Analysis of the effects of candesartan in the mesenteric vascular bed of the cat

The effects of the nonpeptide angiotensin II AT(1) receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 mu g/kg IV. After administration of the AT(1) receptor antagonist in a dose of 3 mu g/kg IV, the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT(1) receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-l, alpha,beta-methylene ATP(1) adenosine, acetylcholine, and bradykinin. Treatment with the AT(1) receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan tan on responses to angiotensin II. Candesartan also decreased presser responses to angiotensin III and IV with a parallel shift at the low dose and a nonparallel shift to the right of the dose-response curve at the high dose, These results indicate that candesartan is a potent, selective, long-acting AT(1) receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.