LOSARTAN INHIBITS THROMBOXANE A(2)-INDUCED PLATELET-AGGREGATION AND VASCULAR CONSTRICTION IN SPONTANEOUSLY HYPERTENSIVE RATS

Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A(2)/prostaglandin H-2 receptors and inhibits the thromboxane A(2) (TxA(2)) analog U46619 -induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA(2)-induced plate let aggregation and vasoconstriction in spontaneously hypertensive rat s (SHRs). Pretreatment with losartan (10 mu M) significantly reduced U 46619-induced, concentration-dependent washed platelet aggregation. Th e inhibition is specific for losartan, because another Ang II AT(1)-re ceptor antagonist, CV11974 (10 mu M), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 mu M) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the AGH-induced endothelium- derived contracting factor (EDCF)-mediated vasoconstriction in the aor tic rings from adult SHRs. U46619 produced dose-dependent vasoconstric tion in aortic vessels of SHRs, which was demonstrated to be blocked b y the potent, selective TxA(2)/PGH(2) receptor antagonist SQ29,548. Pr etreatment with losartan (10(-6)-10(-5) M) inhibited the contractile r esponse of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold i n the presence of 1 and 10 mu M losartan, respectively, without change s in maximal contraction. The active metabolite of losartan, EXP3174, at 1 mu M also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT(2) antagonist PD123319, nor the angiotensin-convertin g enzyme inhibitor lisinopril, each at concentrations of 1 mu M, had a ny effect on the U46619-induced constriction in aortic rings. In concl usion losartan, acting as both AT(1)- and TxA(2)/PGH(2)-receptor antag onists, may enhance its therapeutic profile in the treatment of hypert ension and cardiovascular disease.