The influence of P2Y12 antagonists on vascular NO signalling
Sagan, Ewelina Nina
P2Y12 antagonists are pharmacological agents used clinically in advanced stages of coronary artery disease in order to inhibit ADP-induced activation and aggregation of platelets and prevent deadly thrombotic events. Of the orally-prescribed P2Y12 antagonists available clopidogrel is the most established, it exhibits an excellent safety track record and is a popular drug, and was accredited for years the second-best selling drug in the world. However, since clopidogrel was introduced to the market in 1997 many pleiotropic effects have been noticed, which suggest other off-target yet beneficial effects in addition to its anti-platelet effects.\ud The overall hypothesis being tested in this body of work was that P2Y12 antagonists, clopidogrel in particular, have the positive influence on vascular NO signalling.\ud A vascular model was set up using isolated rabbit aortae in which clopidogrel enhanced NO donor-induced vasorelaxation. Although the precise mechanism was not found, the effect was independent of P2Y12 receptors and possibly linked to decreased superoxide production and improved anti-oxidant/inflammatory status in vessels. This finding might be relevant for patients receiving concomitant therapy with organic nitrates and clopidogrel.\ud In vitro studies revealed novel S-nitrosation properties of P2Y12 antagonists, surprisingly without the need for metabolism to their active form. Newly synthesized SNO derivatives of clopidogrel and prasugrel were more potent in inhibition of platelet aggregation and induction of vasodilation than their parental forms. Although the formation of drug-SNO species has to be confirmed in vivo, they have a potential to increase NO bioavailability in patients.\ud Clopidogrel administration to coronary artery disease patients resulted in upregulated plasma levels of nitrite and cGMP after 2 h-intake of a loading dose, which were further increased after 3 days of a maintenance therapy. This effect was never shown before in man and most likely reflects improved endogenous NO production, but also providing additional protection from the effects of nitrite at the same time.\ud Taken together, the results of this thesis clearly demonstrate the influence of clopidogrel on vascular response to NO as well as NO production, metabolism and bioavailability. It is important to identify these alternative pathways especially in the current era with alternative P2Y12 antagonists that overcome some of the limitations of clopidogrel but may not share all the beneficial properties.