Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure. Differential acute effects according to the renin-angiotensin system activation.
This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, i.v.) or enalaprilat (1 mg/kg, i.v.) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 +/- 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 +/- 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure.
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004285:Dogs; D015773:Enalaprilat / Q000494:pharmacology*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects