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, Poli­clinico 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 C­terminal 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 H2-blockers 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 H2-receptor antago­nists, 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 References . . . . . . . . .

CHAPTER 2a

Peptides: Gastrointestinal Hormones. G. BERTACCINI. With 16 Figures

Gastrin

A. Introduction. . . . . . . . . . . . . . B. Effects on the Lower Esophageal Sphincter

I. Excitation . . . . 1. In Vitro Studies 2. In Vivo Studies

II. Inhibition . . . . C. Effects on the Stomach

I. In Vitro Studies. . 1. Experimental Animals. 2. Humans ...... .

II. In Vivo Studies. . . . . 1. Experimental Animals. 2. Humans ...... .

D. Effects on the Small and Large Intestine. I. In Vitro Studies. . . . .

II. In Vivo Studies. . . . . 1. Experimental Animals. 2. Humans.

E. Conclusions References . .

Cholecystokinin

A. Introduction. . . . . . . . . B. Structure-Activity Relationships

1 6

11 14 14 14 15 18 19 20 20 21 22 22 23 25 25 30 30 31 31 33

40 41

x

C. Effects on the Lower Esophageal Sphincter D. Effects on the Stomach .

I. In Vivo Studies. . . 1. Gastric Emptying.

II. In Vitro Studies. . . E. Effects on Small and Large Intestine

I. In Vivo Studies. . . . . 1. Experimental Animals. 2. Humans ...

II. In Vitro Studies. F. Conclusions . References

Secretin

A. Introduction. B. Action on the Lower Esophageal Sphincter C. In Vivo Effects on the Stomach D. Gastric Emptying . . . . . . E. In Vitro Effects on the Stomach F. Effects on the Intestine G. Conclusions. References . . . . . . .

Gastric Inhibitory Polypeptide

A. Introduction. . . . . . B. Effects on Gastrointestinal Motility.

I. Lower Esophageal Sphincter . II. Intragastric Pressure .

III. Intraluminal Pressure . C. Interactions References .

CHAPTER 2b

Peptides: Candidate Hormones. G. BERTACCINI. With 17 Figures

Substance P

A. Introduction. . . . . . . . . B. Structure-Activity Relationships C. Action on Gut Motility .

I. In Vitro Studies. . 1. Natural Analogs 2. Antagonists .

II. In Vivo Studies . D. Conclusions References . . . . . .

Contents

44 45 45 47 48 50 50 50 54 58 61 63

70 72 73 73 74 75 77 78

81 81 81 81 82 82 82

85 87 87 88 90 94 95

100 101

Contents

Motilin

A. Introduction. . . . . . . . . . . B. Effects on Gastrointestinal Motility .

I. In Vitro Studies. . . . . . . . II. In Vivo Studies. . . . . . . .

1. Action on the Lower Esophageal Sphincter. 2. Action on the Motility of the Stomach and the Intestine .

C. Conclusions References .

Neurotensin

A. Introduction. . . . . . . . . . . B. Structure-Activity Relationships . . C. Effects on the Gastrointestinal Tract

I. In Vitro Studies. II. In Vivo Studies .

References

Bombesin

A. Introduction. . . . . . . . . . . . . . . . . . B. Effects on the Motility of the Gastrointestinal Tract

I. In Vitro Studies. . . . . . . . . . . . . . II. In Vivo Studies. . . . . . . . . . . . . .

1. Effects on the Lower Esophageal Sphincter 2. Effects on the Stomach . . . . . . . . 3. Effects on the Small and Large Intestine.

C. Conclusions . References . . . . . . . . . . . . . . . . . .

CHAPTER 2c

Peptides: Pancreatic Hormones. G. BERTACCINI. With 4 Figures

Glucagon

A. Introduction. . . . . . . . . . . . . . B. Effects on the Lower Esophageal Sphincter C. Effect on the Stomach

I. In Vivo Studies. . . . . II. In Vitro Studies. . . . .

D. Effects on the Small Intestine I. Studies in Experimental Animals

II. Studies in Humans . . . E. Effects on the Large Intestine F. Conclusions . References . . . . . . . . . .

XI

105 106 106 108 108 109 113 113

117 117 118 118 121 123

124 125 125 128 128 129 130 132 134

137 137 138 138 139 140 140 143 144 145 147

XII

Insulin

A. Introduction. . . . . . . . . . . . . . B. Effects on the Lower Esophageal Sphincter C. Effects on the Stomach . . . D. Effect on the Small Intestine. E. Effects on the Large Intestine

I. In Vitro Studies. . F. Mechanism of Action . References . . . . .

Pancreatic Polypeptide

A. Introduction. . . . . . . . . . B. Structure-Activity Relationships . C. Effect on Gastrointestinal Motility References . . . . . . . . . . . .

CHAPTER 2d

Peptides: Other Hormones. G. BERTACCINI. With 4 Figures

Vasopressin

A. Introduction. B. Effects on the Motility of the Gastrointestinal Tract References . . . . . . . . . . . . . . . . . . . .

Calcitonin

A. Introduction. . . . . . . . . . . B. Effects on Gastrointestinal Motility.

I. In Vivo Studies . II. In Vitro Studies.

References

Coherin

A. Introduction. B. Effects of Coherin C. Conclusions . References . . . . .

Thyrotropin-Releasing Hormone

A. Introduction. . B. In Vitro Studies C. In Vivo Studies References . . . .

Contents

150 150 150 151 152 152 153 154

157 157 158 159

161 162 164

165 166 166 167 167

168 168 169 170

170 171 172 173

Contents

CHAPTER 2e

Peptides: Locally Active Peptides ("Vasoactive Peptides"). G. BERTACCINI With 7 Figures

Angiotensin

A. Introduction. . . . . . . . . . . B. Structure-Activity Relationships . . C. Effects on the Gastrointestinal Tract

I. In Vitro Studies. II. In Vivo Studies .

D. Conclusions References

Bradykinin

A. Introduction. . . . . . . . . . . B. Effects on the Gastrointestinal Tract

I. In Vitro Studies. . II. In Vivo Studies. .

C. Mechanism of Action . D. Conclusions References . . . . . . .

CHAPTER 3

Amines: Histamine. G. BERTACCINI. With 4 Figures

A. Introduction. . . . . . . . . . . . . . B. Activity on the Lower Esophageal Sphincter C. Action on the Stomach D. Gastric Emptying . . E. Action on the Intestine F. H 2-Receptors G. Conclusions References . . .

CHAPTER 4

Acidic Lipids: Prostaglandins. A. BENNETT and G. J. SANGER. With 1 Figure

XIII

175 175 176 176 181 183 184

187 190 190 193 195 197 197

201 202 204 207 207 211 214 215

A. Introduction. . . . . . . . . . . . . . . . . . . . . . .. 219 B. Occurrence, Formation, Release, and Degradation of Prostanoids . 220

L Occurrence . . . . . 220 II. Formation and Release . . . . . . . . . . . . . . . 221

III. Degradation. . . . . . . . . . . . . . . . . . . . 222 C. Actions of Prostanoids on the Tone and Reactivity of Isolated

Gastrointestinal Muscle. . . . . . . . . . . . . . . . . 223

XIV Contents

D. Prostanoids and Gastrointestinal Nerves. . . . . . . . . 225 I. Parasympathetic and Noncholinergic Excitatory Nerves 225

II. Adrenergic and Nonadrenergic Inhibitory Nerves. . . 227 III. Other Possible Nerves and Neurotransmitters . . . . 227

E. Prostanoid Antagonists and Different Types of Prostanoid Receptors 228 F. Prostanoids and Peristalsis In Vitro. . . . . . . . . . . . 230 G. Prostanoids and Motility In Vivo. . . . . . . . . . . . . 231 H. Prostanoids as Factors in Disordered Gastrointestinal Motility 233

I. Gastro-Oesophageal Reflux . 233 II. Gastrointestinal Disturbances 233

III. Diarrhoea. . . . . . . 233 I. Bacterial Endotoxins . 234 2. Cholera Exotoxin 234 3. Irradiation . . . . . 235 4. Tumours. . . . . . 235 5. Irritable Colon Syndrome. 236 6. Food Intolerance . . . . 236 7. Idiopathic Intestinal Pseudo-obstruction 237 8. Dysmenorrhoea. . . . . . . . . . 237 9. Idiopathic Postural Hypotension. . . . 237

10. Treatment of Diarrhoea with Nutmeg . 237 1. Beneficial Effects ofProstanoids in Disorders of Gastrointestinal Motility 237

I. Worm ExpUlsion . 237 II. Postoperative Ileus 238

III. Laxatives 238 K. Conclusions 238 References . . . 239

CHAPTER 5

Pharmacology of Adrenergic, Cholinergic, and Drugs Acting on Other Receptors in Gastrointestinal Muscle. E. E. DANIEL

A. General Principles . . . . . . . . . . . . . . . 249 I. Myogenic Activity of Gastrointestinal Muscle. 249

II. Nervous Control of Gastrointestinal Muscle 251 III. Receptors and Receptor Mechanisms 253

B. Drugs Acting on Adrenoceptors 256 I. Alpha-Receptors . . . . . . . . . 256

II. Beta-Receptors . . . . . . . . . . 260 III. Possible Distinction Between Betac and Beta2-Adrenoceptors . 261 IV. Dopamine Receptors . . . . . . . . . . 263 V. Metoclopramide and Domperidone . . . . 265

1. Possible Role as Dopamine Antagonists . 265 2. Clinical Applications . . . . . . . . . 269

C. Cholinergic Receptors in the Gastrointestinal Tract . 270 I. Muscarinic Receptors . . . . . . . . . . . 270

Contents XV

1. Molecular Mode of Action of Cholinergic Agonists . 276 2. Transmission at Gastrointestinal Neuronal Synapses 277

II. Presynaptic Cholinergic Receptors. . . . . 278 III. Nicotinic Receptors . . . . . . . . . . . 280

D. Morphine and Drugs Acting on Opiate Receptors 281 I. Endogenous Opiates. . . . . . . . . . . 281

II. Mode of Opiate Action in Guinea-Pig Intestine 281 III. A Physiological Role for Endogenous Opiates in Guinea-Pig

Intestine. . . . . . . . . . . . . . . . . . . . . . 283 IV. Mode of Opiate Action in Other Species. . . . . . . . 284 V. Central and Peripheral Sites of Action of Opiate Agonists 286

VI. Opiate Receptor Types . . . . . . . . . . . . . 287 VII. Opiate Agonists Selective for Gut Receptors . . . . 289

VIII. Clinical Applications of Opiate Antidiarrhoeal Agents 289 E. Laxatives and Constipating Agents . 290 F. Direct and Indirect Actions . . . . 294 G. Serotonin Receptors and Antagonists 296

I. Early Studies. . . . 296 II. Neuronal Receptors. . . . . . 296

III. Muscle Receptors. . . . . . . 298 H. Histamine Receptors and Antagonists. 299

I. HcReceptors. . . . . . 300 II. H2-Receptors. . . . . . 302

III. Problems of Classification 302 J. Projections for the Future . 304

References . . . . . . . . . . . 305

CHAPTER 6

Hydrophilic Colloids in Colonic Motility. M. A. EASTWOOD and A. N. SMITH With 5 Figures

A. Introduction. . . . . . . . . . . . . . . . . 323 B. The Nature of Stool Bulk and How it is Provided 324

I. Water . 325 II. Bacteria. 326

III. Fibre. . 326 IV. Gas . . 331 V. Bulking Agents 331

C. Actions of Fibre and of Operations on the Colon Muscle in Diverticular Disease . . . . . . . . . . . . . . 334

I. Changes Induced by Operation 335 II. Changes Induced by Cereal Fibre 336

III. Other Agents . . . . . . . . . 339 D. Actions in Other Colonic Diseases . . 342 E. Clinical Application of Fibre and Hydrophilic Colloid Additives 343 References . . . . . . . . . . . . . . . . . . . . . . . . . 343

XVI Contents

CHAPTER 7

Motility and Pressure Studies in Clinical Practice A. TORSOL! and E. CORAZZIARI. With 15 Figures

A. The Esophagus . . . . . . . . . 347 I. Motor Activity . . . . . . . . 347

1. Upper Esophageal Sphincter. 347 2. Esophageal Body. . . . . . 347 3. Lower Esophageal Sphincter . 349

II. Use of Esophageal Manometry in Clinical Practice 350 B. The Stomach . . . 355

I. Motor Activity . . . . . . . . . . . . 355 1. Gastric Filling . . . . . . . . . . . 356 2. Mixing and Grinding of Solid Contents 356 3. Gastric Emptying. . . . . . . . . . 356

II. Gastric Manometry and Studies of Gastric Emptying in Clinical Practice . . . . 357

C. The Small Intestine. . . . . . . . . . . . . . . . . 357 I. Motor Activity . . . . . . . . . . . . . . . . . 357

II. Manometry of the Small Intestine in Clinical Practice 360 D. The Large Bowel. . . . 361

I. Motor Activity . . . 361 1. Ileocecal Sphincter 361 2. Colon. . . . . . 361 3. Rectoanal Region 364 4. Transit of Large Bowel Contents 366

II. Large Bowel Manometry and Transit Time in Clinical Practice 366 E. Conclusions . 369 References . . . . . . . . . . . . . . . . . . . . . . . . .. 370

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

Contents

Part I: Morphological Basis and Neurophysiological Control

CHAPTER 1

Historical Perspective. C. F. CODE

CHAPTER 2

Morphological Basis of Gastrointestinal Motility: Structure and Innervation of Gastrointestinal Tract. H. G. BAUMGARTEN With 11 Figures

CHAPTER 3

Morphological Basis of Gastrointestinal Motility: Ultrastructure and Histochemistry of Endocrine - Paracrine Cells in the Gut E. SOLCIA, C. CAPELLA, R. BUFFA, L. USELLINI, and P. TENTI. With 9 Figures

CHAPTER 4

Ionic Basis of Smooth Muscle Action Potentials. T. TOMITA. With 1 Figure

CHAPTER 5

Electrophysiology of Intestinal Smooth Muscle. R. CAPRILLI, G. FRIERI, and P. VERNIA. With 18 Figures

CHAPTER 6

Electrophysiology of the Enteric Neurons. R. A. NORTH. With 10 Figures

CHAPTER 7

In Vivo Techniques for the Study of Gastrointestinal Motility. E. CORAZZIARI With 7 Figures

CHAPTER 8

In Vitro Techniques for the Study of Gastrointestinal Motility G. J. SANGER and A. BENNETT. With 6 Figures

CHAPTER 9 Nervous Control of Esophageal and Gastric Motility. C. ROMAN

With 18 Figures

XVIII Contents of Part I

CHAPTER 10

Nervous Control of Intestinal Motility. M. COSTA and J. B. FURNESS

CHAPTER II

Identification of Gastrointestinal Neurotransmitters. J. B. FURNESS and M. COSTA

Subject Index