Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie

Vol. 53

Editorial Board G.V. R. Born, Cambridge . A. Farah, Rensselaer, New York H. Herken, Berlin· A. D. Welch, Memphis, Tennessee

Advisory Board S. Ebashi . E. G. Erdos· V. Erspamer . U. S. vo.n Euler· W. S. Feldberg G. B. Koelle· O. Krayer . M. Rocha e Silva· J. R. Vane· P. G. Waser W. Wilbrandt

Pharmacology of Ganglionic Transmission

Contributors

D. M. Aviado . D. A. Brown· A. A. Bunatian· E. V Erina L. Gyermek· WE. Haefely ~ D. A. Kharkevich G. I. Klingman· J. D. Klingman· D. F. J. Mason A. V Meshcherj akov . A. Nistri . D. T. Organisciak 1. P. Quilliam . V 1. Skok . V. TrCka . R. L. Volle

Editor

D. A. Kharkevich

Springer-Verlag Berlin Heidelberg New York 1980

Professor Dr. DIMITRY A. KHARKEVICH, Department of Pharmacology, First Medical Institute, 2/6, B. Pirogovskaja St., USSR Moscow, 119435

With 72 Figures

ISBN-13: 978-3-642-67399-3 DOl: 10.1007/978-3-642-67397-9

e-ISBN-13: 978-3-642-67397-9

Library of Congress Cataloging in Publication Data. Main entry under title: Pharmacology of ganglionic transmission. (Handbook of experimental pharmacology; v. 53) I. Ganglionic blocking agents. 2. Ganglia, Autonomic. 3. Neural transmission. I. Aviado, Domingo M. II. Kharkevich, Dimitry Aleksandrovich. III. Series: Handbuch der ex peri men­tellen Pharmakologie: New Series; v. 53. QP905.H3 vol. 53 [RM323J. 615'.1'08s. [615'.78] 79-9406.

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Contents

Introduction. D.A. KHARKEVICH. Withl Figure.

CHAPTER 1

Ganglionic Transmission: Morphology and Physiology. V.1. SKOK. With 11 Figures

A. Pathways in the Autonomic Ganglia. 9 I. Extramural Ganglia . . . . . 9

II. Intramural Ganglia. . . . . . 10 III. Quantitative Relationship Between Preganglionic Fibres and Neuro-

nes of the Ganglion. . . . . . . . . . . . . . . . . . . 11 IV. Morphology of Neurones in the Ganglia. . . . . . . . . . 12 V. Embryogenesis and Development of Neurones in the Ganglia. 15

B. Synaptic Transmission in Autonomic Ganglia. . . . . . . . 16 I. Properties of Preganglionic Nerve Terminals. . . . . . . . 16

II. Acetylcholine as Excitatory Transmitter in the Ganglia. . . 16 III. Release of Acetylcholine From Preganglionic Nerve Terminals 17 IV. Nicotonic Cholinergic Transmission . . . . . . . . . . 18 V. Electrical Transmission. . . . . . . . . . . . . . . . 20

VI. Generation of Postsynaptic Spike. After-Hyperpolarization. 21 VII. Muscarinic Cholinergic and Adrenergic Transmissions. . 22

VIII. Role of Catecholamines in Transmission Through the Ganglia . 26 IX. Other Chemoceptive Sites in the Ganglion Neurones . 26 X. Inhibition in the Ganglia. . . 26

XI. Natural Activity ofthe Ganglia. 27 C. Summary. 29 References. . . . . . . . . . . . . . 30

CHAPTER 2

Ganglionic Metabolism. J.D. KLINGMAN, D. T. ORGANISCIAK, and G.1. KLINGMAN. With 1 Figure

A. Carbohydrate Metabolism . . . . B. Stimulation. . . . . . . . . . . C. Nonglucose Metabolites Substrates

41 44 45

VI Contents

D. Lipids ............. . 47 52 54 56 57 57

E. Amino Acids . . . . . . . . . . . F. Uptake and Efflux of Amino Acids. G. RNA Protein . H. Protein References. . . .

CHAPTER 3

Methods for the Examination of Ganglion-Blocking Activity. L. GYERMEK.

With 16 Figures

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 63 B. General Physiological and Pharmacological Aspects of the Evaluation of

Ganglion-Blocking Agents . . . . . 63 C. Pharmacological Methods . . . . . . . . . . . . . 65

I. In vivo and in situ Preparations. . . . . . . . . 65 1. Preparation of Superior Cervical Ganglia of Cat. 65 2. Other Sympathetic Ganglion Preparations. . . 78 3. Parasympathetic Ganglion Preparations (in vivo and in situ) . 83 4. Comparative Sensitivity of Sympathetic and Parasympathetic

Ganglia to Ganglionic Blockade. . . . . . . . . . . . .. 86 . II. Isolated Organ and Isolated Ganglion Preparations. . . . . .. 88

1. Isolated Smooth-Muscle Preparations of Gastrointestinal Tract 88 2. Other Isolated Organ Preparations. . . . . . . . . . .. 93 3. Isolated (Excised) Ganglion Preparations. . . . . . . . .. 96

D. Preparations Other Than Autonomic Ganglia Used for Evaluation of Ganglion-Blocking Agents. . . . . . . . . . . . . . . . . . . . . 11)0

I. Preparations of Adrenal Gland and Adrenal Medulla . . . . . . . 100 II. Preparations Using the Response of Chemoreceptors of Carotid and

Aortic Bodies. . . . . . . . . . . . . . . . . . 10 1 III. Other Preparations . . . . . . . . . . . . . . . 102 IV. Antagonism Against the CNS Effects of Nicotine. . 102

1. Nicotine Convulsions and Toxicity. . 103 2. Behavioural Effects of Nicotine. . . . . . . . . 103

E. Screening for Ganglion-Blocking Activity. . . . . . . . 103 I. Blood Pressure Responses in Anaesthetised Animals . . 104

II. Mouse Pupil Mydriasis Test. . . . . . . . . . . . . 104 F. Evaluation of Non-Nicotinic Ganglion-Blocking Agents. . 105 G. Methods for the Determination of Absorption, Distribution, and Excretion

of Ganglion-Blocking Agents. . . . . . . . . . . . . . . . . . . . 106 H. Clinical Testing of Ganglion-Blocking Agents. . . . . . . . . . . . . 107 1. Critical Appraisal of the Experimental Methods Used in the Evaluation of

Ganglion-Blocking Agents . 108 K. Conclusions . 110 References. . . . . . . . . . 111

Contents

CHAPTER 4a

Relationship Between Chemical Structure and Ganglion-Blocking Activity. a) Quaternary Ammonium Compounds.V. TRCKA. With 1 Figure

VII

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 B. Structure-Activity Relationships in Different Structural Types of Quaternary

Ganglion-Blocking Agents . . . . . . . . . . . . 126 I. Mono-Quaternary Ammonium Derivatives. . . . 126

1. Aliphatic Quaternary Ammonium Derivatives . 126 2. Heterocyclic Mono-Quaternary Derivatives. . 135

II. Bis-Quaternary Derivatives . . . . . . . . . . 136 1. Symmetrical Polymethylene Bis-Trialkylammonium Derivatives 136 2. Symmetrical Polymethylene-Bis-Quaternary Cyclic Compounds 139 3. Modifications of the Polymethylene Chain . 141 4. Asymmetrical Bis-Quaternary Compounds. . 141 5. Phosphonium and Sulphonium Derivatives. 145

C. Conclusions . . . . . . . . . . . . . . 150 1. Mono-Quaternary Compounds. . . . . 150 2. Symmetrical Bis-Quaternary Compounds. 150

References. . . . . . . . . . . . . . . . . 151

CHAPTER 4b

Relationship Between Chemical Structure and Ganglion-Blocking Activity. b) Tertiary and Secondary Amines. V. TRCKA

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 155 B. Structure-Activity Relationships in Different Structural Types of Non-

Quaternary Ganglion-Blocking Agents . 158 I. Substituted Aminoalkyl Derivatives . 158

II. Alicyclic Amines. . . . . . . . . . 166 III. Derivatives of 3-Aminoisocamphane . 166 IV. Piperidine Derivatives and Other N-Heterocyclic Compounds. 169

C. Conclusions 177 References. . . . . . . . . . . . . . . . . . . . . . . . . . . 182

CHAPTER 5

Locus and Mechanism of Action of Ganglion-Blocking Agents. D. A. BROWN.

With 7 Figures

A. Introduction . . . . . . . . . . . . . . . . . . B. Competitive Blocking Agents. . . . . . . . . . .

I. Effects on the Transmission of Single Impulses .

185 185 185

VIII Contents

II. Presynaptic Effects. . . 1. Acetylcholine Release 2. Choline Uptake . . 3. Acetylcholine Synthesis 4. Electrical Responses of Preganglionic Nerves and Their Terminals. 5. Post-Tetanic Potentiation (PTP). . . 6. Repetitive Stimulation. . . . . . . 7. Presynaptic Acetylcholine Receptors. 8. Conclusions . . . .

III. Postsynaptic Effects . . . . . . . 1. Neuronal Excitability . . . . . 2. Action on Nicotinic Receptors. 3. Action on Skeletal Muscle Receptors . 4. Action on Muscarinic Receptors. . . 5. Action of Tetraethylammonium (TEA) .

C. Depolarising Agents. . . I. Depolarisation Block . . . .

1. Theory ........ . 2. Experimental Observations.

II. Dissociation of Depolarisation and Block. 1. Off-Set Rates in vivo . . . . . 2. Postactivation Hyperpolarisation . . . 3. Desensitisation. . . . . . . . . . . 4. Differential Sites of Depolarisation and Transmission Block? . 5. Presynaptic Effects? . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . .

D. Intraganglionic Distribution of Ganglion-Blocking Drugs. I. Non-Quaternary Agents . . . . . . . . . . .

1. Active Form of Non-Quaternary Compounds II. Quaternary Ammonium Compounds.

1. Diffusion . . . . . . . . . 2. Receptor-Linked Penetration. 3. Carrier-Mediated Entry

Addendum References.

CHAPTER 6

Action of Ganglion-Blocking Agents on the Cardiovascular System. D. M. AVIADO

A. Introduction . . . . . . . . . . . . . . . . . . . . . . B. Hypotensive Action . . . . . . . . . . . . . . . . . . .

I. Cardiovascular Reflexes and the Central Nervous System II. Circulating Humoral Agents and Injected Drugs.

C. Cardiac Function. . . . . . . . I. Cardiac Output. . . . . . .

1. Decreased Cardiac Output . 2. Increased Cardiac Output .

187 187 188 188 189 190 190 191 192 193 193 194 200 200 201 204 205 205 206 211 211 212 214 215 217 218 219 219 220 221 221 221 222 223 226

237 237 238 238 239 239 239 239

Contents

II. Coronary Vascular Resistance D. Systemic Vascular Beds .

I. Cerebral Circulation. . II. Renal Circulation . . .

III. Pulmonary Circulation. IV. Splanchnic Circulation. V. Limb Circulation

E. Conclusions References. . . . . . .

CHAPTER 7

Action of Ganglion-Blocking Agents on the Gastrointestinal Tract. D. F. 1. MASON

A. Introduction.. . . . . . . . . . B. Salivary Secretion. . . . . . . . C. Oesophagus and Cardiac Sphincter. D. Gastric Motility. . . E. Gastric Secretion . . F. Pancreatic Secretion. G. Small Intestine H. Colon. References.

CHAPTER 8

IX

241 241 242 242 245 247 247 248 249

. 255 256 256 257 258 259 259 261

. 263

Absorption, Distribution, Fate, and Excretion of Ganglion-Blocking Compounds. D.F.l.MASON.

A. Introduction . . . B. Onium Compounds

I. Absorption. II. Distribution .

III. Excretion. . . C. Secondary and Tertiary Amines .

I. Absorption. II. Distribution

III. Excretion. References. . . . .

CHAPTER 9

Nicotinic Ganglion-Stimulating Agents. R. L. VOLLE. With 12 Figures

A. Introduction . . . . . . . . . . . . . . . . . . . B. Pharmacological Ambiguities of Ganglionic Receptors. . . . .

267 267 267 269 271 272 272 273 275 276

281 282

x Contents

C. Post junctional Responses to Acetylcholine and Nicotinic Agents. I. The Acetylcholine Potential ..... .

II. Surface or Demarcation Potentials. . . . D. Blockade of Transmission by Nicotinic Drugs.

I. Depolarisation Blockade. . . . . . . . II. Prolonged Ganglionic Blockade. . . . .

III. Postexcitatory Ganglionic Hyperpolarisation IV. Presynaptic Nerve Terminals

E. Denervated Ganglia . F. Conclusions References. . . . . . .

CHAPTER 10

Non-Nicotinic Chemical Stimulation of Autonomic Ganglia. W. E. HAEFELY.

With 3 Figures

A. Introduction B. Muscarinic Ganglion Stimulants

I. General Information. . 1. Acetylcholine (ACh) . . 2. Muscarine . . . . . . 3. Methacholine (Acetyl-,B-Methylcholine) . 4. Pilocarpine. . . . . . . . . . 5. Carbachol (Carbaminoylcholine) . 6. Arecoline. . . . . . . . . . . 7. Choline .......... . 8. Oxotremorine [1-(2-oxopyrrolidino)-4-pyrrolidino butyne-2] . 9. Furtrethonium (Furfuryltrimethylammonium) and Aceclidine .

10. 4-( m-Chlorophenylcarbamoyloxy)-2-B utyny 1-Trimethyl-ammonium Chloride (McN-A-343) . . . . . . . . . . .

11. n-Benzyl-3-Pyrrolidyl Acetate Methobromide (AHR-602) . 12. Quaternary Amino-Acid Esters. . . . . . . . . . . 13. Benzyltrimethylammonium and Pyridylmethyltrimethyl-

ammonium ................... . 14. Cholinesterase Inhibitors . . . . . . . . . . . . . .

II. Possible Involvement of a Second Messenger in Muscarinic Excitation of Autonomic Ganglia. . . . . . . . . . . . . . . .

C. 5-Hydroxytryptamine (5-HT) and Related Indolealkylamines . D. Histamine . . . . E. Polypeptides . . .

I. Angiotensin II II. Bradykinin. .

III. Various Peptides 1. Posterior Pituitary Hormones 2. Eledoisin and Physalaemin . 3. Substance P . . . . . . . .

284 284 287 289 289 294 297 300 304 306 307

313 315 315 315 322 323 325 327 328 328 328 329

. 329 132 333

333 333

335 336 339 341 341 343 344 344 344 344

Contents

F. Cardiac Glycosides G. Veratrum Alkaloids H. Batrachotoxin . . J. Inorganic Cations.

I. Potassium II. Caesium

III. Barium IV. Calcium

K. Conclusions References. . .

CHAPTER 11

Ganglion Activity of Centrally Acting ~ eurotropic Agents. A. NISTRI and J. P. QUILLIAM. With 1 Figure

A. Introduction . . . . B. Methods ..... . C. Volatile Anaesthetics. D. Central Nervous System Depressants. E. Neuroleptics . . .

I. Phenothiazines . . . II. Thioxanthenes . . .

III. Rauwolfia Alkaloids. IV. Butyrophenones. . .

F. Antidepressants. . . . . I. Monoamine Oxidase Inhibitors (MAO I) .

II. Tricyclic Antidepressants . G. Anti-Manic Drugs. . . . . . . . . . . H. Narcotic Analgesics . . . . . . . . . . J. Central Nervous System-Stimulant Drugs. K. Tranquillisers. . . . L. Anticonvulsant Drugs References. . . . . Note Added in Proof. .

CHAPTER 12

XI

344 346 347 347 347 348 349 349 350

· 351

359 359 362 364 368 368

.369 · 370 .370 · 371 · 371 · 371 .372 · 373 · 374 · 377 .377 · 378 · 385

Ganglionic Actions of Anticholinesterase Agents, Catecholamines, Neuro­Muscular Blocking Agents, and Local Anaesthetics. R. L. VOLLE. With 10 Figures

A. Anticholinesterase Agents . . . . . . . I. Effects on Acetylcholine Metabolism .

II. Nicotinic Ganglionic Transmission. . III. Muscarinic Ganglionic Transmission.

385 386 389 390

XII

B. Catecholamines. . . . . . . . . . . . . . . . . . . . . . I. Catecholamines and the Slow Synaptic Inhibitory Potential.

II. Presynaptic Blockade by Catecholamines. . . . . . III. Catecholamines and Ganglionic Cyclic Nucleotides . IV. Catecholamines as Modulators of Transmission.

C. Neuromuscular Blocking Agents. D. Local Anaesthetics E. Conclusions References. . . . . .

CHAPTER 13

Ganglionic Activity of Cardiovascular Drugs. D. M. AVIADO

A. Introdl:lction . . . . . B. Antihypertensive Drugs

I. Reserpine . . II. Guanethidine. .

C. Vasoconstrictors . . I. Norepinephrine .

II. Angiotensin. . D. Cardiotropic Drugs References. . . . . .

CHAPTER 14

Ganglion-Blocking Agents in Internal Medicine. E. V. ERINA. With 4 Figures

Contents

391 393 397 398 400 402 404 405

.405

411 411 411 412 412 413 413 413 414

A. Introduction . . . . . . . . . . . . . . . . . . . . . 417 B. Ganglion-Blocking Agents in the Treatment of Hypertension. 417

I. Haemodynamic Effects . . . . . . 418 II. Dosage of Methonium Compounds. 419

III. Results of Treatment. . . . . . 421 IV. CNS Effects. . . . . . . . . . 422 V. Effects on the Endocrine System. 423

VI. Undesirable Side Effects. . . . . 423 VII. Oral Dosage of Methonium Preparations 424

VIII. Other Ganglion-Blocking Agents for Oral Use. 425 IX. Recent Developments. . . . . . . . . . . . . 426 X. Contraindications . . . . . . . . . . . . . . 429

C. Ganglion-Blocking Agents in the Treatment of Peptic Ulcer. . 429 I. Combination of Ganglion-Blocking Agents With Other Preparations 432

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

Contents

CHAPTER 15

Ganglion-Blocking Agents in Anaesthesiology. A. A. BUNATIAN and A. V. MESHCHERJAKOV. With 6 Figures

XIII

A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 B. General Characteristics ofthe Use of Ganglion-Blocking Agents for Artificial

Hypotension . . . . . . . . . . . . . . . . . . . . . . . 440 440 441 443

I. Indications for the Use of Ganglion-Blocking Agents. . . . II. Contra indications for the Use of Ganglion-Blocking Agents.

III. Method of Artificial Hypotension. . . . . . . 1. Drugs. . . . . . . . . . . . . . . . . . 2. Degree and Duration of Artificial Hypotension 3. Complications ............ .

.445 447 448

C. Use of Artificial Vasodilatation for Various Surgical Interventions and Pulmonary Oedema. . . . . 449

I. Coarctation of the Aorta. . . . . . . . . . . . . . . . . 449 II. Patent Aiterial Duct. . . . . . . . . . . . . . . . . . . 450

III. Heart Disease Correction With Extracorporeal Circulation . . 452 1. Technique of Artificial Vasodilatation During Cardiopulmonary By-Pass . . . . . . . . . . . . . . . . . . . . . . . . 455

IV. Pulmonary Oedema . . . . . . . . . . . . . . . . . . . 457 1. Technique of Ganglion Blockade in Pulmonary Oedema . 458

V. Neurosurgery. . . . . . . . . . . . . . . . . . . . . . 459 1. Special Features of the Use of Ganglion-Blocking Agents During

Brain Surgery. . 459 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462

Author Index. V. V. MAISKY .465

Subject Index. V. V. MAISKY . .497

List of Contributors

D. M. A VIADO, Dr., Biomedical Research, Allied Chemical Corporate Headquarters, P.O. Box 102 1R, Morristown, NJ 07960/USA

D.A. BROWN, Professor Dr., Department of Pharmacology, The School of Pharmacy, University of London, 29/39, Brunswick Square, GB London, WCIN lAX

A.A. BUNATIAN, Professor Dr., Institute of Clinical and Experimental Surgery, 2/6, B. Pirogovskaja Street, USSR Moscow, 119435

E. V. ERINA, Dr., Institute of Cardiology, USSR Academy of Medical Sciences, 10, Petroverigska per., USSR Moscow, 101837

L. GYERMEK, Professor Dr., University of California, Department of Anesthesiology, School of Medicine, Davis, CA 95020/USA (present affiliation: Wheeler Hospital, Gilroy, CA 95020/USA)

W.E. HAEFELY, Dr., Forschung Pharma, Abt. I (FP/I, Bau 69), Fa. Hoffmann­La Roche & Co AG, GrenzacherstraBe 124, CH 4002 Basel

D.A. KHARKEvIcH, Professor Dr., Department of Pharmacology, First Medical Institute, 2/6, B. Pirogovskaja Street, USSR Moscow, 119435

G.1. KLINGMAN, Dr., Department of Biochemical Pharmacology, School of Pharmacy, SUNY at Buffalo, Buffalo, NY 14214/USA

J.D. KLINGMAN, Professor Dr., Department of Biochemistry, Schools of Medicine and Dentistry, Faculty of Health Sciences, State University of New York at Buffalo, 102 Cary Hall, Buffalo, NY 14214/USA

D.F.J. MASON, Dr., Department of Pharmacology, The Medical College of Saint Bartholomew's Hospital, Charterhouse Square, GB London, EC1M 6BQ

A. V. MESHCHERJAKOV, Dr., Institute of Clinical and Experimental Surgery, 2/6, B. Pirogovskaja Street, USSR Moscow, 119435

A. NISTRI, Dr., Department of Pharmacology, The Medical College of Saint Bartholomew's Hospital, Charterhouse Square, GB London, EC1M 6BQ

D. T. ORGANISCIAK, Dr., Department of Biochemistry, School of Medicine, Wright State University, Dayton, OH/USA

J.P. QUILLIAM, Professor Dr., Department of Pharmacology, The Medical College of Saint Bartholomew's Hospital, Charterhouse Square, GB London, EC1M 6BQ

V.1. SKOK, Professor Dr., Institute of Physiology, Academy of Sciences of UKR.SSR, 4, Bogomoletz Street, USSR Kiev 24

V. TRCKA, Professor Dr., Pharmaceutical and Biochemical Research Institute, 17, Koufimska, CSSR 13000 Praha 3

R.L. VOLLE, Professor Dr., UCONN Health Center, Preclinical and Graduate Education, The University of Connecticut, Farmington, CT 06032/USA