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Title: Influence of the α1-adrenoceptor antagonists naftopidil and doxazosin on human platelet functions in vitro
Author: Al-Arayyed, Najah Abdulwahab
ISNI:       0000 0001 3404 9732
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1995
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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 [alpha]1-adrenoceptor blocking activity, e.g. prazosin, doxazosin and urapidil, have been found to inhibit platelet aggregation in some studies. Naftopidil is a new [alpha]1-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 collagen-induced TXB2 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 collagen-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 [alpha]2-adrenoceptors and suppressant effects on stimulus-induced calcium mobilization. Experiments with specific [alpha]2-adrenoceptor antagonists will be necessary to establish this mode of action. Moreover, the inhibitory action of naftopidil on TXA2 generation may contribute to its marked inhibition of adrenaline-induced platelet activation which is believed to be dependent on the formation of cyclooxygenase metabolites.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Antihypertensive drugs; Cardiovascular disease