Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit.
1. Renin inhibitors may be more advantageous than either angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin-angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma. 2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two-kidney one-clip Goldblatt rabbit. 3. At doses of 2-2.5 mg/kg, i.v., EMD 58265 and 5-10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2-4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF. 4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII. 5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.
Zimmerman
B G
BG
Department of Pharmacology, University of Minnesota, Minneapolis, USA. zimme003@tc.umn.edu
D000803:Angiotensin I / Q000097:blood / Q000187:drug effects; D000804:Angiotensin II / Q000097:blood / Q000187:drug effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015773:Enalaprilat / Q000494:pharmacology*; D008026:Ligation; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits; D012079:Renal Circulation / Q000187:drug effects; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D015773:Enalaprilat; D009842:Oligopeptides; D000092502:Renin Inhibitors; C094806:EMD 58265; C050898:ditekiren