Effects of renin-angiotensin system blockade in guinea pigs.
The goal of the present study was to compare the hemodynamic and biochemical effects of the renin inhibitor Ro 42-5892, the angiotensin converting enzyme inhibitor cilazapril, and the angiotensin II receptor blocker EXP132, the aldehyde derivative of DuP 753. The three drugs were evaluated in guinea pigs, previously treated with furosemide, using their maximal effective doses. Cilazapril decreased arterial blood pressure more than Ro 42-5892 and EXP132. In contrast, Ro 42-5892 and EXP132 had similar effects. The larger decrease of arterial pressure induced by cilazapril was not due to a larger decrease of angiotensin II in plasma and was not influenced by cyclooxygenase inhibition with indomethacin or by bradykinin antagonism with Hoe 140. After binephrectomy, most of the blood pressure-lowering effect of Ro 42-5892 disappeared. In contrast, cilazapril was still markedly effective, pointing to extrarenal effects. We conclude that in furosemide-treated guinea pigs, as opposed to previously published animal models, the decrease of arterial pressure induced by angiotensin converting enzyme inhibitors may be partly due to extrarenal effects not related to the renin-angiotensin system.
Véniant
M
M
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Clozel
J P
JP
Hess
P
P
Fischli
W
W
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000031:analogs & derivatives; D017315:Cilazapril; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005665:Furosemide / Q000494:pharmacology*; D006168:Guinea Pigs; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D019808:Losartan / Q000031:analogs & derivatives; D009392:Nephrectomy; D009842:Oligopeptides / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D012083:Renin / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*; D000092502:Renin Inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D001920:Bradykinin; D017315:Cilazapril; D016861:Cyclooxygenase Inhibitors; D005665:Furosemide; D007093:Imidazoles; D007213:Indomethacin; D019808:Losartan; D009842:Oligopeptides; D011724:Pyridazines; D012083:Renin; D013777:Tetrazoles; D000092502:Renin Inhibitors; C073600:2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde; C065679:icatibant; C066026:losartan carboxylic acid; C065581:remikiren