Effect of captopril and the nonpeptide angiotensin II antagonists, SK&F 108566 and EXP3174, on renal function in dogs with a renal artery stenosis.
Treatment with an angiotensin converting enzyme (ACE) inhibitor can result in acute renal failure in patients with a renal artery stenosis. In the present study the effects of the selective nonpeptide angiotensin II antagonists, SK&F 108566 ((E)-alpha-[[2-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl] methylene]-2-thiophenepropanoic acid) and EXP3174 (2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]imidazole-5-carboxylic acid hydrochloride) (the active metabolite of DuP 753, losartan) were compared with the ACE inhibitor, captopril, in the anesthetized dog which had been uninephrectomized and the remaining renal artery clamped to reduce renal blood flow (RBF) by approximately 50%. All three agents resulted in dose-dependent reductions in mean arterial pressure (MAP), glomerular filtration rate (GFR) and RBF. The maximum responses to captopril and SK&F 108566 were similar with MAP, RBF and GFR all decreasing approximately 30%. EXP3174 also resulted in decreases in GFR and RBF of approximately 30%; however, there was a smaller (approximately 17%) decrease in MAP. The data indicate that the possible bradykinin enhancing activity of ACE inhibitors may not provide any moderating activity of ACE inhibitor-induced reduction in GFR observed in dogs with a renal artery stenosis.
Brooks
D P
DP
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
DePalma
P D
PD
Ruffolo
R R
RR
D000179:Acrylates / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007444:Inulin / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D019808:Losartan; D012039:Regional Blood Flow / Q000187:drug effects; D012078:Renal Artery Obstruction / Q000188:drug therapy; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes
D000179:Acrylates; D007093:Imidazoles; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; D007444:Inulin; D002216:Captopril; C066026:losartan carboxylic acid; D019808:Losartan