The angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in the rat hind-limb vascular bed in vivo

Objective We studied the vasoconstrictor effects of the thromboxane A(2) (T xA(2)) analogue U46619 in the perfused hind limb of rats under constant flo w before and after intravenous injection of irbesartan, an angiotensin II A (1) receptor antagonist, to test whether irbesartan interacts in vivo with the thromboxane A(2)/prostaglandin endoperoxidase Ha (TxA(2)/PGH(2)) recept or. Design Male Sprague- Dawley rats (n = 15, body weight 350-420 g) were anest hetized with thiobutabarbital sodium (Inactin, 100 mg/kg intraperitoneally) , Regional vascular responses to U46619 (0.5 and 1.0 mug) were investigated in the rat hind quarter under conditions of controlled flow before and aft er administration of irbesartan (10 mg/kg, intravenously). In addition, to test the specificity of the effect of irbesartan on U46619, phenylephrine ( 0.5, 1.0 W) and another AT(1) receptor antagonist, candesartan CV11974 (0.3 mg/kg, intravenously) were used, Results The dose-dependent increases in hind-limb perfusion pressure produc ed by U46619 were significantly attenuated by prior injection of irbesartan , at a dose that blocked the angiotensin II (Ang II) presser responses. The specificity for the response was shown with the demonstrations that the in crease in vascular resistance produced by phenylephrine was unchanged by ir besartan and, furthermore, that the increase in vascular produced by U46619 was unchanged by another AT(1) receptor antagonist, candesartan, Conclusion This study demonstrates that irbesartan interacts at the TxA(2)/ PGH2 receptor in the rat's hind limb in vivo, to modify changes in local re gional vascular resistance. The dual antagonistic actions of irbesartan, ac ting at both AT(1) and TxA(2) receptors in blood vessels, may overall enhan ce its therapeutic profile in the treatment of hypertension.