1. Standard Atomic Weights Based on the assigned relative mass of 12C = 12. For the sake of completeness, all known elements are included in the list. Sev-eral 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. Atomic Atomic Atomic Atomic Name Symbol No. Weight Valence Name Symbol No. Weight Valence Actinium Ac 89 227.028 . . . Mercury Hg 80 200.59 1,2 Aluminum Al 13 26.9815 3 (hydrargyrum) Americium Am 95 (243) 3,4,5,6 Molybdenum Mo 42 95.94 3,4,6 Antimony Sb 51 121.75 3,5 Neodymium Nd 60 144.24 3 (stibium) Neon Ne 10 20.1179 0 Argon Ar 18 39.948 0 Neptunium Np 93 237.0482 4,5,6 Arsenic As 33 74.9216 3,5 Nickel Ni 28 58.69 2,3 Astatine At 85 (210) 1,3,5,7 Niobium Nb 41 92.9064 3,5 Barium Ba 56 137.33 2 (columbium) Berkelium Bk 97 (247) 3,4 Nitrogen N 7 14.0067 3,5 Beryllium Be 4 9.0122 2 Nobelium No 102 (259) . . . Bismuth Bi 83 208.980 3,5 Osmium Os 76 190.2 2,3,4,8 Boron B 5 10.81 3 Oxygen O 8 15.9994 2 Bromine Br 35 79.904 1,3,5,7 Palladium Pd 46 106.42 2,4,6 Cadmium Cd 48 112.41 2 Phosphorus P 15 30.9738 3,5 Calcium Ca 20 40.08 2 Platinum Pt 78 195.08 2,4 Californium Cf 98 (251) . . . Plutonium Pu 94 (244) 3,4,5,6 Carbon C 6 12.011 2,4 Polonium Po 84 (209) . . . Cerium Ce 58 140.12 3,4 Potassium K 19 39.0983 1 Cesium Cs 55 132.9054 1 (kalium) Chlorine Cl 17 35.453 1,3,5,7 Praseodymium Pr 59 140.908 3 Chromium Cr 24 51.996 2,3,6 Promethium Pm 61 (145) 3 Cobalt Co 27 58.9332 2,3 Protactinium Pa 91 231.0359 . . . Columbium Radium Ra 88 226.025 2 (see Niobium) Radon Rn 86 (222) 0 Copper Cu 29 63.546 1,2 Rhenium Re 75 186.207 . . . Curium Cm 96 (247) 3 Rhodium Rh 45 102.906 3 Dysprosium Dy 66 162.50 3 Rubidium Rb 37 85.4678 1 Einsteinium Es 99 (252) . . . Ruthenium Ru 44 101.07 3,4,6,8 Erbium Er 68 167.26 3 Samarium Sm 62 150.36 2,3 Europium Eu 63 151.96 2,3 Scandium Sc 21 44.9559 3 Fermium Fm 100 (257) . . . Selenium Se 34 78.96 2,4,6 Fluorine F 9 18.9984 1 Silicon Si 14 28.0855 4 Francium Fr 87 (223) 1 Silver Ag 47 107.868 1 Gadolinium Gd 64 157.25 3 (argentum) Gallium Ga 31 69.72 2,3 Sodium Na 11 22.9898 1 Germanium Ge 32 72.59 4 (natrium) Gold Au 79 196.967 1,3 Strontium Sr 38 87.62 2 (aurum) Sulfur S 16 32.06 2,4,6 Hafnium Hf 72 178.49 4 Tantalum Ta 73 180.9479 5 Helium He 2 4.0026 0 Technetium Tc 43 (98) 6,7 Holmium Ho 67 164.930 3 Tellurium Te 52 127.60 2,4,6 Hydrogen H 1 1.0079 1 Terbium Tb 65 158.925 3 Indium In 49 114.82 3 Thallium Tl 81 204.383 1,3 Iodine I 53 126.905 1,3,5,7 Thorium Th 90 232.038 4 Iridium Ir 77 192.22 3,4 Thulium Tm 69 168.934 3 Iron Fe 26 55.847 2,3 Tin Sn 50 118.71 2,4 (ferrum) (stannum) Krypton Kr 36 83.80 0 Titanium Ti 22 47.88 3,4 Lanthanum La 57 138.906 3 Tungsten W 74 183.85 6 Lawrencium Lr 103 (260) . . . (wolfram) Lead Pb 82 207.2 2,4 Uranium U 92 238.029 4,6 (plumbum) Vanadium V 23 50.9415 3,5 Lithium Li 3 6.941 1 Xenon Xe 54 131.29 0 Lutetium Lu 71 174.967 3 Ytterbium Yb 70 173.04 2,3 Magnesium Mg 12 24.305 2 Yttrium Y 39 88.9059 3 Manganese Mn 25 54.9380 2,3,4,6,7 Zinc Zn 30 65.39 2 Mendelevium Md 101 (258) . . . Zirconium Zr 40 91.224 4 Modified and reproduced, with permission from Lide DR (editor-in-chief): CRC Handbook of Chemistry and Physics, 83rd ed. CRC Press, 20022003.

2. 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

3. 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.

4. Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi SECTION I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1. The General & Cellular Basis of Medical Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Introduction 1 Transport Across Cell Membranes 28 General Principles 1 The Capillary Wall 35 Functional Morphology of the Cell 8 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 2. Excitable Tissue: Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 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 3. Excitable Tissue: Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 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 4. Synaptic & Junctional Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 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 iii

5. iv / CONTENTS 5. 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 6. Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Introduction 129 Polysynaptic Reflexes: The Withdrawal Reflex 134 Monosynaptic Reflexes: General Properties of Reflexes 137 The Stretch Reflex 129 7. Cutaneous, Deep, & Visceral Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Introduction 138 Temperature 142 Pathways 138 Pain 142 Touch 141 Other Sensations 147 Proprioception 142 8. 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 9. 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

6. 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

7. vi / CONTENTS Insulin Excess 344 Effects of Other Hormones & Exercise Regulation of Insulin Secretion 345 on Carbohydrate Metabolism 351 Glucagon 348 Hypoglycemia & Diabetes Mellitus in Humans 353 Other Islet Cell Hormones 350 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 Hyper- Effects 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

8. 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 CONTENTS / vii

9. 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

10. CONTENTS / ix Regulation of Na+ & Cl Excretion 723 Effects of Disordered Renal Function 725 Regulation of K+ Excretion 724 The Bladder 726 Diuretics 724 39. Regulation of Extracellular Fluid Composition & Volume. . . . . . . . . . . . . . . . . . . . . . . . . . . 729 Introduction 729 Defense of Specific Ionic Composition 730 Defense of Tonicity 729 Defense of H+ Concentration 730 Defense of Volume 729 Section VIII References 738 Self-Study: Objectives, Essay Questions, & Multiple-Choice Questions (black edges) . . . . . . 739 Answers to Quantitative & Multiple-Choice Questions (black edges). . . . . . . . . . . . . . . . . . . 807 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811 General References 811 Some Standard Respiratory Symbols 821 Normal Values & the Statistical Equivalents of Metric, United States, Evaluation of Data 811 & English Measures 821 Abbreviations & Symbols Commonly Greek Alphabet 822 Used in Physiology 814 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823 Standard Atomic Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inside Front Cover Ranges of Normal Values in Human Whole Blood, Plasma, or Serum . . . . . . . . Inside Back Cover

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12. Preface This book is designed to provide a concise summary of mammalian and, particularly, of human physiology that medical students and others can use by itself or can supplement with readings in other texts, monographs, and re-views. Pertinent aspects of general and comparative physiology are also included. Summaries of relevant anatomic considerations will be found in each section, but this book is written primarily for those who have some knowledge of anatomy, chemistry, and biochemistry. Examples from clinical medicine are given where pertinent to illustrate physiologic points. In many of the chapters, physicians desiring to use this book as a review will find short discus-sions of important symptoms produced by disordered function. Review of Medical Physiology also includes a self-study section to help students review for Board and other exami-nations and an appendix that contains general references, a discussion of statistical methods, a glossary of abbrevia-tions, acronyms, and symbols commonly used in physiology, and several useful tables. The index is comprehensive and specifically designed for ease in locating important terms, topics, and concepts. In writing this book, the author has not been able to be complete and concise without also being dogmatic. I be-lieve, however, that the conclusions presented without detailed discussion of the experimental data on which they are based are supported by the bulk of the current evidence. Much of this evidence can be found in the papers cited in the credit lines accompanying the illustrations. Further discussions of particular subjects and information on sub-jects not considered in detail can be found in the references listed at the end of each section. Information about ser-ial review publications that provide up-to-date discussion of various physiologic subjects is included in the note on general references in the appendix. In the interest of brevity and clarity, I have in most instances omitted the names of the many investigators whose work made possible the view of physiology presented here. This omission is in no way intended to slight their contributions, but including their names and specific references to original papers would greatly increase the length of the book. In this twenty-second edition, as in previous editions, the entire book has been revised, with a view to eliminat-ing errors, incorporating suggestions of readers, updating concepts, and discarding material that is no longer rele-vant. In this way, the book has been kept concise while remaining as up-to-date and accurate as possible. Since the last edition, research on the regulation of food intake has continued at a rapid pace, and this topic has been ex-panded in the current edition. So has consideration of mitochondria and molecular motors, with emphasis on the ubiquity of the latter. Chapter 38 on renal function has been reorganized as well as updated. The section on estro-gen receptors has been revised in terms of the complexity of the receptor and the way this relates to tailor-made estrogens used in the treatment of disease. Other topics on which there is new information include melanopsin, pheromones related to lactation, von Willebrand factor, and the complexity of connexons. The self-study section has been updated, with emphasis placed on physiology in relation to disease, in keeping with the current trend in the United States Medical Licensing Examinations (USMLE). I am greatly indebted to the many individuals who helped with the preparation of this book. Those who were es-pecially helpful in the preparation of the twenty-second edition include Drs. Stephen McPhee, Dan Stites, David Gardner, Igor Mitrovic, Michael Jobin, Krishna Rao, and Johannes Werzowa. Andrea Chase provided invaluable secretarial assistance, and, as always, my wife made important contributions.Special thanks are due to Jim Ransom, who edited the first edition of this book over 42 years ago and now has come back to make helpful and worthwhile comments on the two most recent editions. Many associates and friends provided unpublished illustrative materials, and numerous authors and publishers generously granted permission to reproduce illustrations from other books and journals. I also thank all the students and others who took the time to write to me offering helpful criticisms and suggestions. Such comments are always welcome, and I solicit additional corrections and criticisms, which may be addressed to me at Department of Physiology University of California San Francisco, CA 94143-0444 USA Since this book was first published in 1963, the following translations have been published: Bulgarian, Chinese (2 independent translations), Czech (2 editions), French (2 independent translations), German (4 editions), Greek (2 editions), Hungarian, Indonesian (4 editions), Italian (9 editions), Japanese (17 editions), Korean, Malaysian, xi

13. xii / PREFACE Polish (2 editions), Portuguese (7 editions), Serbo-Croatian, Spanish (19 editions), Turkish (2 editions), and Ukranian. Various foreign English language editions have been published, and the book has been recorded in Eng-lish on tape for the blind. The tape recording is available from Recording for the Blind, Inc., 20 Rozsel Road, Princeton, NJ 08540 USA. For computer users, the book is now available, along with several other titles in the Lange Medical Books series, in STAT!-Ref, a searchable Electronic Medical Library (http://www.statref.com), from Teton Data Systems, P.O. Box 4798 Jackson, WY 83001 USA. More information about this and other Lange and McGraw-Hill books, including addresses of the publishers international offices, is available on McGraw-Hills web site, www.AccessMedBooks.com. William F. Ganong, MD San Francisco March 2005

14. The General & Cellular Basis of Medical Physiology 1 1 SECTION I Introduction INTRODUCTION In unicellular organisms, all vital processes occur in a single cell. As the evolution of multicellular organisms has progressed, various cell groups have taken over par-ticular functions. In humans and other vertebrate ani-mals, the specialized cell groups include a gastrointesti-nal system to digest and absorb food; a respiratory system to take up O2 and eliminate CO2; a urinary sys-tem to remove wastes; a cardiovascular system to dis-tribute food, O2, and the products of metabolism; a re-productive system to perpetuate the species; and nervous and endocrine systems to coordinate and inte-grate the functions of the other systems. This book is concerned with the way these systems function and the way each contributes to the functions of the body as a whole. This chapter presents general concepts and princi-ples that are basic to the function of all the systems. It also includes a short review of fundamental aspects of cell physiology. Additional aspects of cellular and mole-cular biology are considered in the relevant chapters on the various organs. GENERAL PRINCIPLES Organization of the Body The cells that make up the bodies of all but the simplest multicellular animals, both aquatic and terrestrial, exist in an internal sea of extracellular fluid (ECF) en-closed within the integument of the animal. From this fluid, the cells take up O2 and nutrients; into it, they discharge metabolic waste products. The ECF is more dilute than present-day seawater, but its composition closely resembles that of the primordial oceans in which, presumably, all life originated. In animals with a closed vascular system, the ECF is divided into two components: the interstitial fluid and the circulating blood plasma. The plasma and the cel-lular elements of the blood, principally red blood cells, fill the vascular system, and together they constitute the total blood volume. The interstitial fluid is that part of the ECF that is outside the vascular system, bathing the cells. The special fluids lumped together as transcellular fluids are discussed below. About a third of the total body water (TBW) is extracellular; the remaining two thirds is intracellular (intracellular fluid). Body Composition In the average young adult male, 18% of the body weight is protein and related substances, 7% is mineral, and 15% is fat. The remaining 60% is water. The dis-tribution of this water is shown in Figure 11. The intracellular component of the body water ac-counts for about 40% of body weight and the extracel-lular component for about 20%. Approximately 25% of the extracellular component is in the vascular system (plasma = 5% of body weight) and 75% outside the blood vessels (interstitial fluid = 15% of body weight). The total blood volume is about 8% of body weight. Measurement of Body Fluid Volumes It is theoretically possible to measure the size of each of the body fluid compartments by injecting substances that will stay in only one compartment and then calcu-lating the volume of fluid in which the test substance is

15. 2 / CHAPTER 1 Blood plasma: 5% body weight Interstitial fluid: 15% body weight Intracellular fluid: 40% body weight Skin Kidneys Stomach Intestines Lungs Extra-cellular fluid: 20% body weight Figure 11. Body fluid compartments. Arrows repre-sent fluid movement. Transcellular fluids, which consti-tute a very small percentage of total body fluids, are not shown. distributed (the volume of distribution of the injected material). The volume of distribution is equal to the amount injected (minus any that has been removed from the body by metabolism or excretion during the time allowed for mixing) divided by the concentration of the substance in the sample. Example: 150 mg of su-crose is injected into a 70-kg man. The plasma sucrose level after mixing is 0.01 mg/mL, and 10 mg has been excreted or metabolized during the mixing period. The volume of distribution of the sucrose is 150 mg 10 mg 0.01 mg/mL = 14,000 mL Since 14,000 mL is the space in which the sucrose was distributed, it is also called the sucrose space. Volumes of distribution can be calculated for any substance that can be injected into the body, provided the concentration in the body fluids and the amount removed by excretion and metabolism can be accurately measured. Although the principle involved in such measure-ments is simple, a number of complicating factors must be considered. The material injected must be nontoxic, must mix evenly throughout the compartment being measured, and must have no effect of its own on the distribution of water or other substances in the body. In addition, either it must be unchanged by the body dur-ing the mixing period, or the amount changed must be known. The material also should be relatively easy to measure. Plasma Volume, Total Blood Volume, & Red Cell Volume Plasma volume has been measured by using dyes that become bound to plasma proteinparticularly Evans blue (T-1824). Plasma volume can also be measured by injecting serum albumin labeled with radioactive io-dine. Suitable aliquots of the injected solution and plasma samples obtained after injection are counted in a scintillation counter. An average value is 3500 mL (5% of the body weight of a 70-kg man, assuming unit density). If one knows the plasma volume and the hematocrit (ie, the percentage of the blood volume that is made up of cells), the total blood volume can be calculated by multiplying the plasma volume by 100 100 hematocrit Example: The hematocrit is 38 and the plasma vol-ume 3500 mL. The total blood volume is 3500 100 100 38 = 5645 mL The red cell volume (volume occupied by all the circulating red cells in the body) can be determined by subtracting the plasma volume from the total blood volume. It may also be measured independently by in-jecting tagged red blood cells and, after mixing has oc-curred, measuring the fraction of the red cells that is tagged. A commonly used tag is 51Cr, a radioactive iso-tope of chromium that is attached to the cells by incu-bating them in a suitable chromium solution. Isotopes of iron and phosphorus (59Fe and 32P) and antigenic tagging have also been employed.

16. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 3 Extracellular Fluid Volume The ECF volume is difficult to measure because the limits of this space are ill defined and because few sub-stances mix rapidly in all parts of the space while re-maining exclusively extracellular. The lymph cannot be separated from the ECF and is measured with it. Many substances enter the cerebrospinal fluid (CSF) slowly because of the bloodbrain barrier (see Chapter 32). Equilibration is slow with joint fluid and aqueous humor and with the ECF in relatively avascular tissues such as dense connective tissue, cartilage, and some parts of bone. Substances that distribute in ECF appear in glandular secretions and in the contents of the gas-trointestinal tract. Because they are separated from the rest of the ECF, these fluidsas well as CSF, the fluids in the eye, and a few other special fluidsare called transcellular fluids. Their volume is relatively small. Perhaps the most accurate measurement of ECF vol-ume is that obtained by using inulin, a polysaccharide with a molecular weight of 5200. Mannitol and sucrose have also been used to measure ECF volume. A gener-ally accepted value for ECF volume is 20% of the body weight, or about 14 L in a 70-kg man (3.5 L = plasma; 10.5 L = interstitial fluid). Interstitial Fluid Volume The interstitial fluid space cannot be measured directly, since it is difficult to sample interstitial fluid and since substances that equilibrate in interstitial fluid also equi-librate in plasma. The volume of the interstitial fluid can be calculated by subtracting the plasma volume from the ECF volume. The ECF volume/intracellular fluid volume ratio is larger in infants and children than it is in adults, but the absolute volume of ECF in chil-dren is, of course, smaller than in adults. Therefore, de-hydration develops more rapidly and is frequently more severe in children. Intracellular Fluid Volume The intracellular fluid volume cannot be measured di-rectly, but it can be calculated by subtracting the ECF volume from the TBW. TBW can be measured by the same dilution principle used to measure the other body spaces. Deuterium oxide (D2O, heavy water) is most frequently used. D2O has slightly different properties from those of H2O, but in equilibration experiments for measuring body water it gives accurate results. Tri-tium oxide (3H2O) and aminopyrine have also been used for this purpose. The water content of lean body tissue is constant at 7172 mL/100 g of tissue, but since fat is relatively free of water, the ratio of TBW to body weight varies with the amount of fat present. TBW is somewhat lower in women than men, and in both sexes, the values tend to decrease with age (Table 11). Units for Measuring Concentration of Solutes In considering the effects of various physiologically im-portant substances and the interactions between them, the number of molecules, electric charges, or particles of a substance per unit volume of a particular body fluid are often more meaningful than simply the weight of the substance per unit volume. For this reason, con-centrations are frequently expressed in moles, equiva-lents, or osmoles. Moles A mole is the gram-molecular weight of a substance, ie, the molecular weight of the substance in grams. Each mole (mol) consists of approximately 6 1023 mole-cules. The millimole (mmol) is 1/1000 of a mole, and the micromole (mmol) is 1/1,000,000 of a mole. Thus, 1 mol of NaCl = 23 + 35.5 g = 58.5 g, and 1 mmol = 58.5 mg. The mole is the standard unit for expressing the amount of substances in the SI unit system (see Ap-pendix). The molecular weight of a substance is the ratio of the mass of one molecule of the substance to the mass of one twelfth the mass of an atom of carbon-12. Since molecular weight is a ratio, it is dimensionless. The dal-ton (Da) is a unit of mass equal to one twelfth the mass of an atom of carbon-12, and 1000 Da = 1 kilodalton (kDa). The kilodalton, which is sometimes expressed simply as K, is a useful unit for expressing the molecu-lar mass of proteins. Thus, for example, one can speak of a 64-K protein or state that the molecular mass of the protein is 64,000 Da. However, since molecular Table 11. Total body water (as percentage of body weight) in relation to age and sex. Age (years) Male (%) Female (%) 1018 59 57 1840 61 51 4060 55 47 Over 60 52 46

17. 4 / CHAPTER 1 weight is a dimensionless ratio, it is incorrect to say that the molecular weight of the protein is 64 kDa. Equivalents The concept of electrical equivalence is important in physiology because many of the important solutes in the body are in the form of charged particles. One equivalent (eq) is 1 mol of an ionized substance divided by its valence. One mole of NaCl dissociates into 1 eq of Na+ and 1 eq of Cl. One equivalent of Na+ = 23 g; but 1 eq of Ca2+ = 40 g/2 = 20 g. The milliequivalent (meq) is 1/1000 of 1 eq. Electrical equivalence is not necessarily the same as chemical equivalence. A gram equivalent is the weight of a substance that is chemically equivalent to 8.000 g of oxygen. The normality (N) of a solution is the num-ber of gram equivalents in 1 liter. A 1 N solution of hy-drochloric acid contains 1 + 35.5 g/L = 36.5 g/L. pH The maintenance of a stable hydrogen ion concentra-tion in the body fluids is essential to life. The pH of a solution is the logarithm to the base 10 of the reciprocal of the H+ concentration ([H+]), ie, the negative loga-rithm of the [H+]. The pH of water at 25 C, in which H+ and OH ions are present in equal numbers, is 7.0 (Figure 12). For each pH unit less than 7.0, the [H+] is increased tenfold; for each pH unit above 7.0, it is decreased tenfold. Buffers Intracellular and extracellular pH are generally main-tained at very constant levels. For example, the pH of the ECF is 7.40, and in health, this value usually varies less than 0.05 pH unit. Body pH is stabilized by the buffering capacity of the body fluids. A buffer is a sub-stance that has the ability to bind or release H+ in solu-tion, thus keeping the pH of the solution relatively con-stant despite the addition of considerable quantities of acid or base. One buffer in the body is carbonic acid. This acid is only partly dissociated into H+ and bicar-bonate: H2CO3H+ + HCO3 . If H+ is added to a so-lution of carbonic acid, the equilibrium shifts to the left and most of the added H+ is removed from solution. If OH is added, H+ and OH combine, taking H+ out of solution. However, the decrease is countered by more dissociation of H2CO3, and the decline in H+ concen-tration is minimized. Other buffers include the blood proteins and the proteins in cells. The quantitative as-pects of buffering and the respiratory and renal adjust-ments that operate with buffers to maintain a stable ECF pH of 7.40 are discussed in Chapter 39. Diffusion Diffusion is the process by which a gas or a substance in solution expands, because of the motion of its particles, to fill all of the available volume. The particles (mole-cules or atoms) of a substance dissolved in a solvent are in continuous random movement. A given particle is equally likely to move into or out of an area in which it is present in high concentration. However, since there are more particles in the area of high concentration, the total number of particles moving to areas of lower con-centration is greater; ie, there is a net flux of solute par-ticles from areas of high to areas of low concentration. The time required for equilibrium by diffusion is pro-portionate to the square of the diffusion distance. The magnitude of the diffusing tendency from one region to another is directly proportionate to the cross-sectional area across which diffusion is taking place and the con-centration gradient, or chemical gradient, which is the difference in concentration of the diffusing sub-stance divided by the thickness of the boundary (Ficks law of diffusion). Thus, J = DA c x where J is the net rate of diffusion, D is the diffusion coefficient, A is the area, and c/x is the concentra-tion gradient. The minus sign indicates the direction of diffusion. When considering movement of molecules from a higher to a lower concentration, c/x is nega- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 101 102 103 104 105 106 107 108 109 1010 1011 1012 1013 1014 pH H+ concentration (mol/L) ALKALINE ACIDIC For pure water, [H+] = 107 mol/L Figure 12. pH. (Reproduced, with permission, from Alberts B et al: Molecular Biology of the Cell, 4th ed. Gar-land Science, 2002.)

18. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 5 tive, so multiplying by DA gives a positive value. The permeabilities of the boundaries across which diffusion occurs in the body vary, but diffusion is still a major force affecting the distribution of water and solutes. Osmosis When a substance is dissolved in water, the concentra-tion of water molecules in the solution is less than that in pure water, since the addition of solute to water re-sults in a solution that occupies a greater volume than does the water alone. If the solution is placed on one side of a membrane that is permeable to water but not to the solute, and an equal volume of water is placed on the other, water molecules diffuse down their concen-tration gradient into the solution (Figure 13). This processthe diffusion of solvent molecules into a re-gion in which there is a higher concentration of a solute to which the membrane is impermeableis called osmosis. It is an important factor in physiologic processes. The tendency for movement of solvent mole-cules to a region of greater solute concentration can be prevented by applying pressure to the more concen-trated solution. The pressure necessary to prevent sol-vent migration is the osmotic pressure of the solution. Osmotic pressure, like vapor pressure lowering, freezing-point depression, and boiling-point elevation, depends on the number rather than the type of particles in a solution; ie, it is a fundamental colligative property of solutions. In an ideal solution, osmotic pressure (P) is related to temperature and volume in the same way as the pressure of a gas: P = nRT V where n is the number of particles, R is the gas con-stant, T is the absolute temperature, and V is the vol-ume. If T is held constant, it is clear that the osmotic pressure is proportionate to the number of particles in solution per unit volume of solution. For this reason, the concentration of osmotically active particles is usu-ally expressed in osmoles. One osmole (osm) equals the gram-molecular weight of a substance divided by the number of freely moving particles that each molecule liberates in solution. The milliosmole (mosm) is 1/1000 of 1 osm. If a solute is a nonionizing compound such as glu-cose, the osmotic pressure is a function of the number of glucose molecules present. If the solute ionizes and forms an ideal solution, each ion is an osmotically ac-tive particle. For example, NaCl would dissociate into Na+ and Cl ions, so that each mole in solution would supply 2 osm. One mole of Na2SO4 would dissociate into Na+, Na+, and SO4 2, supplying 3 osm. However, the body fluids are not ideal solutions, and although the dissociation of strong electrolytes is complete, the num-ber of particles free to exert an osmotic effect is reduced owing to interactions between the ions. Thus, it is actu-ally the effective concentration (activity) in the body fluids rather than the number of equivalents of an elec-trolyte in solution that determines its osmotic effect. This is why, for example, 1 mmol of NaCl per liter in the body fluids contributes somewhat less than 2 mosm of osmotically active particles per liter. The more con-centrated the solution, the greater the deviation from an ideal solution. The osmolal concentration of a substance in a fluid is measured by the degree to which it depresses the freezing point, with 1 mol of an ideal solution depress-ing the freezing point 1.86 C. The number of millios-moles per liter in a solution equals the freezing point depression divided by 0.00186. The osmolarity is the number of osmoles per liter of solution (eg, plasma), whereas the osmolality is the number of osmoles per kilogram of solvent. Therefore, osmolarity is affected by the volume of the various solutes in the solution and the temperature, while the osmolality is not. Osmoti-cally active substances in the body are dissolved in water, and the density of water is 1, so osmolal concen-trations can be expressed as osmoles per liter (osm/L) of water. In this book, osmolal (rather than osmolar) con-centrations are considered, and osmolality is expressed in milliosmoles per liter (of water). Semipermeable membrane Pressure Figure 13. Diagrammatic representation of osmosis. Water molecules are represented by small open circles, solute molecules by large solid circles. In the diagram on the left, water is placed on one side of a membrane permeable to water but not to solute, and an equal vol-ume of a solution of the solute is placed on the other. Water molecules move down their concentration gradi-ent into the solution, and, as shown in the diagram on the right, the volume of the solution increases. As indi-cated by the arrow on the right, the osmotic pressure is the pressure that would have to be applied to prevent the movement of the water molecules.

19. 6 / CHAPTER 1 Note that although a homogeneous solution con-tains osmotically active particles and can be said to have an osmotic pressure, it can exert an osmotic pressure only when it is in contact with another solution across a membrane permeable to the solvent but not to the solute. Osmolal Concentration of Plasma: Tonicity The freezing point of normal human plasma averages 0.54 C, which corresponds to an osmolal concentra-tion in plasma of 290 mosm/L. This is equivalent to an osmotic pressure against pure water of 7.3 atm. The os-molality might be expected to be higher than this, be-cause the sum of all the cation and anion equivalents in plasma is over 300. It is not this high because plasma is not an ideal solution and ionic interactions reduce the number of particles free to exert an osmotic effect. Ex-cept when there has been insufficient time after a sud-den change in composition for equilibrium to occur, all fluid compartments of the body are in or nearly in os-motic equilibrium. The term tonicity is used to de-scribe the osmolality of a solution relative to plasma. Solutions that have the same osmolality as plasma are said to be isotonic; those with greater osmolality are hypertonic; and those with lesser osmolality are hypo-tonic. All solutions that are initially isosmotic with plasma (ie, that have the same actual osmotic pressure or freezing-point depression as plasma) would remain isotonic if it were not for the fact that some solutes dif-fuse into cells and others are metabolized. Thus, a 0.9% saline solution remains isotonic because there is no net movement of the osmotically active particles in the so-lution into cells and the particles are not metabolized. On the other hand, a 5% glucose solution is isotonic when initially infused intravenously, but glucose is me-tabolized, so the net effect is that of infusing a hypo-tonic solution. It is important to note the relative contributions of the various plasma components to the total osmolal concentration of plasma. All but about 20 of the 290 mosm in each liter of normal plasma are con-tributed by Na+ and its accompanying anions, princi-pally Cl and HCO3 . Other cations and anions make a relatively small contribution. Although the concentra-tion of the plasma proteins is large when expressed in grams per liter, they normally contribute less than 2 mosm/L because of their very high molecular weights. The major nonelectrolytes of plasma are glucose and urea, which in the steady state are in equilibrium with cells. Their contributions to osmolality are normally about 5 mosm/L each but can become quite large in hyperglycemia or uremia. The total plasma osmolality is important in assessing dehydration, overhydration, and other fluid and electrolyte abnormalities. Hyperos-molality can cause coma (hyperosmolar coma; see Chapter 19). Because of the predominant role of the major solutes and the deviation of plasma from an ideal solution, one can ordinarily approximate the plasma os-molality within a few milliosmoles per liter by using the following formula, in which the constants convert the clinical units to millimoles of solute per liter: Osmolality = 2[Na+] + 0.055[Glucose] + 0.36[BUN] (mosm/L) (mEq/L) (mg/dL) (mg/dL) BUN is the blood urea nitrogen. The formula is also useful in calling attention to abnormally high concen-trations of other solutes. An observed plasma osmolality (measured by freezing-point depression) that greatly ex-ceeds the value predicted by this formula probably indi-cates the presence of a foreign substance such as ethanol, mannitol (sometimes injected to shrink swollen cells osmotically), or poisons such as ethylene glycol or methanol (components of antifreeze). Regulation of Cell Volume Unlike plant cells, which have rigid walls, animal cell membranes are flexible. Therefore, animal cells swell when exposed to extracellular hypotonicity and shrink when exposed to extracellular hypertonicity. However, cell swelling activates channels in the cell membrane that permit increased efflux of K+, Cl, and small or-ganic solutes referred to collectively as organic os-molytes. Water follows these osmotically active parti-cles out of the cell, and the cell volume returns to normal. Ion channels and other membrane transport proteins are discussed in detail in a later section of this chapter. Nonionic Diffusion Some weak acids and bases are quite soluble in cell membranes in the undissociated form, whereas they cross membranes with difficulty in the ionic form. Consequently, if molecules of the undissociated sub-stance diffuse from one side of the membrane to the other and then dissociate, there is appreciable net movement of the undissociated substance from one side of the membrane to the other. This phenomenon, which occurs in the gastrointestinal tract (see Chapter 25) and kidneys (see Chapter 38), is called nonionic diffusion. Donnan Effect When an ion on one side of a membrane cannot diffuse through the membrane, the distribution of other ions to which the membrane is permeable is affected in a

20. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 7 predictable way. For example, the negative charge of a nondiffusible anion hinders diffusion of the diffusible cations and favors diffusion of the diffusible anions. Consider the following situation, X Y K+ Cl Prot K+ Cl m in which the membrane (m) between compartments X and Y is impermeable to Prot but freely permeable to K+ and Cl. Assume that the concentrations of the an-ions and of the cations on the two sides are initially equal. Cl diffuses down its concentration gradient from Y to X, and some K+ moves with the negatively charged Cl because of its opposite charge. Therefore [K+ X] > [K+ Y] Furthermore, [K+ X] + [Cl X] + [Prot X] > [K+ Y] + [Cl Y] ie, more osmotically active particles are on side X than on side Y. Donnan and Gibbs showed that in the presence of a nondiffusible ion, the diffusible ions distribute them-selves so that at equilibrium, their concentration ratios are equal: [K+ X] = [Cl Y] [K+ Y] [Cl X] Cross-multiplying, [K+ X] [Cl X] = [K+ Y] [Cl Y] This is the GibbsDonnan equation. It holds for any pair of cations and anions of the same valence. The Donnan effect on the distribution of ions has three effects in the body. First, because of proteins (Prot) in cells, there are more osmotically active parti-cles in cells than in interstitial fluid, and since animal cells have flexible walls, osmosis would make them swell and eventually rupture if it were not for Na+K+ adenosine triphosphatase (ATPase) pumping ions back out of cells (see below). Thus, normal cell volume and pressure depend on Na+K+ ATPase. Second, because at equilibrium the distribution of permeant ions across the membrane (m in the example used here) is asym-metric, an electrical difference exists across the mem-brane whose magnitude can be determined by the Nernst equation (see below). In the example used here, side X will be negative relative to side Y. The charges line up along the membrane, with the concentration gradient for Cl exactly balanced by the oppositely di-rected electrical gradient, and the same holds true for K+. Third, since there are more proteins in plasma than in interstitial fluid, there is a Donnan effect on ion movement across the capillary wall (see below). Forces Acting on Ions The forces acting across the cell membrane on each ion can be analyzed mathematically. Chloride ions are pre-sent in higher concentration in the ECF than in the cell interior, and they tend to diffuse along this concentra-tion gradient into the cell. The interior of the cell is negative relative to the exterior, and chloride ions are pushed out of the cell along this electrical gradient. An equilibrium is reached at which Cl influx and Cl ef-flux are equal. The membrane potential at which this equilibrium exists is the equilibrium potential. Its magnitude can be calculated from the Nernst equa-tion, as follows: ECl = RT In ] [Clo ] FZCl [Cli where ECl = equilibrium potential for Cl R = gas constant T = absolute temperature F = the faraday (number of coulombs per mole of charge) ZCl = valence of Cl (1) [Clo ] = Cl concentration outside the cell ] = Cl concentration inside the cell [Cli Converting from the natural log to the base 10 log and replacing some of the constants with numerical val-ues, the equation becomes ECl = 61.5 log ] at 37 C [Cli ] [Clo Note that in converting to the simplified expression the concentration ratio is reversed because the 1 va-lence of Cl has been removed from the expression. ECl, calculated from the values in Table 12, is 70 mV, a value identical to the measured resting membrane potential of 70 mV. Therefore, no forces other than those represented by the chemical and elec-trical gradients need be invoked to explain the distribu-tion of Cl across the membrane. A similar equilibrium potential can be calculated for K+: EK = RT In +] = 61.5 log [Ko +] at 37 C [Ko +] [Ki FZK [Ki +]

21. 8 / CHAPTER 1 Table 12. Concentration of some ions inside and outside mammalian spinal motor neurons. Concentration (mmol/L of H2O) Equilibrium Inside Outside Potential Ion Cell Cell (mV) Na+ 15.0 150.0 +60 K+ 150.0 5.5 90 Cl 9.0 125.0 70 Resting membrane potential = 70 mV where EK = equilibrium potential for K+ ZK = valence of K+ (+1) [Ko +] = K+ concentration outside the cell [Ki +] = K+ concentration inside the cell R, T, and F as above In this case, the concentration gradient is outward and the electrical gradient inward. In mammalian spinal motor neurons, EK is 90 mV (Table 12). Since the resting membrane potential is 70 mV, there is some-what more K+ in the neurons than can be accounted for by the electrical and chemical gradients. The situation for Na+ is quite different from that for K+ and Cl. The direction of the chemical gradient for Na+ is inward, to the area where it is in lesser concen-tration, and the electrical gradient is in the same direc-tion. ENa is +60 mV (Table 12). Since neither EK nor ENa is at the membrane potential, one would expect the cell to gradually gain Na+ and lose K+ if only passive electrical and chemical forces were acting across the membrane. However, the intracellular concentration of Na+ and K+ remain constant because there is active transport of Na+ out of the cell against its electrical and concentration gradients, and this transport is coupled to active transport of K+ into the cell (see below). Genesis of the Membrane Potential The distribution of ions across the cell membrane and the nature of this membrane provide the explanation for the membrane potential. The concentration gradi-ent for K+ facilitates its movement out of the cell via K+ channels, but its electrical gradient is in the opposite (inward) direction. Consequently, an equilibrium is reached in which the tendency of K+ to move out of the cell is balanced by its tendency to move into the cell, and at that equilibrium there is a slight excess of cations on the outside and anions on the inside. This condition is maintained by Na+K+ ATPase, which pumps K+ back into the cell and keeps the intracellular concentra-tion of Na+ low. The Na+K+ pump is also electrogenic, because it pumps three Na+ out of the cell for every two K+ it pumps in; thus, it also contributes a small amount to the membrane potential by itself. It should be em-phasized that the number of ions responsible for the membrane potential is a minute fraction of the total number present and that the total concentrations of positive and negative ions are equal everywhere except along the membrane. Na+ influx does not compensate for the K+ efflux because the K+ channels (see below) make the membrane more permeable to K+ than to Na+. FUNCTIONAL MORPHOLOGY OF THE CELL Revolutionary advances in the understanding of cell structure and function have been made through use of the techniques of modern cellular and molecular biol-ogy. Major advances have occurred in the study of em-bryology and development at the cellular level. Devel-opmental biology and the details of cell biology are beyond the scope of this book. However, a basic knowl-edge of cell biology is essential to an understanding of the organ systems in the body and the way they func-tion. The specialization of the cells in the various organs is very great, and no cell can be called typical of all cells in the body. However, a number of structures (or-ganelles) are common to most cells. These structures are shown in Figure 14. Many of them can be isolated by ultracentrifugation combined with other techniques. When cells are homogenized and the resulting suspen-sion is centrifuged, the nuclei sediment first, followed by the mitochondria. High-speed centrifugation that generates forces of 100,000 times gravity or more causes a fraction made up of granules called the micro-somes to sediment. This fraction includes organelles such as the ribosomes and peroxisomes. Cell Membrane The membrane that surrounds the cell is a remarkable structure. It is made up of lipids and proteins and is semipermeable, allowing some substances to pass through it and excluding others. However, its perme-ability can also be varied because it contains numerous regulated ion channels and other transport proteins that can change the amounts of substances moving across it. It is generally referred to as the plasma membrane. The nucleus is also surrounded by a membrane of this

22. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 9 Secretory granules Centrioles Smooth endoplasmic reticulum Golgi apparatus Lipid droplets Rough endoplasmic reticulum Lysosomes Mitochondrion Nuclear envelope Nucleolus Globular heads Figure 14. Diagram showing a hypothetical cell in the center as seen with the light microscope. It is surrounded by various organelles. (After Bloom and Fawcett. Reproduced, with permission, from Junqueira LC, Carneiro J, Kelley RO: Basic Histology, 9th ed. McGraw-Hill, 1998.) type, and the organelles are surrounded by or made up of a membrane. Although the chemical structures of membranes and their properties vary considerably from one location to another, they have certain common features. They are generally about 7.5 nm (75 ) thick. The chemistry of proteins and lipids is discussed in Chapter 17. The major lipids are phospholipids such as phosphatidyl-choline and phosphatidylethanolamine. The shape of the phospholipid molecule is roughly that of a clothes-pin (Figure 15). The head end of the molecule con-tains the phosphate portion and is relatively soluble in water (polar, hydrophilic). The tails are relatively in-soluble (nonpolar, hydrophobic). In the membrane, the hydrophilic ends of the molecules are exposed to the aqueous environment that bathes the exterior of the cells and the aqueous cytoplasm; the hydrophobic ends meet in the water-poor interior of the membrane. In prokaryotes (cells such as bacteria in which there is no nucleus), the membranes are relatively simple, but in eukaryotes (cells containing nuclei), cell membranes contain various glycosphingolipids, sphingomyelin, and cholesterol. Many different proteins are embedded in the mem-brane. They exist as separate globular units and many pass through the membrane (integral proteins), whereas others (peripheral proteins) stud the inside and outside of the membrane (Figure 15). The amount of protein varies with the function of the mem-brane but makes up on average 50% of the mass of the membrane; ie, there is about one protein molecule per 50 of the much smaller phospholipid molecules. The proteins in the membranes carry out many functions. Some are cell adhesion molecules that anchor cells to their neighbors or to basal laminas. Some proteins function as pumps, actively transporting ions across the

23. 10 / CHAPTER 1 Figure 15. Biologic membrane. The phospholipid molecules each have two fatty acid chains (wavy lines) attached to a phosphate head (open circle). Proteins are shown as irregular colored globules. Many are integral proteins, which extend through the membrane, but pe-ripheral proteins are attached to the inside (not shown) and outside of the membrane, sometimes by glyco-sylphosphatidylinositol (GPI) anchors. membrane. Other proteins function as carriers, trans-porting substances down electrochemical gradients by facilitated diffusion. Still others are ion channels, which, when activated, permit the passage of ions into or out of the cell. The role of the pumps, carriers, and ion channels in transport across the cell membrane is discussed below. Proteins in another group function as receptors that bind neurotransmitters and hormones, initiating physiologic changes inside the cell. Proteins also function as enzymes, catalyzing reactions at the surfaces of the membrane. In addition, some glycopro-teins function in antibody processing and distinguish-ing self from nonself (see Chapter 27). The uncharged, hydrophobic portions of the pro-teins are usually located in the interior of the mem-brane, whereas the charged, hydrophilic portions are lo-cated on the surfaces. Peripheral proteins are attached to the surfaces of the membrane in various ways. One common way is attachment to glycosylated forms of phosphatidylinositol. Proteins held by these glyco-sylphosphatidylinositol (GPI) anchors (Figure 15) include enzymes such as alkaline phosphatase, various antigens, a number of cell adhesion molecules, and three proteins that combat cell lysis by complement (see Chapter 27). Over 40 GPI-linked cell surface proteins have now been described. Other proteins are lipidated, ie, they have specific lipids attached to them (Figure 16). Proteins may be myristolated, palmitoylated, or prenylated (ie, attached to geranylgeranyl or farnesyl groups). The protein structureand particularly the enzyme contentof biologic membranes varies not only from cell to cell but also within the same cell. For example, some of the enzymes embedded in cell membranes are different from those in mitochondrial membranes. In epithelial cells, the enzymes in the cell membrane on the mucosal surface differ from those in the cell mem-brane on the basal and lateral margins of the cells; ie, the cells are polarized. This is what makes transport across epithelia possible (see below). The membranes are dynamic structures, and their constituents are being constantly renewed at different rates. Some proteins are anchored to the cytoskeleton, but others move laterally in the membrane. For example, receptors move in the membrane and aggregate at sites of endocytosis (see below). Underlying most cells is a thin, fuzzy layer plus some fibrils that collectively make up the basement membrane or, more properly, the basal lamina. The basal lamina and, more generally, the extracellular ma-trix are made up of many proteins that hold cells to-gether, regulate their development, and determine their growth. These include collagens, laminins (see below), fibronectin, tenascin, and proteoglycans. Mitochondria Over a billion years ago, aerobic bacteria were engulfed by eukaryotic cells and evolved into mitochondria, providing the eukaryotic cells with the ability to form the energy-rich compound ATP by oxidative phosphenylation. Mitochondria perform other func-tions, including a role in the regulation of apoptosis (see below), but oxidative phosphorylation is the most crucial. Hundreds to thousands of mitochondria are in each eukaryotic cell. In mammals, they are generally sausage-shaped (Figure 14). Each has an outer mem-brane, an intermembrane space, an inner membrane, which is folded to form shelves (cristae), and a central matrix space. The enzyme complexes responsible for oxidative phosphorylation are lined up on the cristae (Figure 17). Consistent with their origin from aerobic bacteria, the mitochondria have their own genome. There is much less DNA in the mitochondrial genome than in the nuclear genome (see below), and 99% of the pro-teins in the mitochondria are the products of nuclear genes, but mitochondrial DNA is responsible for cer-tain key components of the pathway for oxidative phos-phorylation. Specifically, human mitochondrial DNA is a double-stranded circular molecule containing

24. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 11 Lipid membrane Cytoplasmic or external face of membrane N H O Gly Protein Protein Protein Protein Protein COOH N-Myristoyl S-Cys O O C CH2 O CH C H2 O O O P O Inositol O C O C NH2 S-Palmitoyl S-Cys NH2 Geranylgeranyl S-Cys NH2 C C Farnesyl GPI anchor (Glycosylphosphatidylinositol) Hydrophobic domain Hydrophilic domain Figure 16. Protein linkages to membrane lipids. Some are linked by their amino terminals, others by their car-boxyl terminals. Many are attached via glycosylated forms of phosphatidylinositol (GPI anchors). (Reproduced, with permission, from Fuller GM, Shields D: Molecular Basis of Medical Cell Biology. McGraw-Hill, 1998.) 16,569 base pairs (compared with over a billion in nu-clear DNA). It codes for 13 protein subunits that are associated with proteins encoded by nuclear genes to form four enzyme complexes plus two ribosomal and 22 transfer RNAs (see below) that are needed for pro-tein production by the intramitochondrial ribosomes. The enzyme complexes responsible for oxidative phosphorylation illustrate the interactions between the products of the mitochondrial genome and the nuclear genome. For example, complex I, reduced nicotinamide adenine dinucleotide dehydrogenase (NADH), is made up of 7 protein subunits coded by mitochondrial DNA and 39 subunits coded by nuclear DNA. The origin of the subunits in the other complexes is shown in Figure 17. Complex II, succinate dehydrogenase-ubiquinone oxidoreductase, complex III, ubiquinone-cytochrome c oxidoreductase, and complex IV, cytochrome c oxidase, act with complex I coenzyme Q, and cytochrome c to convert metabolites to CO2 and water. In the process, complexes I, III, and IV pump protons (H+) into the intermembrane space. The protons then flow through complex V, ATP synthase, which generates ATP. ATP synthase is unique in that part of it rotates in the gene-sis of ATP. Sperms contribute few, if any, mitochondria to the zygote, so the mitochondria come almost entirely from the ovum and their inheritance is almost exclusively maternal. Mitochondria have no effective DNA repair system, and the mutation rate for mitochondrial DNA is over 10 times the rate for nuclear DNA. A large number of relatively rare diseases have now been traced to mutations in mitochondrial DNA. These include for the most part disorders of tissues with high metabolic rates in which energy production is defective as a result of abnormalities in the production of ATP. Lysosomes In the cytoplasm of the cell there are large, somewhat irregular structures surrounded by membrane. The in-terior of these structures, which are called lysosomes, is more acidic than the rest of the cytoplasm, and external material such as endocytosed bacteria as well as worn-out cell components are digested in them. Some of the enzymes involved are listed in Table 13. When a lysosomal enzyme is congenitally absent, the lysosomes become engorged with the material the enzyme normally degrades. This eventually leads to one

25. 12 / CHAPTER 1 H+ CoQ H+ H+ H+ AS ADP ATP Cyt c Intramemb space Inner mito membrane Matrix space Complex Subunits from mDNA Subunits from nDNA I II III IV V 7 0 1 3 2 39 4 10 10 14 Figure 17. Formation of ATP by oxidative phosphorylation in mitochondria. As enzyme complexes I through IV convert 2-carbon metabolic fragments to CO2 and H2O), protons (H+) are pumped into the intermembrane space. The proteins diffuse back to the matrix space via complex V, ATP synthase, in which ADP is converted to ATP. The enzyme complexes are made up of subunits coded by mitochondrial DNA (mDNA) and nuclear DNA (nDNA), and the figures document the contribution of each DNA to the complexes. See text for further details. of the lysosomal storage diseases. For example, - galactosidase A deficiency causes Fabrys disease, and - galactocerebrosidase deficiency causes Gauchers dis-ease. These diseases are rare, but they are serious and can be fatal. Another example is the lysosomal storage disease called TaySachs disease, which causes mental retardation and blindness. Peroxisomes Peroxisomes are found in the microsomal fraction of cells. They are 0.5 mm in diameter and are surrounded by a membrane. This membrane contains a number of peroxisome-specific proteins that are concerned with transport of substances into and out of the matrix of the peroxisome. The matrix contains more than 40 en-zymes, which operate in concert with enzymes outside the peroxisome to catalyze a variety of anabolic and catabolic reactions. Several years ago, a number of syn-thetic compounds were found to cause proliferation of peroxisomes by acting on receptors in the nuclei of cells. These receptors (PPARs) are members of the nu-clear receptor superfamily, which includes receptors for steroid hormones, thyroid hormones, certain vitamins, and a number of other substances (see below). When activated, they bind to DNA, producing changes in the production of mRNAs. Three PPAR receptors, , and have been characterized. PPAR- and PPAR- have received the most attention because PPAR-s are activated by feeding and initiate increases in enzymes involved in energy storage, whereas PPAR-s are acti-vated by fasting and increase energy-producing enzyme activity. Thiazolidinediones are synthetic ligands for PPAR-s and they increase sensitivity to insulin, though their use in diabetes has been limited by their toxic side effects. Fibrates, which lower circulating triglycerides, are ligands for PPAR-s. Cytoskeleton All cells have a cytoskeleton, a system of fibers that not only maintains the structure of the cell but also permits it to change shape and move. The cytoskeleton is made up primarily of microtubules, intermediate filaments, and microfilaments, along with proteins that anchor them and tie them together. In addition, proteins and organelles move along microtubules and microfilaments from one part of the cell to another propelled by molec-ular motors. Table 13. Some of the enzymes found in lysosomes and the cell components that are their substrates. Enzyme Substrate Ribonuclease RNA Deoxyribonuclease DNA Phosphatase Phosphate esters Glycosidases Complex carbohydrates; glyco-sides and polysaccharides Arylsulfatases Sulfate esters Collagenase Proteins Cathepsins Proteins

26. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 13 Microtubules (Figures 18 and 19) are long, hol-low structures with 5-nm walls surrounding a cavity 15 nm in diameter. They are made up of two globular protein subunits: - and -tubulin. A third subunit, - tubulin, is associated with the production of micro-tubules by the centrosomes (see below). The and subunits form heterodimers (Figure 19), which aggre-gate to form long tubes made up of stacked rings, with each ring usually containing 13 subunits. The tubules also contain other proteins that facilitate their forma-tion. The assembly of microtubules is facilitated by warmth and various other factors, and disassembly is fa-cilitated by cold and other factors. The end where as-sembly predominates is called the + end, and the end where disassembly predominates is the end. Both processes occur simultaneously in vitro. Because of their constant assembly and disassembly, microtubules are a dynamic portion of the cell skeleton. They provide the tracks along with several different molecular motors for transport vesicles, organelles such as secretory granules, and mitochondria from one part of the cell to another. They also form the spindle, which moves the chromosomes in mitosis. Micro-tubules can transport in both directions. Microtubule assembly is prevented by colchicine and vinblastine. The anticancer drug paclitaxel (Taxol) binds to microtubules and makes them so sta-ble MF MT that organelles cannot move. Mitotic spindles can-not form, and the cells die. Intermediate filaments are 814 nm in diameter and are made up of various subunits. Some of these fila-ments connect the nuclear membrane to the cell mem-brane. They form a flexible scaffolding for the cell and help it resist external pressure. In their absence, cells rupture more easily; and when they are abnormal in hu-mans, blistering of the skin is common. Microfilaments (Figure 18) are long solid fibers 46 nm in diameter that are made up of actin. Not only is actin present in muscle (see Chapter 3), but it and its mRNA are present in all types of cells. It is the most abundant protein in mammalian cells, sometimes accounting for as much as 15% of the total protein in the cell. Its structure is highly conserved; for example, 88% of the amino acid sequences in yeast and rabbit actin are identical. Actin filaments polymerize and de-poidymerize in vivo, and it is not uncommon to find polymerization occurring at one end of the filament while depolymerization is occurring at the other end. The fibers attach to various parts of the cytoskeleton (Figure 110). They reach to the tips of the microvilli on the epithelial cells of the intestinal mucosa. They are also abundant in the lamellipodia that cells put out when they crawl along surfaces. The actin filaments in-teract with integrin receptors and form focal adhesion Figure 18. Left: Electron micrograph of the cytoplasm of a fibroblast, showing microfilaments (MF) and micro-tubules (MT). (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology, 10th ed. McGraw-Hill, 2003.) Right: Distribution of microtubules in fibroblasts. The cells are treated with a fluorescently labeled antibody to tubu-lin, making microtubules visible as the light-colored structures. (Reproduced, with permission, from Connolly J et al: Immunofluorescent staining of cytoplasmic and spindle microtubules in mouse fibroblasts with antibody to protein. Proc Natl Acad Sci U S A 1977;74:2437.)

27. 14 / CHAPTER 1 24 nm 5 nm () End (+) End Cross section Longitudinal section -Tubulin -Tubulin Tubulin heterodimers Figure 19. Microtuble, showing assembly by addition of - and -tubulin dimers and disassembly by removal of these units. (Modified from Borison WF, Boupaep EL: Medical Physiology, Saunders, 2003). complexes, which serve as points of traction with the surface over which the cell pulls itself. In addition, some molecular motors use microfilaments as tracks. Molecular Motors The molecular motors that move proteins, organelles, and other cell parts (their cargo) to all parts of the cell are 100500-kDa ATPases. They attach to their cargo and their heads bind to microtubules or actin polymers. Hydrolysis of ATP in their heads causes the molecules to move. There are two types of molecular motors: those producing motion along microtubules and those producing motion along actin (Table 14). Examples are shown in Figure 111, but each type is a member of a superfamily, with many forms throughout the animal kingdom. The conventional form of kinesin is a double-headed molecule that moves its cargo toward the + ends of microtubules. One head binds to the microtubule and then bends its neck while the other head swings forward and binds, producing almost continuous movement. Some kinesins are associated with mitosis and meiosis. Other kinesins perform different func-tions, including, in some instances, moving cargo to the end of microtubules. Dyneins have two heads, with their neck pieces embedded in a complex of proteins (Figure 111). Cy-toplasmic dynein has a function like that of conven-tional kinesin, except that it moves particles and mem-branes to the end of the microtubules. Axonemal dynein oscillates and is responsible for the beating of flagella and cilia (see below). The multiple forms of myosin in the body are divided into 18 classes. The heads of myosin molecules bind to actin and produce motion by bending their neck regions (myosin II) or walking along microfilaments, one head after the other (myosin V). In these ways, they perform functions as diverse as contraction of muscle (see Chapter 3) and cell migration. Actin Adducin Tropomyosin Glycophorin C Ankyrin chain Tropomodulin chain Anion exchanger (Band 3) Membrane 4.1 4.1 4.2 Actin 4.9 Spectrin Figure 110. Membrane-cytoskeleton attachments in the red blood cell, showing the various proteins that anchor actin microfilaments to the membrane. Some are identified by numbers (4.1, 4.2, 4.9), whereas others have received names. (Reproduced, with permission, from Luna EJ, Hitt AL: Cytoskeleton-plasma membrane interactions. Science 1992;258:955.)

28. THE GENERAL & CELLULAR BASIS OF MEDICAL PHYSIOLOGY / 15 Table 14. Examples of molecular motors. Microtubule-based Conventional kinesin Dyneins Actin-based Myosins IV Centrosomes Near the nucleus in the cytoplasm of eukaryotic animal cells is a centrosome. The centrosome is made up of two centrioles and surrounding amorphous pericentri-olar material. The centrioles are short cylinders arranged so that they are at right angles to each other. Microtubules in groups of three run longitudinally in the walls of each centriole (Figure 14). Nine of these triplets are spaced at regular intervals around the cir-cumference. The centrosomes are microtubule-organizing cen-ters (MTOCs) that contain -tubulin. The micro-tubules grow out of this -tubulin in the pericentriolar material. When a cell divides, the centrosomes dupli-cate themselves, and the pairs move apart to the poles of the mitotic spindle, where they monitor the steps in cell division. In multinucleate cells, a centrosome is near each nucleus. Cilia Cells have various types of projections. True cilia are dynein-driven motile processes that are used by unicel-lular organisms to propel themselves through the water and by multicellular organisms to propel mucus and other substances over the surface of various epithelia. They resemble centrioles in having an array of nine tubular structures in their walls, but they have in addi-tion a pair of microtubules in the center, and two rather than three microtubules are present in each of the nine circumferential structures. The basal granule, on the other hand, is the structure to which each cilium is an-chored. It has nine circumferential triplets, like a centri-ole, and there is evidence that basal granules and centri-oles are interconvertible. Cell Adhesion Molecules Cells are attached to the basal lamina and to each other by cell adhesion molecules (CAMs) that are promi-nent parts of the intercellular connections described below. These adhesion proteins have attracted great at-tention in recent years because they are important in embryonic development and formation of the nervous system and other tissues; in holding tissues together in Cytoplasmic dynein 4 nm Cargo Light chains Conventional kinesin 80 nm Cargo-binding domain Head 1 Head 2 Head 2 Head 1 Actin ADP ADP ATP Myosin V Figure 111. Three examples of molecular motors. Conventional kinesin is shown attached to cargo, in this case a membrane-bound organelle. The way that myosin V walks along a microtuble is also shown. Note that the heads of the motors hydrolyze ATP and use the energy to produce motion.

29. 16 / CHAPTER 1 Tight junction (zonula occludens) Zonula adherens Desmosomes Gap junctions Hemidesmosome Figure 112. Intercellular junctions in the mucosa of the small intestine. Focal adhesions are not shown in detail. adults; in inflammation and wound healing; and in the metastasis of tumors. Many pass through the cell mem-brane and are anchored to the cytoskeleton inside the cell. Some bind to like molecules on other cells (ho-mophilic binding), whereas others bind to other mole-cules (heterophilic binding). Many bind to laminins, a family of large cross-shaped molecules with multiple re-ceptor