Clopidogrel, prasugrel, and ticagrelor are antiplatelet agents used for the treatment of acute coronary syndromes. Clopidogrel is known to improve endothelial function in patients with coronary disease but little is known about either the more potent thienopyridine prasugrel, or the irreversible P2Y12 inhibitor ticagrelor. The ability of clopidogrel to undergo S-nitrosation is recognised, and the thienopyridines’ ability to form S-nitrosothiols (RSNO) has been confirmed in vitro, a finding of significant interest given the potent anti-aggregatory and vasomodulatory properties exhibited by S-nitrosothiols. This study sought to investigate firstly, the effect of co-administration of oral nitrates and proton pump inhibitors on NO metabolites in patients treated with clopidogrel. Secondly, the effect of acute and chronic prasugrel treatment on NO metabolite formation was investigated, with particular emphasis on SNO bio-synthesis in-vivo. This lead to further interest in ticagrelor which, unlike the thienopyridines, lacks a free thiol group, to examine the effect of changing pH on its ability to dissolve, react and inhibit platelets, and ultimately establish whether ticagrelor could form RSNO. Ozone-based chemiluminescence techniques were employed to measure the principal NO metabolites in blood samples, and platelet aggregation was measured using multiple electrode aggregometry. The ability of clopidogrel and prasugrel to form RSNO is demonstrated both in vitro and in vivo. An acute rise in plasma RSNO levels occurs following a loading dose of prasugrel in patients with coronary disease. Ticagrelor’s platelet inhibitory response to ADP was found to decrease after lowering of the pH in vitro. However in the presence of nitrite and decreasing pH, it readily formed ticagrelor-induced RSNO which resulted in augmented platelet inhibition compared to ticagrelor alone. These are exciting and novel findings with the potential to shape both our understanding of RSNO, and the pleiotropic effects of these commonly prescribed anti-platelet drugs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:709580 |
| Date | January 2016 |
| Creators | Thornhill, Laurence |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/99215/ |
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