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Home , Digestion, Gastric acid

A History of Gastric and A History of Gastric Secretion and Digestion Experimental Studies to 1975

HORACE W. DAVENPORT William Beaumont Professor of Physiology Emeritus The University of Michigan

Springer New Y ork 1992 Copyright © 1992 by the American Physiological Society Originally published by American Physiological Society in 1992 Softcoverreprint of the bardeover 1st edition 1992

All rights reserved. No partoftbis publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission ofOxford University Press.

Library ofCongress Cataloging-in-Publication Data Davenport, Horace Willard, 1912- A history of gastric secretion and digestion : experimental studiesto 1975 I Horace W. Davenport. p. cm. lncludes bibliographical references and index. ISBN 978-1-4614-7602-3 (eBook) DOI 10.1007/978-1-4614-7602-3 I. -History. 2. Gastric-Secretion-Research-History. 3. Digestion-Research-History. I. Title. [DNLM: I. Digestion. 2. Gastric -secretion. 3. Gastroenterology-history. 4. Research-history. 5. -chemistry. 6. Stomach-physiology. Wlll.l D247h] QP145.D325 1992 612.3'2'072-dc20 DNLM/DLC for Library ofCongress 91-31832

987654321 For Charles F. Code, known to every gastroenterologist as "Charlie Code" and as their preeminent physiologist for the last fifty years Preface

For centuries men speculated about the process of gastric digestion, but Iate in the eighteenth and early in the nineteenth centuries physiologists, both physicians and laymen, began to accumulate experimental evidence about its . At the same time, others discovered that the stomach is capable of secreting a strong mineral acid, and the questions of how that secretion is produced and how it is controlled became enduring problems. A Iittle later, the discovery that an acid extract of dead is capable of digesting meat put the study of gastric secretion and digestion on a firm mechanistic foundation. From that time to the present, physi• ologists have assiduously investigated gastric secretion and digestion, with the result that knowledge ofthose topics is as comprehensive and penetrating as isthat about other physiological processes. In addition, that knowledge is the basis of discrimi• nating and effective clinical practice. I have described the experimental study of gastric secretion and digestion for two reasons. The firstisthat the successes and some ofthe failures ofphysiologists over two centuries are important parts of intellectual history that deserve to be recorded. The second is that some of those who use the accumulated knowledge every day are curious about its genesis. I assume that my readers have the technical knowledge to understand what I have written. If my account does not fully satisfy their curiosity, I have provided references that will open the path to further study. This account is necessarily conditioned by my own knowledge, ability, and enterprise, and those have their Iimits. Furthermore, I Iimit my account by begin• ning with the period 1777 to 1833 when the pioneers of experimental gastroenter• ology, Edward Stevens, William Beaumont, Johann Eberle, and their contempo• raries, began to gather experimental evidence. I end in 1975, the date of Charlie Code's retirement from the Mayo Clinic and Mayo Foundation, for ifl attempted to bring the account more nearly up-to-date, it would have degenerated into an indigestible review of current work. I have myself studied gastric physiology in the laboratory for more than 40 viii / PREFACE years, and some readers may think I have unduly emphasized my own work. That may be the case, and the limits of my own outlook may have prevented me from giving appropriate weight to the work ofothers. A far more restrictive limit has been imposed by an attitude typical of one who has been a professor of physiology in an American medical school all bis professionallife. I and my colleagues on medical faculties assume, often unconsciously, that the proper aim of physiological research is to reach an understanding of normal and abnormal function in the being. We may work at the molecular or subcellular level, or we may use the ubiquitous medical student or patient as our experimental , but our goal is the same. Consequently, when I write about the history ofthe physiology of gastric secretion and digestion, I am writing about a very limited number of species, the human sub• ject and the dog, cat, and frog. I completely ignore physiology and the large and diverse knowledge of the physiology of the stomach in other species, invertebrate as well as . I make no apology for the narrowness of my out• look, for I believe my potential readers share it.

Ann Arbor, Mich. H.W.D. September 1991 Acknowledgments

My greatest debt is to the University of Michigan and to Jack Kostyo and John Williams, my successors as chairmen ofthe department ofphysiology, for allowing me the use of an office long past my retirement from the faculty. The university's Taubman Medical Library and Hateher Graduate Library have been rieb resources, and their reference librarians have been uniformly helpful. I am grateful to the many gastroenterologists who made my task easier by sending me their bib• liographies and in particular to Paul Guth, who took the trouble to find a Iist of Morton Grossman's numerous publications. Charlie Code gave me a copy ofhis even moreimpressive bibliography and a guide to the work ofhis colleagues at the Mayo Clinic. Code read my original typescript, and bis comments and corrections improved it. I am, however, entirely responsible for errors, oversights, and misin• terpretations. Contents

1 . Secretion of , 3

Site of Secretion, 3 Structure ofthe Oxyntic Cell, 4 Site of Appearance of Acid, 5

Concentration of Acid, 8 Free and Combined Acid in the Human Stomach, 8 In the Dog: Two Components, l3 The Problem ofTonicity, 18 An Alternative to Two Components: Back-, 19

Secretion of Anions, 24 Bromide and Chloride, 24 Active Secretion ofChloride: Adrian Hogben, 27 Iodide, 29

Mechanism of Acid Secretion, 32 in Parietal Cells, 33 Thiocyanate and Carbonic Anhydrase, 36 Carbonic Anhydrase and Sulfanilamide, 39 Digression on Sulfonamide Secretion into Gastric Juice, 41

Postwar Theories of the Mechanism, 46 The Redox Theory: E. J. Conway, 46 Acid Secretion by the Frog Stomach: Robert E. Davies, 47 ls the Ratio ofQuotients Greater Than 4?, 51 xii / CONTENTS

Electrophysiology ofSecretion: Warren S. Rehm, 56 Electrolyte Composition ofthe Gastric Mucosa, 59 Chloride Transport by Isolated Oxyntic Cells, 62 Asymmetry ofthe Gastric Mucosa, 64 Identification ofPotassium Fluxes, 67 Thiocyanate Again, 67 Potential Differences Caused by Ion Transport, 68 Energy for Acid Secretion, 69 The Canalicular Membrane, 71 SUMMARY Secretion of Hydrochiarie Acid as of 1975, 74

2. Pepsinsand Pepsinogens, 76

Chemistry of to 1900, 76 : Their Names, 76 Characterization of Proteins, 77 Organic Components of Proteins, 78 Gastric Digestion ofProteins, 78 The Discovery of , 80 Does Gastric Juice Merely Dissolve Proteins?, 81 ChiefCells and Their Contents, 82

Chemistry of Pepsin and lts Substrate, 84 The Bond, 84 Characteristics of Proteins: Their Individuality, 85 Characteristics of Proteins: Molecular Weight, 85 Characteristics of Proteins: Sequence, 85 Characteristics of Proteins: Configuration, 86

Pepsin as a and a Proteolytic , 87 Is Pepsin a Protein?, 87 Activity ofPepsin: Bonds Split, 89 Pepsinogen: Crystallization and Properties, 89 Pepsinogen in Urine and , 89 Source ofUropepsin, 91 Clinical Studies ofSerum Pepsinogen and Uropepsin, 92 Uropepsin and Stress, 92

Multiple Pepsinsand Pepsinogens, 94 Questions About Pepsin, 94 S.Oren S.Orensen's Contribution, 94 Pepsin's pH Activity Curve, 95 CONTENTS / xiii

New Methods, New Pepsins, 96 SUMMARY Pepsinsand Pepsinagens as of 1975, 99

3. and Cell Renewal, 101

The Second Component of Gastric Secretion, 101 ldentification ofthe Second Component, 101 lnorganic Constituents by Extrapolation, 102 lnorganic Constituents by Analysis, 103 Mucus: The Organic Constituent, 104 Sources ofGastric Mucus, 105 Structure ofGastric Mucus, 107 Heterogeneity ofGastric Mucus, 111 Discovery ofthe lntrinsic Factor, 111 Nature ofthe lntrinsic Factor, 115 Source ofthe lntrinsic Factor, 116 Gastrone, 11 7 Functions ofMucus, 117 M ucus and Pepsin: Diffusion and Inhibition, 118 Mucus and Diffusion of Acid, 123 Nervous Control ofMucus Secretion, 123

Cell Turnover, 125 Early Studies ofCell Replacement, 125 Arrest of Mitosis, 125 Radioautography, 126 Synthesis ofCell Components, 126 Use ofTritiated Thymidine, 127 Origin ofParietal and ChiefCells, 128 SUMMARY Mucus and Cell Renewal as of 1975, 131

4. Reflex Control of Gastric Secretion, 134

Inhibition of Gastric Secretion, 134

Local Reflex Stimulation, 136

Gastric and Vagal Reflexes, 138 Pouches and Their Reflex Control, 140 Reflexes from the lntestine, 144 Efferent Pathways, 144 The Peripheral Nerve Center, 145 xiv / CONTENTS

Insulin and the Vagus, 146 2-Deoxy-o- and the Vagus, 148 The Vasovagal Reflex, 148 Psychic Secretion in Man, 148 SUMMARY Reflex Control of Gastric Secretion as of 1975, 151

5. , 153

Histamine and Peptic Ulcer, 153 Frank Mann and Experimental Peptic Ulceration, 153 Preventing Mann-Williamson Ulcers: Urogastrone, 155 Charlie Code's Apprenticeship with Histamine, 157 Charlie Code's Apprenticeship as a Gastroenterologist, 159

Histamine as a Stimulant of Gastric Secretion, 160 Histamine as a Stimulant of Acid Secretion, 160 Histamine as a Stimulant of Pepsin Secretion, 161 Quantitative Studies: Mass, 162 Histalog, 165 lnteractions of Histamine with Other Stimulants, 165

H2 Blockade, 167

ls Histamine the Final Common Mediator?, 168 Methylation of Histamine in the Gastric Mucosa, 177 SUMMARY Histamine and Peptic Ulcer as of 1975, 184

6. Chemical Control of Gastric Secretion, 187

Chemical Control of Pancreatic Secretion, 187 Discovery of , 188

Chemical Control of Gastric Secretion, 190 J. S. Edkins and , 190 Russian Acceptance of Chemical Control, 191 lvy's Proof ofa Humoral Mechanism, 194

Confirmation of Humoral Control of Gastric Secretion, 195 R. K. S. Lim in Edinburgh, 195 R. K. S. Lim in Chicago, 196 R. K. S. Lim in China: Stimulation ofSecretion, 199 R. K. S. Lim in China: Inhibition ofSecretion, 200 Tests ofthe Gastrin Hypothesis, 201 CONTENTS I XV

From Humor to , 204 Proof of a Hormonal Mechanism, 204 Analysis ofGastrin Release: Chemical Releasers, 205 Analysis ofGastrin Release: Vagal Control, 208 Acid Inhibition ofGastrin Release, 210 Local Nervous Control of Gastrin Release, 211 An Antral Chalone?, 214

Chemistry of Gastrin, 216 Sirnon Komarov's Gastrin, 217 Failures to Isolate Gastrin, 219 Gregory and Tracy's Success, 221 , 223 Numbering the Gastrin Sequence, 223 In the Last Ditch: A. C. Ivy and '"Gastreen," 226

Radioimmunoassay of Gastrin, 226 Yalow and Berson Begin to Measure Gastrin, 229 Multiple , 229 Comparative Potency ofthe Gastrins, 231

Cellular Source of Gastrin, 233 The , 233 G Cells in Disease, 234 Multiple Endocrine Adenomatosis, 235 The APUD Concept, 236 A Common Orig~n for APUD Cells?, 236

To 1975,239 Reevaluation of Neural Control, 241 Bombesin as a Gastrin Releaser, 242 What Is Enterogastrone?, 243 Noncompetitive and Competitive Inhibition, 246 Trophic Actions ofGastrin and , 251 SUMMARY Chemical Control of Gasric Secretion as of 1975, 256

7. The Gastric Mucosalßarrier, 258

The Concept of the Gastric Mucosal Barrier, 258 Cope's and Code's Studies ofthe Barrier, 260 A Problem and lts Proposed Solution, 261 xvi / CONTENTS

Significance of a Broken Barrier, 263 Fatty Acidsand Their Salts, 264 Detergents, 265 Urea, 266

Stimulation of Secretion, 267 Aspirin Darnage to the Gastric Mucosa, 267 Histamine Release, 269 Stimulation ofPepsin Secretion, 271

Back-Diffusion: Fact or Fiction?, 272 Li+ asa Markerfor H+, 273 Evidence for lncreased Mucosal Permeability, 273 SUMMARY The Gastric Mucosol Barrier as of 1975,275

8. Gastric Blood Flow and Secretion, 277

Anatomy of the Gastric Circulation, 278

Functional Significance of Arterial Anastomoses, 281

Physical Methods for Estimating Gastric Blood Flow, 281 Through the Mucosa, 281 Through the Entire Stomach, 282 Blood Flow Fractionated, 286 Blood Flow Partitioned: Arteriovenous Shunts, 291 Gastric Blood Flow in Goteborg, 292 Stress and Gastric Blood Flow, 293

A Chemical Method for Measuring Mucosal Flow, 295 Aminopyrine Clearance, 295 Uncritical Use of Aminopyrine Clearance: Mucosal Damage, 298 Uncritical Use of Aminopyrine Clearance: lschemia, 300 Critical Study of Aminopyrine Clearance: Microspheres, 303 SUMMARY Gastric Blood Flow and Secretion to 1975,307

9. Gastric Digestion and Absorption, 309

Gastric Absorption of Drugs, 309

Gastric Digestion, 313 Methods for Study of Gastric Digestion, 313 Early Chemistry, 314 CONTENTS / xvii

Enzymatic Digestion of as of 1900, 316 Salivary Digestion ofStarch in the Stomach, 317 Consequences of Separation of Gastric Contents, 318 in the Stomach: Lactic Acid, 320 Gastric Digestion ofFat, 321 Gastric Response to Protein in a Meal, 324 Gastric Digestion and Absorption ofProtein to 1907,326

E. S. London's Study of Digestion and Absorption, 329 London 's Program and Methods, 330 Gastric Digestion ofProtein, 332 Gastric Absorption ofProtein Digestion Products, 334 Gastric Digestion and Absorption ofCarbohydrate, 336 Gastric Digestion ofFat, 336 Gastric Digestion ofMixtures, 337

From 1912 to 1975, 340 SUMMARY Gastric Digestion and Absorption as of 1975, 341

Notesand References, 345 Name Index, 403 Subjectlndex,409