Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation

A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A(2) (TxA(2))/ prostaglandin H-2 (PGH(2)) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA(2)- dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TsA(2) analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA(2), telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [H-3]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did net modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD 123319. These results suggest that some AT-1-receptor antagonists reduce TxA(2)-dependent activation independent of Ang II involvement.