Angiotensin II AT1 receptor antagonists and platelet activation

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT 1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT 1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A 2 (TXA 2 ) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [ 3 H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA 2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA 2 /PGH 2 platelet receptor may be different from those involved in AT 1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.