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(Hypertension. 1997;30:1260-1266.)
© 1997 American Heart Association, Inc.

Articles

Analysis of the Effects of Candesartan in the Mesenteric Vascular Bed of the Cat

Hunter C. Champion; Philip J. Kadowitz

From the Department of Pharmacology, Tulane University School of Medicine, New Orleans, La.

Correspondence to Philip J. Kadowitz, PhD, Department of Pharmacology SL83, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112. E-mail champion{at}mailhost.tcs.tulane.edu

Abstract The effects of the nonpeptide angiotensin II AT₁ 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 µg/kg IV. After administration of the AT₁ receptor antagonist in a dose of 3 µg/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 AT₁ receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1, ,ß-methylene ATP, adenosine, acetylcholine, and bradykinin. Treatment with the AT₂ receptor antagonist PD123,319 or with sodium meclofenamate did not alter the inhibitory effects of candesartan on responses to angiotensin II. Candesartan also decreased pressor 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 AT₁ receptor antagonist that, depending on dose, can produce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV.

Key Words: angiotensin peptides • vasoconstriction • angiotensin receptor subtypes

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