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Influence of the [Alpha] 1-Adrenoceptor Antagonists

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Influence of the [Alpha] 1-Adrenoceptor Antagonists INFLUENCE OF THE - ADRENOCEPTOR ANTAGONISTS NAFTOPIDIL AND DOXAZOSIN ON HUMAN PLATELET FUNCTIONS IN VITRO by NAJAH AL-ARAYYED A THESIS PRESENTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY of the UNIVERSITY OF LONDON 1995 DEPARTMENT OF MEDICINE DIVISION OF TOXICOLOGY AND PHARMACOLOGY UNIVERSITY COLLEGE AND MIDDLESEX SCHOOL OF MEDICINE ProQuest Number: 10017365 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10017365 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT The enhanced platelet activity in hypertension has been suggested to contribute to the increased risk of cardiovascular disease in this condition. Various antihypertensive drugs have been examined both in vitro and in vivo for their ability to inhibit platelet activation. Antihypertensive drugs which possess selective a^-adrenoceptor blocking activity, e.g. prazosin, doxazosin and urapidil, have been found to inhibit platelet aggregation in some studies. Naftopidil is a new a^-adrenoceptor blocker but its effects on platelet function have not yet been studied. The main objective of the present study, therefore, was to study the effects of naftopidil in comparison with doxazosin on human platelet aggregation and secretory responses in vitro. The effects of the calcium channel blocker nifedipine were also investigated for comparative purposes. When platelet aggregation was induced by individual agonists, naftopidil but not doxazosin caused slight inhibitions of adrenaline- and serotonin- induced aggregation. Both drugs, however, failed to inhibit aggregation induced by ADP and collagen. Moreover, naftopidil markedly and, to a lesser extent, doxazosin inhibited the aggregation induced by sub-threshold concentrations of adrenaline in combination with sub-threshold concentrations of ADP, collagen or serotonin. In a washed platelet system naftopidil and, to a lesser extent, doxazosin inhibited adrenaline-induced aggregation. In the same system, naftopidil inhibited partially collagen-induced platelet aggregation. Naftopidil and doxazosin also inhibited the release of the a-granular component, platelet-derived growth factor, induced by adrenaline but not that induced by collagen. — In the presence of naftopidil and doxazosin apparent increases in platelet serotonin release were observed possibly indicating that these drugs block the uptake mechanism for serotonin in platelets. Nifedipine was found to inhibit collagen-induced platelet aggregation and release of serotonin but it did not inhibit the release of PDGF. In order to clarify the modes of action of naftopidil, doxazosin and nifedipine as inhibitors of platelet activation, their effects on platelet signal transduction mechanisms were studied in washed platelets. Naftopidil and doxazosin inhibited the mobilization of intra platelet calcium induced by collagen and adrenaline. Naftopidil but not doxazosin inhibited adrenaline- and coUagen-induced TXB 2 generation. The platelet cyclic AMP, which mediates platelet inhibition, was not affected by either naftopidil or doxazosin. However, both drugs prevented the decline in platelet cyclic AMP stimulated by adrenaline. In comparison with naftopidil and doxazosin, nifedipine produced a greater inhibition of coUagen-induced calcium mobilization and also inhibited the collagen- induced TXB2 production, comparable in its extent to that produced by naftopidil. Overall, it is concluded that naftopidil and, to a lesser extent, doxazosin inhibit platelet activation, possibly through antagonistic actions on platelet « 2-adrenoceptors and suppressant effects on stimulus-induced calcium mobilization. Experiments with specific (%2-adrenoceptor antagonists will be necessary to establish this mode of action. Moreover, the inhibitory action of naftopidil on TXA 2 generation may contribute to its marked inhibition of adrenaline-induced platelet activation which is believed to be dependent on the formation of cyclooxygenase metabolites. - 3 - Table of Contents Abstract....................................................................................................................... 2 Table of Contents ...................................................................................................... 4 Acknowledgments ................................................................................................ 15 Abbreviations ........................................................................................................ 16 List of Figures ........................................................................................................ 17 List of Tables .............................................................................................................21 Chapter 1 General Introduction ................................................................... 25 1.1. General features of platelet anatomy and the related activities .... 26 1.1.1. The peripheral zone ..........................................................................26 1.1.1.1. Plasma membrane..............................................................................26 1.1.1.2. Glycocalyx .................................. 29 1.1.1.3. Submembrane area (membrane skeleton) .........................................29 1.1.1.4. The surface-connected open canalicular system ................................ 29 1.1.2. Cytoplasmic matrix ............................................................................ 30 1.1.2.1. Microfilaments (actin-containing filaments) .......................................30 1.1.2.2. Microtubules (tubulin system) ........................................................... 31 1.1.3. Cytoplasmic organelles ................................................................... 31 1.1.3.1. Mitochondria .................................................................................. 32 1.1.3.2. «-granules (protein storage granules) ...............................................32 1.1.3.3. Dense granules (amines storage granules) .........................................33 1.1.3.4. Lysosomes and peroxisomes ............................................................. 33 1.1.4. Dense tubular system (membrane system) .........................................34 — Table of Contents 1.2. Physiological platelet stimulatory agonists and their receptors .... 35 1.2.1. Catecholamines ............................................................................. 35 1.2.2. Collagen ....................... 36 1.2.3. Adenosine 5 - Diphosphate (A D P ) ................................................... 36 1.2.4. Vasopressin . .' ............................................................................ 37 1.2.5. Serotonin (5-hydroxytryptamine, 5-H T ) ...........................................37 1.2.6. Thrombin ........................................................................................ 37 1.2.7. Thromboxane A 2 (TxAj) and prostaglandin H 2 (PGH2) .................... 38 1.2.8. Platelet-activating factor (PAF) ....................................................... 38 1.3.^ Signal transduction mechanisms involved in the regulation of platelet function ............................................................... 39 1.3.1. Phospholipasè C and the phosphoinositide pathway ........................ 39 1.3.1.1. Inositol 1, 4, 5-trisphosphate (IP 3) and Calcium Mobilization .... 41 1.3.1.2. Sn-1, 2-DAG and PKC activation ..................................................... 42 1.3.2. Phospholipasè A 2 and the arachidonic acid pathway ........................42 1.3.3. Regulation of cAMP formation ......................................................... 45 1.4. Role of platelet aggregatory and procoagulant activities in haemostasis and thrombosis .............................................. 46 1.5. In vitro methods used to assess potential antiplatelet effects of drugs ............................................................................... 48 1.5.1. Isolation of human platelets from whole blood for in vitro studies of platelet function .................................................. 48 1.5.2. Platelet aggregation in platelet-rich plasma ...................................... 49 1.5.3. Platelet aggregation in whole blood .................................................50 1.5.4. Platelet adhesion .............................................................................. 50 1.5.5. Platelet release reaction ....................................................................51 1.5.6. Platelet biochemical indices ............................................................. 51 - 5 - Table o f Contents 1.6. Involvement of platelets in primary hypertension and coronary heart disease ........................................................ 52 1.6.1. Definition of primary hypertension ................................................ 52 1.6.2. Mechanism of primary hypertension .............................................. 53 1.6.3. Disturbances of platelet ion transport as observed in primary hypertension .........................................................
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