Novel Angiotensin II AT₁ Receptor Antagonist Irbesartan Prevents Thromboxane A₂-Induced Vasoconstriction in Canine Coronary Arteries and Human Platelet Aggregation1

Abstract

This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT₁ receptor antagonist irbesartan interacts with the thromboxane A₂/prostaglandin endoperoxide H₂(TxA₂/PGH₂) 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 [³H]SQ29,548, a TxA₂ receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA₂analogs U46619 and autoradioagraphic receptor binding to the TxA₂ receptor antagonist [³H]SQ29,548 were studied with and without irbesartan. The TxA₂ analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC₅₀ = 11.6 ± 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC₅₀ of U46619 was increased 6- and 35-fold in the presence of 1 and 10 μM of irbesartan without a change of maximal contraction. At 1 μM, irbesartan is 2-fold more potent than the AT₁ receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT₁ receptor antagonists (CV11974 and valsartan), the AT₂ receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA₂/PGH₂ receptor agonist prostaglandin F_2α (PGF_2α). Neither the nitric oxide synthase inhibitorN^ω-nitro-l-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [³H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT₁ and TxA₂ receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis.