Responses to L-163,491, a nonpeptide angiotensin II mimic, in the pulmonary vascular bed of the cat.
Pulmonary vascular responses to 5,7-dimethyl-2-ethyl-3-[[2'-[butyloxycarbonyl)amino-sulfonyl]-5'-(3-meth oxybenzyl)-[1,1'-biphenyl]-4-yl]methyl]-3H-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'-(1H-tetrazol-5-yl)bipheny l-4]-methyl)imidazole-5-carboxylic acid, an angiotensin II AT1 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 A2 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 significant angiotensin AT1 receptor-mediated vasoconstrictor activity in the pulmonary vascular bed of the cat. These data also show 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.
Kaye
A D
AD
Departments of Anesthesiology and Pharmacology, Tulane University Medical Center, New Orleans, LA 70112-2699, USA.
Nossaman
B D
BD
Kivlighn
S
S
Ibrahim
I N
IN
De Witt
B J
BJ
Kadowitz
P J
PJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007093:Imidazoles; C096715:L 163491; D011725:Pyridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D001920:Bradykinin