Abstract
The aim of this study was to evaluate the acute effects of E-3174, a human active metabolite of the AT1 receptor antagonist, losartan, on hemodynamic functions in dogs with severe heart failure (HF). In dogs, insignificant plasma levels of E-3174 are present following administration of losartan, and therefore, the effects of these two drugs can be studied independently in the dog. HF was established by rapid pacing of the right ventricle (250-270 beats/min) for 4 weeks. We examined changes in cardiovascular functions after acute intravenous administration of losartan (1mg/kg) and E-3174 (0.3 and 1mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1mg/kg), under condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac output, and LV dilatation. E-3174 at 0.3 and 1mg/kg reduced pulmonary artery pressure (−13±6% and −22±3% from baseline, respectively, p<0.05), pulmonary capillary wedge pressure (−18±4% and −36±10%, p<0.05) and mean arterial pressure (−24±2% and −36±7%, p<0.05), increased stroke volume (SV: +12±7% p>0.05; +36±19%, p<0.05), and reduced peripheral resistance (−23±5% and −41±9%, p<0.05), but had no effect on the first derivative of left ventricular pressure (dP/dt/P) or the time constant for relaxation. Effects of losartan at 1mg/kg were similar to those of 0.3mg/kg of E-3174. Enalapril at 1mg/kg caused changes comparable to those seen after E-3174 administration (1mg/kg), except that the increase in SV (+16±8%, p<0.05) with enalapril was not as great as that with E-3174. Both losartan at 1mg/kg and E-3174 at 0.3 and 1mg/kg increased fractional shortening to a similar extent (FS: +52±12%, +47±8% and +56±8%), while enalapril at 0.3 and 1mg/kg had no significant effects on FS. Reflex elevation of plasma renin activity induced by 1mg/kg of E-3174 was similar to that caused by 1mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these effects of E-3174 were comparable to those produced by enalapril, and were 3 times stronger than those by losartan. (Hypertens Res 2001; 24: 65-74)
