The aim of the work presented in this thesis was to investigate of effect of endothelin-1 on <I>in vitro</I> 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 <I>in vitro</I> 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 ET<SUB>B</SUB> 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 ET<SUB>B</SUB> receptor antagonist but not BQ 123, an ET<SUB>A</SUB> receptor antagonist. <I>In vivo</I> administration of endothelin-1 inhibited <I>ex vivo</I> 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 <I>in vivo</I> 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 ET<SUB>B</SUB> receptor. Platelet cyclic GMP accumulation is also stimulated by ET<SUB>B</SUB> 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.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:649592 |
Date | January 1997 |
Creators | Dockrell, Mark Edward Carl |
Publisher | University of Edinburgh |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | http://hdl.handle.net/1842/21202 |
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