Table Of ContentREGULATORY
MECHANISMS
.
-1n-
GASTROINTESTINAL
FUNCTION
Edited by
T. S. GAGINELLA
First published 1995 by CRC Press
Taylor & Francis Group
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Reissued 2018 by CRC Press
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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
