REGULATORY MECHANISMS . -1n- GASTROINTESTINAL FUNCTION Edited by T. S. GAGINELLA First published 1995 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2018 by CRC Press © 1995 by Taylor & Francis CRC Press is an imprint of Taylor & Francis Group, an lnforma business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: 95008329 Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-1-138-50643-5 (hbk) ISBN 13: 978-0-203-71050-0 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com PREFACE The gastrointestinal tract is controlled physiologically by complex neural, paracrine, and hormonal factors. Gastrointestinal secretion and motility can be modulated pharmacologically by drugs that directly or indirectly influence gut blood flow, neurotransmitter release in the enteric nervous system or peptide hormone libera­ tion. This book brings together a variety of topics from the perspective of current knowledge on regulation of gastrointestinal function. An alternative title might have been Integrative Mechanisms in Gastrointestinal Pharmacology, for, al­ though physiology is discussed, the emphasis is on pharmacologic regulation of the mucosa and muscle of the gastrointestinal tract. At first glance, the topics appear diverse, but perusal of the entire text will convince the reader of the interrelation­ ships and coordination among the mechanisms discussed. The authors of each chapter were chosen for their insight into areas of research in which they have had practical experience. When appropriate, they have included information on methodology in terms of ways to avoid pitfalls in interpretation of experimental results. The importance of bicarbonate secretion in providing protection against ulcer­ ation of the duodenal mucosa is covered in great detail and should awaken the reader to this important but infrequently reviewed area of research. Calcium and cyclic AMP are recognized as intracellular mediators of intestinal secretion. Be­ cause an understanding of their interrelationships is essential to unraveling the mechanism(s) responsible for chloride secretion by the intestinal mucosa, these are thoroughly discussed. Likewise, an appreciation for the integrative complexity of intestinal fluid secretion cannot be gained without knowledge of the mechanisms discussed in the chapters concerned with neural reflex modulation, microcircula­ tion, and nitric oxide. Serotonin, a well-recognized effector of smooth muscle contractility, is covered, as are the important but less often recognized mediators, dopamine and endothelins. The central nervous system also modulates gastrointes­ tinal motor (and secretory) activity. The book is thus rounded-out by inclusion of the last chapter, which covers the involvement of brain loci in the control of gastrointestinal function. I wish to thank all of the authors for their scholarly contributions to this book. The team assembled is truly an international one. It has been personally satisfying to see their efforts result in a book that, it is hoped, will provide those who read it with better appreciation and greater insight into the exciting challenges we still face in gastrointestinal research. T. S. Gaginella Madison, Wisconsin THE EDITOR Timothy S. Gaginella, Ph.D., is Adjunct Professor of Pharmacology in the School of Pharmacy, the University of Wisconsin, and is a consultant to the pharmaceutical industry. Dr. Gaginella earned a B.S. degree in Pharmacy in 1968, an M.S. in 1972, and a Ph.D. in Pharmacology in 1974, all from the University of Wisconsin, Madison. After a two-year Research Fellowship in gastroenterology at the Mayo Clinic, Dr. Gaginella joined the Ohio State University College of Phar­ macy as Assistant Professor of Pharmacology. Subsequently, he held the positions of Associate Professor of Pharmacology at the College of Pharmacy and Associate Professor of Medicine and Physiology at the College of Medicine, The Ohio State University; Research Group Chief, Department of Pharmacology, Hoffmann LaRoche, Inc.; Director of Gastrointestinal Biology, Searle Research and Develop­ ment; and Vice President, Aphton Corporation. Dr. Gaginella is a member of the American Gastroenterological Association, the American Physiological Society, the American Society for Pharmacology and Experimental Therapeutics (ASPET), and the Gastrointestinal Research Group (GRG). He is chairman of the ASPET Section for Gastrointestinal Pharmacology, chairman of the Gastrointestinal Pharmacology Section of the International Union of Pharmacology (IUPHAR), and a member of the GRG Steering Committee. Dr. Gaginella serves as a Specific Field Editor for Gastrointestinal Pharmacol­ ogy for the Journal of Pharmacology and Experimental Therapeutics, and he has been or is now a member of the editorial boards of the American Journal of Physiology, Digestive Diseases, and Sciences and Annals of Pharmacotherapy. Dr. Gaginella's research interests include the effect of drugs on gastrointestinal absorption and secretion, particularly the mechanism of action of laxatives, antidiarrheal drugs, and drugs used as therapy for inflammatory bowel disease. His research has been funded by the NIH, the Crohn's and Colitis Foundation, and the pharmaceutical industry. Dr. Gaginella is the recipient of an NIH Research Career Development award, and has served on various NIH grant review committees. He is co-inventor on one patent, and his bibliography includes more than 150 peer- reviewed research articles and reviews. CONTRIBUTORS Vincenzo Calderaro, M.D. David Mailman, Ph.D. Faculty of Medicine Professor of Biology Institute of Pharmacology Department of Biology and Toxicology University of Houston Second University Houston, Texas Naples, Italy Timothy S. Gaginella, Ph.D. Richard W. McCallum, M.D. Adjunct Professor of Pharmacology Department of Internal Medicine School of Pharmacy Division of Gastroenterology University of Wisconsin University of Virginia Health Madison, Wisconsin Sciences Center Charlottesville, Virginia Pamela J. Hornby, Ph.D. Associate Professor Mark J. S. Miller, Ph.D. Department of Pharmacology Professor and Experimental Therapeutics Department of Pediatrics Louisiana State University Louisiana State University Medical Center Medical Center New Orleans, Louisiana New Orleans, Louisiana Mats Jodal, M.D., Ph.D. Associate Professor of Physiology Susumu Okabe, Ph.D. Department of Physiology and Professor Pharmacology Department of Applied Pharmacology Göteborg University of Medicine Kyoto Pharmaceutical University Göteborg, Sweden Kyoto, Japan Zbigniew K. Krowicki, M.D., Ph.D. Research Assistant Professor Chung Owyang, M.D. Department of Pharmacology Professor of Internal Medicine and Experimental Therapeutics Division of Gastroenterology Louisiana State University University of Michigan Medical Center Medical Center New Orleans, Louisiana Ann Arbor, Michigan Ove Lundgren, M.D., Ph.D. Professor of Physiology Giles A. Rae, Ph.D. Department of Physiology and Full Professor of Pharmacology Pharmacology Department of Pharmacology Göteborg University of Medicine Universidade Federal de Santa Catarina Göteborg, Sweden Florianopolis, Brazil Francesco Rossi, M.D. Koji Takeuchi, Ph.D. Faculty of Medicine Professor Institute of Pharmacology Department of Pharmacology and Ex­ and Toxicology perimental Therapeutics Second University Kyoto Pharmaceutical University Naples, Italy Kyoto, Japan Terence K. Smith, Ph.D. John W. Wiley, M.D. Assistant Professor Associate Professor Departments of Internal Medicine Department of Internal Medicine and Physiology Division of Gastroenterology Division of Gastroenterology Gastroenterology Research Unit University of Virginia Health University of Michigan Sciences Center Medical Center Charlottesville, Virginia Ann Arbor, Michigan Toku Takahashi, M.D., Ph.D. Research Investigator Department of Internal Medicine Division of Gastroenterology University of Michigan Medical Center Ann Arbor, Michigan TABLE OF CONTENTS Chapter 1 Gastroduodenal Bicarbonate Secretion — Pharmacologie Modulation and Contribution to Mucosal Protection..................................................................1 Takeuchi and Okabe Chapter 2 Intestinal Chloride Secretion: Cyclic AMP and Ca2+ Interactions....................27 Calderaro and Rossi Chapter 3 Neural Reflex Modulation of Intestinal Epithelial Transport.............................99 Jodal and Lundgren Chapter 4 Importance of the Microcirculation to Intestinal Secretion.............................. 145 Mailman Chapter 5 Nitric Oxide as a Mediator of Intestinal Mucosal Function............................. 199 Miller and Gaginella Chapter 6 Serotonin Mediation of Intestinal Peristalsis......................................................219 Smith and McCallum Chapter 7 Dopaminergic Mechanisms in Gastrointestinal Motility...................................241 Wiley, Takahashi, and Owyang Chapter 8 Pharmacology of Endothelins in the Gastrointestinal Tract.............................257 Rae Chapter 9 Hindbrain Neuroactive Substances Controlling Gastrointestinal Function.......................................................................................277 Krowicki and Hornby Index 321