Responses to L-163,491, a nonpeptide angiotensin II mimic, in the pulmonary vascular bed of the cat

Abstract Pulmonary vascular responses to 5,7-dimethyl-2-ethyl-3-[[2′-[(butyloxycarbonyl)amino-sulfonyl]-5′-(3-methoxybenzyl)-[1,1′-biphenyl]-4-yl]methyl]-3 H -imidazo[4,5-b]pyridine (L-163,491), a novel nonpeptide angiotensin agonist, and angiotensin IV, the 3–8 amino acid fragment of angiotensin, were compared with responses to angiotensin II. Responses were investigated in the intact-chest cat under conditions of controlled blood flow and intralobar injections of angiotensin II, L-163,491, and angiotensin IV caused dose-related increases in lobar arterial pressure. When comparable in lobar arterial pressure of the three agents were examined, L-163,491 was approximately 3-fold less potent than angiotensin IV and approximately 100-fold less potent than angiotensin II when doses are expressed on a nmol basis. DuP 532, 2-propyl-4-pentafluoroethyl-1-([2′-(1 H -tetrazol-5-yl)biphenyl-4]-methyl)imidazole-5-carboxylic acid, an angiotensin II AT 1 receptor antagonist, reduced pulmonary vasoconstrictor responses to angiotensin II, angiotensin IV and L-163,491, but did not significantly change pressor responses to serotonin, norepinephrine, or the thromboxane A 2 mimic, U46619. PD 123319, an angiotensin II subtype 2 receptor antagonist, did not significantly change pressor responses to L-163,491, angiotensin II, or angiotensin IV. Captopril, the angiotensin-converting enzyme inhibitor, decreased pulmonary vasoconstrictor responses to angiotensin I and enhanced vasodilator responses to bradykinin, but did not significantly change pressor responses to L-163,491. These data show that L-163,491 has significant angiotensin AT 1 receptor-mediated vasoconstrictor activity in the pulmonary vascular bed of the cat. These data also show that the nonpeptide agonist has 3-fold less activity compared to angiotensin IV and is approximately 100-fold less potent than angiotensin II in the feline pulmonary vascular bed.