L-163,491 is a partial angiotensin AT(1) receptor agonist in the hindquarters vascular bed of the cat

Responses to the nonpeptide angiotensin II agonist 5,7-dimethyl-2-ethyl-3-[ [2'-([butyloxycarbonyl) aminosulfonyl]-5'-(3-methyoxy-benzyl)-[1, 1'-biphen yl]-4-yl]methyl]-H-3-imidazo[4,5-b]pyridine (L-163,491) were investigated a nd compared with responses to angiotensin II, angiotensin IV and norepineph rine in the hindquarters vascular bed of the cat under constant-flow condit ions. Injections of L-163,491 into the hindquarter perfusion circuit caused dose-related increases in hindquarters perfusion pressure. In relative ter ms, angiotensin II was more potent than norepinephrine, which was more pote nt than angiotensin IV and L-163,491 in increasing hindlimb vascular resist ance. The slope of the dose-response curve for L-163,491 was flat, while th e apparent affinity of the compound for angiotensin AT, receptors was sligh tly greater than angiotensin IV. Responses to L-163,491 were inhibited by t he angiotensin AT, receptor antagonist DuP 532 (2-propyl-4-pentafluoroethyl -1-E2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid) and were not altered by the angiotensin AT(2) receptor antagonist PD123,319 (S(+)-1-[[4-(Dimethylamino)-3-methylphenyl]-5-(diphenylacetyl)-4,5,6,7- te trahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditribluoroacetate). H owever, the increase in hindlimb perfusion pressure in response to angioten sin II and angiotensin IV was significantly decreased following injection o f L-163,491. These data suggest that the nonpeptide angiotensin analog L-16 3,491 has partial agonist activity, which is dependent on the stimulation o f angiotensin AT, receptors in the hindquarters vascular bed of the cut. (C ) 2000 Elsevier Science B.V. All rights reserved.