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Title: Endothelial factors and platelet activity : endothelin-1, a new modulator
Author: Dockrell, Mark Edward Carl
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1997
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The aim of the work presented in this thesis was to investigate of effect of endothelin-1 on in vitro human platelet aggregation, to characterise the endothelin receptor subtype present on platelets and examine the effect of the peptide on the intracellular second messengers cyclic AMP and cyclic GMP. In addition the role of endothelin-1 in the modulation of platelet aggregation in subjects with high blood pressure has also been exmained. Analysis of the effect of endothelin-1 on in vitro platelet aggregation, by the use of transmittance aggregometry, has identified that 1. Endothelin-1 alone has a slight but significant aggregatory effect. 2. Endothelin-1 potentiates primary and inhibits secondary aggregation induced by adrenaline but not ADP. 3. Both endothelin-1 and sarafotoxin S6c, an ETB receptor selective agonist, potentiate adrenaline-induced primary aggregation in a dose dependent manner, furthermore endothelin-1 potentiation of aggregation is inhibited by BQ 788, and ETB receptor antagonist but not BQ 123, an ETA receptor antagonist. In vivo administration of endothelin-1 inhibited ex vivo secondary platelet aggregation to adrenaline but not to ADP. No significant effect was seen on primary platelet aggregation induced by either aggregating agent. In vitro aggregation using a concentration of endothelin-1 estimated to be approximately the same as that achieved by in vivo administration produced similar results. Endothelin-1 and sarafotoxin S6c both caused a dose dependent accumulation of cyclic GMP but not cyclic AMP in platelets. In conclusion, endothelin-1 appears to modulate human platelet aggregation in a bi-directional manner. The potentiation of primary aggregation is dependent on the platelet aggregating agent employed and appears to be mediated by the ETB receptor. Platelet cyclic GMP accumulation is also stimulated by ETB receptor agonists. In addition, platelet responsiveness to endothelin-1 is altered in subjects with high blood pressure and in patients with essential hypertension, and the potentiation of platelet aggregation by endothelin-1 may be associated with a genetic component of high blood pressure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available