Mediators and Drugs in Gastrointestinal Motility II: Endogenous and Exogenous Agents

401 Pages·1982·25.647 MB·English

by  G. Bertaccini (auth.), Professor Giulio Bertaccini M.D. (eds.)

Mediators and Drugs in
Gastrointestinal Motility II
Endogenous and Exogenous Agents
Contributors
A. Bennett· G. Bertaccini . E. Corazziari . E. E. Daniel
M.A. Eastwood· G.l Sanger' A.N. Smith· A. Torsoli
Editor
G. Bertaccini
Springer-Verlag Berlin Heidelberg New York 1982
Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 59/11
Editorial Board
G. V. R. Born, London· A. Farah, Rensselaer, New York
H. Herken, Berlin· A. D. Welch, Memphis, Tennessee
Advisory Board
S. Ebashi· E. G. Erdos· V Erspamer· U. S. von Euler· W S. Feldberg
G. B. Koelle· O. Krayer· M. Rocha e Silva· 1. R. Vane· P G. Waser
ISBN-13: 978-3-642-68476-0 e-ISBN-I3 978-3-642-68474-6
001: 10.1007/978-3-642-68474-6
List of Contributors
Professor A. BENNETT, Department of Surgery, King's College Hospital, Medical
School, University of London, Denmark Hill, GB-London SE58RX
Professor G. BERTACCINI, Head of the Department of Pharmacology, School of
Medicine, University of Parma, 1-43100 Parma
Professor E. CORAZZIARI, Cattedra di Gastroenterologia, II Clinica Medica,
Policlinico Umberto I, University of Rome, 1-00100 Roma
Professor E. E. DANIEL, Faculty of Health Sciences, Department of Neurosciences,
McMaster University, 1200 Main Street West, Hamilton, Ontario,
Canada L8S 4J9
Dr. M. A. EASTWOOD, Gastrointestinal Unit, University of Edinburgh, Western
General Hospital, GB-Edinburgh EH42XU
Dr. G. J. SANGER, Beecham Pharmaceuticals, Medicinal Research Centre,
GB-Harlow, Essex CM 19 SAD
A. N. SMITH, Gastrointestinal Unit, University of Edinburgh, Western General
Hospital, GB-Edinburgh EH42XU
Professor A. TORSOLI, Cattedra di Gastroenterologia, II Clinica Medica, Poli
clinico Umberto I, University of Rome, 1-00100 Roma
Preface
This volume places more emphasis on endogenous mediators of gut motility than
on drugs used to treat patients with deranged motility. In this respect it resembles
most other books on gastroenterology, for while only a relatively small number of
drugs are really useful for a rational therapy, a tremendous amount of data is
available on neural and hormonal factors regulating the motility of the alimentary
canal. Moreover, it must be considered that some of the drugs which can routinely
be employed to modify deranged motility of the digestive system are represented by
pure or slightly modified endogenous compounds (e.g., cholecystokinin, its C
terminal octapeptide and caerulein), and it is easy to foresee that their number is
destined to increase in the near future. Other drugs are simply antagonists of
physiological substances acting on specific receptors (e.g., histamine H -blockers
2
and opioid compounds).
The real explosion of research in this field and the extreme specialization often
connected with the use of very sophisticated techniques and methodologies would
probably have required a larger number of experts to cover some very specific fields
from both an anatomical (lower esophageal sphincter, stomach, pylorus, small and
large intestine) and a biochemical (hormones, candidate hormones, locally active
substances, neurotransmitters etc.) point of view. However, in order to avoid
involving too many collaborators (originally only one volume on gastrointestinal
motility had been planned) and because many outstanding investigators were
already engaged at the time when the work had to be organized. I decided to write
about some topics myself although I had scarcely done sufficient work to justify
authorship: I hope that this decision will at least result in greater homogeneity and
perhaps objectivity. To avoid excessive length, the motility of the biliary system was
not included in this volume, which nevertheless, attempts to provide the reader with
the best of more than 2,000 papers. Our aim has been to interpret and clarify
concepts derived from different disciplines and to provide not only an exhaustive
compilation of data but also a synthesis, sometimes critical, of most pieces of
information. Controversies were reported even though they sometimes represented
a certain overlapping: however, in my opinion the diversity of views may be
provocative and may act as a useful incentive for workers in the field.
As for exogenous agents, the book is not intended to be encyclopedic in its
treatment of gastrointestinal pharmacology: the most important agents, such as the
drugs acting on opioid receptors, some anticholinergics, and some laxatives, are
extensively discussed, whereas others, like the new histamine H -receptor antago
2
nists, which are mainly involved in secretory processes are barely mentioned.
Finally a consistent number of figures and tables summarizes useful information
VIII Preface
and clarifies the most impressive data. The literature survey which formed the basis
for the book was concluded in July 1981.
I wish to thank Professor H. HERKEN for selecting me as Editor of this volume
and for giving me the opportunity of reporting in many chapters the results of my
personal experience. I am very grateful to the authors for accepting the invitation to
contribute, even though not all ofthem managed to meet the deadline for delivery of
manuscripts. The delay in publication which this caused is offset by the excellent
quality of this work. I should also like to thank Dr. GABRIELLA CORUZZI and Dr.
CARMELO SCARPIGNATO of the Institute of Pharmacology, University of Parma
Medical School, who helped me to overcome all the difficulties (and there were
quite a lot) which I encountered during the drawing up of the manuscript and the
collection of references.
GmLIO BERTACCINI
Contents
CHAPTER 1
Endogenous Substances Which Can Affect Gastrointestinal Motility
G. BERTACCINI. With 1 Figure
General Introduction 1
References . . . . . . . . . 6
CHAPTER 2a
Peptides: Gastrointestinal Hormones. G. BERTACCINI. With 16 Figures
Gastrin
A. Introduction. . . . . . . . . . . . . . 11
B. Effects on the Lower Esophageal Sphincter 14
I. Excitation . . . . 14
1. In Vitro Studies 14
2. In Vivo Studies 15
II. Inhibition . . . . 18
C. Effects on the Stomach 19
I. In Vitro Studies. . 20
1. Experimental Animals. 20
2. Humans ...... . 21
II. In Vivo Studies. . . . . 22
1. Experimental Animals. 22
2. Humans ...... . 23
D. Effects on the Small and Large Intestine. 25
I. In Vitro Studies. . . . . 25
II. In Vivo Studies. . . . . 30
1. Experimental Animals. 30
2. Humans. 31
E. Conclusions 31
References . . 33
Cholecystokinin
A. Introduction. . . . . . . . . 40
B. Structure-Activity Relationships 41
x Contents
C. Effects on the Lower Esophageal Sphincter 44
D. Effects on the Stomach . 45
I. In Vivo Studies. . . 45
1. Gastric Emptying. 47
II. In Vitro Studies. . . 48
E. Effects on Small and Large Intestine 50
I. In Vivo Studies. . . . . 50
1. Experimental Animals. 50
2. Humans ... 54
II. In Vitro Studies. 58
F. Conclusions . 61
References 63
Secretin
A. Introduction. 70
B. Action on the Lower Esophageal Sphincter 72
C. In Vivo Effects on the Stomach 73
D. Gastric Emptying . . . . . . 73
E. In Vitro Effects on the Stomach 74
F. Effects on the Intestine 75
G. Conclusions. 77
References . . . . . . . 78
Gastric Inhibitory Polypeptide
A. Introduction. . . . . . 81
B. Effects on Gastrointestinal Motility. 81
I. Lower Esophageal Sphincter . 81
II. Intragastric Pressure . 81
III. Intraluminal Pressure . 82
C. Interactions 82
References . 82
CHAPTER 2b
Peptides: Candidate Hormones. G. BERTACCINI. With 17 Figures
Substance P
A. Introduction. . . . . . . . . 85
B. Structure-Activity Relationships 87
C. Action on Gut Motility . 87
I. In Vitro Studies. . 88
1. Natural Analogs 90
2. Antagonists . 94
II. In Vivo Studies . 95
D. Conclusions 100
References . . . . . . 101
Contents XI
Motilin
A. Introduction. . . . . . . . . . . 105
B. Effects on Gastrointestinal Motility . 106
I. In Vitro Studies. . . . . . . . 106
II. In Vivo Studies. . . . . . . . 108
1. Action on the Lower Esophageal Sphincter. 108
2. Action on the Motility of the Stomach and the Intestine . 109
C. Conclusions 113
References . 113
Neurotensin
A. Introduction. . . . . . . . . . . 117
B. Structure-Activity Relationships . . 117
C. Effects on the Gastrointestinal Tract 118
I. In Vitro Studies. 118
II. In Vivo Studies . 121
References 123
Bombesin
A. Introduction. . . . . . . . . . . . . . . . . . 124
B. Effects on the Motility of the Gastrointestinal Tract 125
I. In Vitro Studies. . . . . . . . . . . . . . 125
II. In Vivo Studies. . . . . . . . . . . . . . 128
1. Effects on the Lower Esophageal Sphincter 128
2. Effects on the Stomach . . . . . . . . 129
3. Effects on the Small and Large Intestine. 130
C. Conclusions . 132
References . . . . . . . . . . . . . . . . . . 134
CHAPTER 2c
Peptides: Pancreatic Hormones. G. BERTACCINI. With 4 Figures
Glucagon
A. Introduction. . . . . . . . . . . . . . 137
B. Effects on the Lower Esophageal Sphincter 137
C. Effect on the Stomach 138
I. In Vivo Studies. . . . . 138
II. In Vitro Studies. . . . . 139
D. Effects on the Small Intestine 140
I. Studies in Experimental Animals 140
II. Studies in Humans . . . 143
E. Effects on the Large Intestine 144
F. Conclusions . 145
References . . . . . . . . . . 147
XII Contents
Insulin
A. Introduction. . . . . . . . . . . . . . 150
B. Effects on the Lower Esophageal Sphincter 150
C. Effects on the Stomach . . . 150
D. Effect on the Small Intestine. 151
E. Effects on the Large Intestine 152
I. In Vitro Studies. . 152
F. Mechanism of Action . 153
References . . . . . 154
Pancreatic Polypeptide
A. Introduction. . . . . . . . . . 157
B. Structure-Activity Relationships . 157
C. Effect on Gastrointestinal Motility 158
References . . . . . . . . . . . . 159
CHAPTER 2d
Peptides: Other Hormones. G. BERTACCINI. With 4 Figures
Vasopressin
A. Introduction. 161
B. Effects on the Motility of the Gastrointestinal Tract 162
References . . . . . . . . . . . . . . . . . . . . 164
Calcitonin
A. Introduction. . . . . . . . . . . 165
B. Effects on Gastrointestinal Motility. 166
I. In Vivo Studies . 166
II. In Vitro Studies. 167
References 167
Coherin
A. Introduction. 168
B. Effects of Coherin 168
C. Conclusions . 169
References . . . . . 170
Thyrotropin-Releasing Hormone
A. Introduction. . 170
B. In Vitro Studies 171
C. In Vivo Studies 172
References . . . . 173