocks AT1 receptors, and PD-123177 and several other drugs selectively block AT2 receptors Table 24–2 Conditions that increase renin secretion Na+ depletion Diuretics Hypotension Hemorrhage Upright posture Dehydration Cardiac failure Cirrhosis Constriction of renal artery or aorta Various psychologic stimuli ENDOCRINE FUNCTIONS OF THE KIDNEYS, HEART, & PINEAL GLAND Role of Renin in Clinical Hypertension ERYTHROPOIETIN Structure & Function When an individual bleeds or becomes hypoxic, hemoglobin synthesis is enhanced, and production and release of red blood cells from the bone marrow (erythropoiesis) are increased (see Chapter 27) Conversely, when the red cell volume is increased above normal by transfusion, the erythropoietic activity of the bone marrow decreases These adjustments are brought about by changes in the circulating level of erythropoietin, a circulating glycoprotein that contains 165 amino acid residues and four oligosaccharide chains that are necessary for its activity in vivo Its blood level is markedly increased in anemia (Figure 24–5) Erythropoietin increases the number of erythropoietin-sensitive committed stem cells in the bone marrow that are converted to red blood cell precursors and subsequently to mature erythrocytes (see Figure 27–2) The receptor for erythropoietin is a linear protein with a single transmembrane domain that is a member of the cytokine receptor superfamily (see Chapter 1) The receptor has tyrosine kinase activity, and it activates a cascade of serine and threonine kinases, resulting in inhibited apoptosis of red cells and their increased growth and development The principal site of inactivation of erythropoietin is the liver, and the hormone has a half-life in the circulation of about hours However, the increase in circu- 459 105 Plasma erythropoietin (U/L) Constriction of one renal artery causes a prompt increase in renin secretion and the development of sustained hypertension (renal or Goldblatt hypertension) Removal of the ischemic kidney or the arterial constriction cures the hypertension if it has not persisted too long In general, the hypertension produced by constricting one renal artery with the other kidney intact (one-clip, two-kidney Goldblatt hypertension; see Table 33–5) is associated with increased circulating renin The clinical counterpart of this condition is renal hypertension due to atheromatous narrowing of one renal artery or other abnormalities of the renal circulation However, plasma renin activity is usually normal in one-clip one-kidney Goldblatt hypertension The explanation of the hypertension in this situation is unsettled However, many patients with hypertension respond to treatment with ACE inhibitors or losartan even when their renal circulation appears to be normal and they have normal or even low plasma renin activity The role of renin in a feedback mechanism that helps maintain the constancy of ECF volume through regulation of aldosterone secretion has been described in Chapter 20 / 104 103 102 101 100 0.10 0.20 0.30 0.40 0.50 0.60 Hematocrit Figure 24–5 Plasma erythropoietin levels in normal blood donors (triangles) and patients with various forms of anemia (squares) (Reproduced, with permission, from Erslev AJ: Erythropoietin N Engl J Med 1991;324:1339.) lating red cells that it triggers takes 2–3 days to appear, since red cell maturation is a relatively slow process Loss of even a small portion of the sialic acid residues in the carbohydrate moieties that are part of the erythropoietin molecule shortens its half-life to minutes, making it biologically ineffective Sources In adults, about 85% of the erythropoietin comes from the kidneys and 15% from the liver Both these organs contain the mRNA for erythropoietin Erythropoietin can also be extracted from the spleen and salivary glands, but these tissues not contain the mRNA and consequently not appear to manufacture the hormone When renal mass is reduced in adults by renal disease or nephrectomy, the liver cannot compensate and anemia develops Erythropoietin is produced by interstitial cells in the peritubular capillary bed of the kidneys and by perivenous hepatocytes in the liver It is also produced in the brain, where it exerts a protective effect against excitotoxic damage triggered by hypoxia; and in the uterus and oviducts, where it is induced by estrogen and appears to mediate estrogen-dependent angiogenesis The gene for the hormone has been cloned, and recombinant erythropoietin produced in animal cells is available for clinical use as epoetin alfa The recombi- 460 / CHAPTER 24 nant erythropoietin is of value in the treatment of the anemia associated with renal failure; 90% of the patients with end-stage renal failure who are on dialysis are anemic as a result of erythropoietin deficiency Erythropoietin is also used to stimulate red cell production in individuals who are banking a supply of their own blood in preparation for autologous transfusions during elective surgery (see Chapter 27) g Regulation of Secretion The usual stimulus for erythropoietin secretion is hypoxia, but secretion of the hormone can also be stimulated by cobalt salts and androgens Recent evidence suggests that the O2 sensor regulating erythropoietin secretion in the kidneys and the liver is a heme protein that in the deoxy form stimulates and in the oxy form inhibits transcription of the erythropoietin gene to form erythropoietin mRNA Secretion of the hormone is facilitated by the alkalosis that develops at high altitudes Like renin secretion, erythropoietin secretion is facilitated by catecholamines via a β-adrenergic mechanism, although the renin–angiotensin system is totally separate from the erythropoietin system HORMONES OF THE HEART & OTHER NATRIURETIC FACTORS Structure The existence of various natriuretic hormones has been postulated for some time Two of these are secreted by the heart The muscle cells in the atria and, to a much lesser extent, in the ventricles contain secretory granules (Figure 24–6) The granules increase in number when NaCl intake is increased and extracellular fluid expanded, and extracts of atrial tissue cause natriuresis The first natriuretic hormone isolated from the heart was atrial natriuretic peptide (ANP), a polypeptide with a characteristic 17-amino-acid ring formed by a disulfide bond between two cysteines The circulating form of this polypeptide has 28 amino acid residues (Figure 24–7) It is formed from a large precursor molecule that contains 151 amino acid residues, including a 24-amino-acid signal peptide ANP was subsequently isolated from other tissues, including the brain, where it exists in two forms that are smaller than circulating ANP A second natriuretic polypeptide was isolated from porcine brain and named brain natriuretic peptide (BNP; also known as B-type natriuretic peptide) It is also present in the brain in humans, but more is present in the human heart, including the ventricles The circulating form of this hormone contains 32 amino acid residues It has the same 17-member ring as ANP, though some of the amino acid residues in the m G N Figure 24–6 ANP granules (g) interspersed between mitochondria (m) in rat atrial muscle cell G, Golgi complex; N, nucleus The granules in human atrial cells are similar × 17,640 (Courtesy of M Cantin.) ring are different (Figure 24–7) A third member of this family has been named C-type natriuretic peptide (CNP) because it was the third in the sequence to be isolated It contains 22 amino acid residues (Figure 24–7), and there is also a larger 53-amino-acid form CNP is present in the brain, the pituitary, the kidneys, and vascular endothelial cells However, very little is present in the heart and the circulation, and it appears to be primarily a paracrine mediator Actions ANP and BNP in the circulation act on the kidneys to increase Na+ excretion, and injected CNP has a similar effect They appear to produce this effect by dilating afferent arterioles and relaxing mesangial cells Both of these actions increase glomerular filtration (see Chapter 38) In addition, they act on the renal tubules to inhibit Na+ reabsorption Other actions include an increase in capillary permeability, leading to extravasation of fluid and a decline in blood pressure In addition, they relax vascular smooth muscle in arterioles and venules CNP has a greater dilator effect on veins than ANP and BNP These peptides also inhibit renin secretion and counteract the pressor effects of catecholamines and angiotensin II In the brain, ANP is present in neurons, and an ANP-containing neural pathway projects from the anteromedial part of the hypothalamus to the areas in the lower brainstem that are concerned with neural regulation of the cardiovascular system In general, the effects of ANP in the brain are opposite to those of angiotensin II, and ANP-containing neural circuits appear ENDOCRINE FUNCTIONS OF THE KIDNEYS, HEART, & PINEAL GLAND / 461 28 ANP 32 BNP CNP 22 GLSKGCFGLKLDRIGSMSG CFG DRI MS S LGC L H 2N H 2N H2N HOOC HOOC HOOC ANP BNP CNP Figure 24–7 Human ANP, BNP, and CNP Top: Single-letter codes for amino acid residues aligned to show common sequences (colored) Bottom: Shape of molecules Note that one cysteine is the carboxyl terminal amino acid residue in CNP, so there is no carboxyl terminal extension from the 17-member ring (Modified from Imura H, Nakao K, Itoh H: The natriuretic peptide system in the brain: Implication in the central control of cardiovascular and neuroendocrine functions Front Neuroendocrinol 1992;13:217.) to be involved in lowering blood pressure and promoting natriuresis CNP and BNP in the brain probably have functions similar to those of ANP, but detailed information is not available Natriuretic Peptide Receptors Three different natriuretic peptide receptors (NPR) have been isolated and characterized (Figure 24–8) The NPR-A and NPR-B receptors both span the cell membrane and have cytoplasmic domains that are NPR-A NPR-B guanylyl cyclases ANP has the greatest affinity for the NPR-A receptor, and CNP has the greatest affinity for the NPR-B receptor The third receptor, NPR-C, binds all three natriuretic peptides but has a markedly truncated cytoplasmic domain Some evidence suggests that it acts via G proteins to activate phospholipase C and inhibit adenylyl cyclase However, it has also been argued that this receptor does not trigger any intracellular change and is instead a clearance receptor that removes natriuretic peptides from the bloodstream and then releases them later, helping to maintain a steady blood level of the hormones NPR-C Secretion & Metabolism ECF CM Cytoplasm Guanylyl cyclase domain Figure 24–8 Diagrammatic representation of natriuretic peptide receptors The NPR-A and NPR-B receptor molecules have intracellular guanylyl cyclase domains, whereas the clearance receptor, NPR-C, has only a small cytoplasmic domain CM, cell membrane The concentration of ANP in plasma is about fmol/mL in normal humans ingesting moderate amounts of NaCl ANP secretion is increased when the ECF volume is increased by infusion of isotonic saline and when the atria are stretched BNP secretion is increased when the ventricles are stretched ANP secretion is also increased by immersion in water up to the neck (Figure 24–9), a procedure that counteracts the effect of gravity on the circulation and increases central venous and consequently atrial pressure Note that immersion also decreases the secretion of renin and aldosterone Conversely, a small but measurable decrease in plasma ANP occurs in association with a decrease in central venous pressure on rising from the supine to the 462 CHAPTER 24 / ANP (fmol/mL) Circulating ANP has a short half-life It is metabolized by neutral endopeptidase (NEP), which is inhibited by thiorphan Therefore, administration of thiorphan increases circulating ANP IMMERSION 15 10 Na+–K+ ATPase-Inhibiting Factor Another natriuretic factor is present in blood This factor produces natriuresis by inhibiting Na+–K+ ATPase and raises rather than lowers blood pressure Current evidence indicates that it may well be the digitalis-like steroid ouabain and that it comes from the adrenal glands However, its physiologic significance is not yet known PRA (ng AI/mL /hr) PINEAL GLAND The pineal gland (epiphysis), believed by Descartes to be the seat of the soul, has at one time or another been regarded as having a wide variety of functions It is now known to secrete melatonin, and it may function as a timing device to keep internal events synchronized with the light–dark cycle in the environment Anatomy Aldosterone (ng/dL) 10 0 Time (hrs) Figure 24–9 Effect of immersion in water up to the neck for hours on plasma concentrations of ANP, PRA, and aldosterone (Modified and reproduced, with permission, from Epstein M et al: Increases in circulating atrial natriuretic factor during immersion-induced central hypervolaemia in normal humans Hypertension 1986;4 [Suppl 2]:593.) standing position Thus, it seems clear that the atria respond directly to stretch in vivo and that the rate of ANP secretion is proportionate to the degree to which the atria are stretched by increases in central venous pressure Similarly, BNP secretion is proportionate to the degree to which the ventricles are stretched Plasma levels of both hormones are elevated in congestive heart failure, and their measurement is seeing increasing use in the diagnosis of this condition The pineal arises from the roof of the third ventricle under the posterior end of the corpus callosum and is connected by a stalk to the posterior commissure and habenular commissure There are nerve fibers in the stalk, but they apparently not reach the gland The pineal stroma contains neuroglia and parenchymal cells with features suggesting that they have a secretory function (Figure 24–10) Like other endocrine glands, the pineal has highly permeable fenestrated capillaries In young animals and infants, the pineal is large, and the cells tend to be arranged in alveoli It begins to involute before puberty, and, in humans, small concretions of calcium phosphate and carbonate (pineal sand) appear in the tissue Because the concretions are radiopaque, the normal pineal is often visible on x-ray films of the skull in adults Displacement of a calcified pineal from its normal position indicates the presence of a space-occupying lesion such as a tumor in the brain Melatonin The amphibian pineal contains an indole, N-acetyl5-methoxytryptamine, named melatonin because it lightens the skin of tadpoles by an action on melanophores However, it does not appear to play a physiologic role in the regulation of skin color, and it is present in mammals, including humans Melatonin and the enzymes responsible for its synthesis from serotonin by N-acetylation and O-methylation (Figure 24–11) are present in pineal parenchymal cells, and the hormone is secreted by them into the blood and the ENDOCRINE FUNCTIONS OF THE KIDNEYS, HEART, & PINEAL GLAND / 463 Third ventricle Corpus callosum Pineal SCN Eye Pituitary Superior cervical ganglion Spinal cord Figure 24–10 Left: Sagittal section of human brainstem showing the pineal and its innervation (lines) Retinohypothalamic fibers synapse in the suprachiasmatic nuclei (SCN), and there are connections from the SCN to the intermediolateral gray column in the spinal cord Preganglionic neurons pass from the spinal cord to the superior cervical ganglion, and the postganglionic neurons project from this ganglion to the pineal in the nervi conarii Right: Histology of pineal gland Drawing of hematoxylin-and-eosin-stained section (Reproduced, with permission, from Fawcett DW: Bloom and Fawcett, A Textbook of Histology, 11th ed Saunders, 1986.) cerebrospinal fluid It is also synthesized in other organs Two melatonin-binding sites have been characterized: a high-affinity ML1 site and a low affinity ML2 site Two subtypes of the ML1 receptor have been cloned: Mel 1a and Mel 1b All the receptors are coupled to G proteins, with ML1 receptors inhibiting adenylyl cyclase and ML2 receptors stimulating phosphoinositide hydrolysis Regulation of Secretion In humans and all other species studied to date, melatonin synthesis and secretion are increased during the dark period of the day and maintained at a low level during the daylight hours (Figure 24–12) This remarkable diurnal variation in secretion is brought about by norepinephrine secreted by the postganglionic sympathetic nerves (nervi conarii) that innervate the pineal (Figure 24–10) The norepinephrine acts via β-adrenergic receptors in the pineal to increase intracellular cAMP, and the cAMP in turn produces a marked increase in N-acetyltransferase activity This results in increased melatonin synthesis and secretion The discharge of the sympathetic nerves to the pineal is entrained to the light–dark cycle in the envi- ronment via the retinohypothalamic nerve fibers to the suprachiasmatic nuclei The way these bring about entrainment of circadian rhythms is discussed in Chapter 14 From the hypothalamus, descending pathways converge on the intermediolateral gray column of the thoracic spinal cord and end on the preganglionic sympathetic neurons that in turn innervate the superior cervical ganglion, the site of origin of the postganglionic neurons to the pineal Circulating melatonin is rapidly metabolized in the liver by 6-hydroxylation followed by conjugation, and over 90% of the melatonin that appears in the urine is in the form of 6-hydroxy conjugates and 6-sulfatoxymelatonin The pathway by which the brain metabolizes melatonin is unsettled but may involve cleavage of the indole nucleus Function of the Pineal Gland Injected melatonin has effects on the gonads, but at least in some species these effects are sometimes stimulating and sometimes inhibitory, depending on the time of day the hormone is injected This observation led to the hypothesis that the diurnal change in melatonin secretion functions as a timing signal that coordinates endocrine and other internal events with the 464 / CHAPTER 24 Tryptophan Serotonin N-Acetyltransferase 5-Hydroxytryptophan HO Pineal paren- N -Acetylserotonin chymal Hydroxyindolecells O O-methyltransferase CH2 CH2 NH2 N H 5-Hydroxytryptamine (serotonin) Melatonin Blood Melatonin N-Acetyltransferase + Acetyl-CoA CH2 CH2 NH–C–CH3 N H N-Acetyl-5-hydroxytryptamine (N-acetylserotonin) HIOMT + S-Adenosylmethionine — — O CH3O CH2 CH2 NH–C–CH3 N H N-Acetyl-5-methoxytryptamine (melatonin) 6-Hydroxymelatonin (in liver) and other metabolites (in brain) Figure 24–11 Formation and metabolism of melatonin HIOMT, hydroxyindole O-methyltransferase For details of the synthesis and metabolism of serotonin, see Figure 4–24 light–dark cycle in the environment Evidence supporting this timing function of melatonin includes the observation that in blind people with free-running circadian rhythms (see Chapter 14), melatonin injections entrain the rhythms The melatonin and other receptors on which the hormone is acting to produce its timing effects remain to be determined It has been argued that the pineal normally inhibits the onset of puberty in humans, because pineal tumors are sometimes associated with sexual precocity How- Plasma melatonin (pg mL− 1) HO 12 24 Time (hrs) Figure 24–12 Diurnal rhythms of various compounds in the pineal and melatonin in blood The shaded area represents the hours of darkness during the 24-hour day 75 Young men 50 25 18 22 02 06 10 14 18 Clock time (h) Plasma melatonin (pg mL− 1) — — O 75 Old men 50 25 18 22 02 06 10 Clock time (h) 14 18 Figure 24–13 Daily plasma melatonin values (means ± SE) in men age 20–27 years and men age 67–84 years The colored bar on the horizontal axis indicates time in bed (Reproduced, with permission, from Turek F: Melatonin hype hard to swallow Nature 1996;379:295 Copyright 1996 by Macmillan Magazines Ltd.) 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