Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-Induced vasoconstriction in canine coronary arteries and human platelet aggregation

This study was conducted to investigate whether the novel orally active non peptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan intera cts with the thromboxane A(2)/prostaglandin endoperoxide H-2 (TxA(2)/PGH(2) ) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [H-3] SQ29,548, a TxA(2) receptor an tagonist, in canine coronary sections was determined. Blood for platelet ag gregation studies was collected by venous puncture from healthy human volun teers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Va scular reactivity and platelet aggregation in response to the TxA(2) analog s U46619 and autoradioagraphic receptor binding to the TxA(2) receptor anta gonist [H-3] SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (E C50 5 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induc ed vasoconstriction, and the dose-response curve was shifted to the right i n a dose-dependent manner. The EC50 of U46619 was increased 6- and 35-fold in the presence of 1 and 10 mu M of irbesartan without a change of maximal contraction. At 1 mu M, irbesartan is 2-fold more potent than the AT(1) rec eptor antagonist losartan in the inhibition of U46619-induced vasoconstrict ion in canine coronary arteries. In contrast, neither AT(1) receptor antago nists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U4 6619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vas oconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglan din F-2 alpha (PGF(2 alpha)). Neither the nitric oxide synthase inhibitor N -omega-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indom ethacin had any effect on irbesartan's attenuation of U46619-induced vasoco nstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbe sartan at high concentrations significantly competed for [H-3]SQ29,548 bind ing in canine coronary sections. U46619 stimulated dose-dependent human pla telet aggregation of platelet-rich plasma. Preincubation with irbesartan si gnificantly inhibited platelet aggregation in a concentration-dependent man ner. In conclusion, the dual antagonistic actions of irbesartan by acting a t both the AT(1) and TxA(2) receptors in blood vessels and platelets may ov erall enhance its therapeutic profile in the treatment of hypertension, ath erosclerosis, and arterial thrombosis.