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, intera cts 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 diffe rent angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA(2)- d ependent human platelet activation. Platelets were obtained from healthy vo lunteers. Platelets were stimulated with the TsA(2) analogue, U46619 (10(-6 ) M). U46619-stimulated platelet activation was significantly reduced by bo th losartan and irbesartan in a dose-dependent manner. Only maximal doses o f 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 pla telet activation involved by TxA(2), telmisartan showed a higher effect tha n valsartan and EXP3174 but lower than either losartan and irbesartan. Losa rtan or irbesartan reduced the binding of [H-3]-U46619 to platelets, an eff ect that was observed with lower ability with the other AT-1 antagonists. A lthough platelets expressed AT-1-type receptors, exogenous Ang II did net m odify platelet activation. This effect was not modified by blocking the AT- 2 receptor with PD 123319. These results suggest that some AT-1-receptor an tagonists reduce TxA(2)-dependent activation independent of Ang II involvem ent.