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

Abstract

Responses to the nonpeptide angiotensin II agonist 5,7-Dimethyl-2-ethyl-3-[[2′-([butyloxycarbonyl) aminosulfonyl]-5′-(3-methyoxybenzyl)-[1,1′-biphenyl]-4-yl]methyl]- 3H-imidazo[4,5-b]pyridine (L-163,491) were investigated and compared with responses to angiotensin II, angiotensin IV and norepinephrine in the hindquarters vascular bed of the cat under constant-flow conditions. Injections of L-163,491 into the hindquarter perfusion circuit caused dose-related increases in hindquarters perfusion pressure. In relative terms, angiotensin II was more potent than norepinephrine, which was more potent than angiotensin IV and L-163,491 in increasing hindlimb vascular resistance. The slope of the dose–response curve for L-163,491 was flat, while the apparent affinity of the compound for angiotensin AT 1 receptors was slightly greater than angiotensin IV. Responses to L-163,491 were inhibited by the angiotensin AT 1 receptor antagonist DuP 532 (2-propyl-4-pentafluoroethyl-1-[2′-(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]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditribluoroacetate). However, the increase in hindlimb perfusion pressure in response to angiotensin II and angiotensin IV was significantly decreased following injection of L-163,491. These data suggest that the nonpeptide angiotensin analog L-163,491 has partial agonist activity, which is dependent on the stimulation of angiotensin AT 1 receptors in the hindquarters vascular bed of the cat.