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THE ROLE of the 5-HT Ta RECEPTOR in CENTRAL CARDIOVASCULAR REGULATION Printed By: Duphar B.V

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THE ROLE of the 5-HT Ta RECEPTOR in CENTRAL CARDIOVASCULAR REGULATION Printed By: Duphar B.V THE ROLE OF THE 5-HT tA RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION Printed by: Duphar B.V. C.J. van Houtenlaan 36 1381 CP Weesp The Netherlands Isbn 90-9004025-0 Cover design by F. W. Pompe. © G.H. Dreteler, Elst, 1991 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying. recording, or otherwise. without written permission from the publisher. THE ROLE OF THE S-HT1A RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION DE ROL VAN DE 5-HT1A RECEPTOR IN DE CENTRALE CARDIOVASCULAIRE REGULA TIE PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF.DR. C.J. RIJNVOS EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP WOENSDAG 27 MAART 1991 OM 15.45 UUR door GERRIE HENDRIKA DRETELER GEBOREN TE DELDEN PROMOTIECOMMISSIE PROMOTOR: PROF.DR. P.R. SAXENA OVERIGE LEDEN: PROF.DR. A.J. MAN IN 'T VELD PROF.DR. P.A. VAN ZWIETEN DR. J.F.M. SMITS CO-PROMOTOR: DR. W. WOUTERS The investigations described in this thesis have been performed at the Institute of Pharmacology, Erasmus University Rotterdam, the Department of Pharmacology. Duphar B.V., Weesp, The Netherlands and the Department of Pharmacology, Royal Free Hospital School of Medicine, London, U.K. The work was supported by Duphar B.V., Weesp. CONTENTS page CHAPTER I General introduction 1.1 Serotonin (5-HT) I l.l.l Localisation of 5-HT I 1.1.2 Function of 5-HT 2 1.2 5-HT receptors 2 1.2.1 Classification 2 1.2.2 Functional responses of 5-HT receptors 7 1.3 Overall regulation of the circulation II 1.3.1 Nervous control of the circulation 11 1.4 5-HT and cardiovascular regulation 13 1.4.1 5-HT and peripheral cardiovascular regulation 13 1.4.2 5-HT and central cardiovascular regulation 15 1.4.3 Cardiovascular effects of central 5-HT receptor interaction 18 1.5 The 5-HT1A receptor agonists 8-0H-DPAT and flesinoxan 20 1.6 Aim of the thesis 21 CHAPTER2 5-HT1A receptor agonist-induced cardiovascular effects 33 CHAPTER3 Systemic and regional haemodynamic effects of the 37 'putative 5-HT1A receptor agonist flesinoxan in the cat (Dreteler, G.H., Wouters, W. & Saxena. P.R. (1989) J. Cardiovasc. Pharmacol., 14, 770-776) CHAPTER4 Systemic and regional haemodynamic effects of the 5-HT1A 55 receptor agonists flesinoxan and 8-0H-DPAT in the conscious rat (Dreteler, G.H., Wouters, W., Toorop, G.P., Jansen, J.A.P. & Saxena. P.R. (in press) J. Cardiovasc. Pharmacol.) - i - CHAPTERS Comparison of the cardiovascular effects of the 5-HT1A 69 receptor agonist flesinoxan with that of 8-0H-DPAT in the rat (Dreteler, G.H., Wouters, W. & Saxena, P.R. (1990) Eur. J. Pharmacol., 180, 339-349) CHAPTER6 Cardiovascular effects of centrally administered 5-HT1A 89 receptor agonists CHAPTER7 Pressor effects following microinjection of 5-HT1A receptor 95 agonists into the raphe obscurus of the anaesthetized rat (Dreteler, G.H., Wouters, W., Saxena, P.R. & Ramage, A.G. (in press) Br. J. Pharmacol.) CHAPTERS Cardiovascular effects of microinjection of 5-HT, 109 8-0H-DPAT and flesinoxan into the hypothalamus of the rat (Dreteler, G.H., Wouters, W. & Saxena, P.R. (submitted) Eur. J. Pharmacol.) CHAPTER9 General discussion 123 9.1 The cardiovascular effects of 5-HT1A receptor agonists 123 9.2 The central mechanism of 5-HT1A receptor agonist­ 125 induced cardiovascular changes 9.3 Clinical significance of 5-HT1A receptor activation in 130 antihypertensive treatment SUMMARY 135 SAMENV AITING 139 LIST OF PUBLICATIONS 143 DANKWOORD 145 CURRICULUM VITAE 147 APPENDIX 149 - ii - CHAPTER 1 GENERAL INTRODUCTION 1.1 Serotonin The indole alkylamine serotonin (5-hydroxytryptamine; 5-HT) was isolated and chemically characterized about four decades ago, and is now generally accepted to function as a neurotransmitter and neuromodulatory agent. 5-HT is formed enzymatically from the essential amino acid tryptophan by hydroxylation, followed by decarboxylation (Fig. 1). Tryptophan tryptophan hydroxylase 5-Hydroxytryptophan aromatic L-amino acid decarboxylase 5-Hydroxytryptamine Fig. 1: Synthesis of 5-hydroxytryptamine. 1.1.1 Localisation of 5-HT 5-HT appears to be present in most plants and animals. In mammals. 5-HT is widely distributed and can be localized in nerve cells and fibers in specific brain areas (Dahlstrom & Fuxe, 1965; Steinbusch, 198 I ) as well as in several peripheral structures - 1 - like the enterochromaffin cells of the gastrointestinal mucosa, the pineal gland. blood platelets, nerves of the gastrointestinal tract and blood vessels, the blood vessel wall. in mast cells (rodents), and in lung, kidney, spleen, thyroid and heart tissue. With the exception of the platelets, 5-HT is synthesized in most tissues in which it is stored. Over 90% of the 5-HT content in the peripheral structures of the body is found in the enterochromaffin cells. From these cells 5-HT enters the circulation where it will be taken up by the platelets or removed by the liver or the endothelial cells in the lungs to be metabolized into 5-hydroxyindolacetic acid (5-HIAA) and excreted. 1.1.2 Function of 5-HT 5-HT exerts a variety of effects in the body. As the substance is not able to cross the blood brain barrier (Lexchin et al., 1977), there is an apparent discrimination between its peripheral and its central function. In the periphery 5-HT is involved in contraction of smooth muscle cells, aggregation of blood platelets and presynaptic depression of transmission in autonomic neurones. In the central nervous system 5-HT serves as a neurotransmitter and appears to play a role in the regulation of e.g. memory. appetite. anxiety, sleep, depression, body temperature, sexual behaviour and the cardiovascular system. 1.2 5-HT receptors 1.2.1 Classification Receptor site analysis has been one of the most productive approaches to understand the different actions of 5-HT in the central and peripheral nervous systems. In 1957. Gaddum and Picarelli described two distinct 5-HT receptor subtypes i.e. the 'D' and 'M' receptor. In guinea pig ileum, 5-HT evokes a contractile response resulting from activation of two different mechanisms: a direct action on the smooth muscle and an indirect action mediated by the release of acetylcholine from parasympathetic nerve endings. Because the former of these mechanisms was blocked by dibenzylline (D) and the latter by morphine (M), the excitatory 5-HT receptors on smooth muscle and parasympathetic nerve endings were designated D- and M-receptors. respectively. Although in this study the antagonists used were not selective for 5-HT, the distinction made between these two types of 5-HT receptors is still valid. - 2 - Following the development and application of radioligand binding techniques the existence of more different 5-HT receptor types became apparent. In 1974, Bennett and Aghajanian first successfully applied these techniques to serotonin receptors using [3H]LSD to label brain membrane sites. The second radioligand used to label 5-HT receptors was [3H]5-HT (Bennett and Snyder, 1976; Fillion et al., 1978; Nelson et al.. 1978). Further progress was made when [3H]spiperone also appeared to label 5-HT recognition sites. About two decades after the characterization of the 'D' and 'M' receptors by Gaddum and Picarelli, Peroutka and Snyder (1979) reported differences between the binding characteristics of [3H]5-HT, PH]LSD and PHJspiperone. Evidence was presented that [3H]5-HT and [3H]spiperone labelled distinct populations of 5-HT membrane recognition sites and that [3H]LSD appeared to label both these sites. In this paper the authors suggested to designate the binding sites labelled by [3H]5-HT as 5-HT1 and the binding sites labelled by [3H]spiperone as 5-HT2 receptors. The present state in the 5-HT receptor field is that there exist four main receptor populations, designated the 5-HT1 , 5-HT2 , 5-HT3 and the recently discovered 5-HT4 receptor. Initially, the distinction made between the 5-HT1 and the 5-HT2 receptor was purely based on radioligand binding studies using rather unselective drugs. Not until selective agonists and antagonists became available. could these 5-HT receptor sites be better characterized. In contrast with the 5-HT1 and 5-HT2 receptor types. the revelation of the 5-HT3 and 5-HT4 receptor types was at first based on functional receptor correlates. The development and discovery of selective drugs and, in the case of the 5- HT3 receptor, radioligand binding studies have provided more information on these 5-HT receptor populations. It became evident that the 5-HT1 subdivision of the 5-HT receptor family was heterogeneous. Pedigo and co-workers ( 1981) discovered a high and low affinity site for spiperone, designated as 5-HT1A and 5-HT16 recognition sites, respectively. A third subtype, based on the high affinity displacement of [3H]5-HT by the ergot derivative mesulergine, was identified in the choroid plexus of various animal species and designated as 5-HT1c binding site (Pazos et al .. 1985; Hoyer et al.. 1985). Most recently, based on studies of the bovine caudate nucleus using [3H]5-HT as radio ligand in the presence of 8-0H-DPAT (5-HT1A) and mesulergine (5-HTJC), the existence of a 5- HT10 recognition site has been reported (Heuring and Peroutka. 1987). Unfortunately. full characterization of the 5-HT1 binding sites was hampered, since few selective and specific agonists and no specific antagonists were available. So Bradley and co-workers - 3 - ( 1986) suggested to designate this heterogeneous receptor group as '5-HT1 -like ·, representing a group of binding sites for which 5-carboxamidotryptamine (5-CT) and 5- HT show a high affmity and the effects of 5-HT cannot be blocked by 5-HT2 or 5-HT3 receptor antagonists.
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