Acute effects of E-3174, a human active metabolite of losartan, on the cardiovascular system in tachycardia-induced canine heart failure

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 pl asma 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 af ter acute intravenous administration of losartan (1 mg/kg) and E-3174 (0.3 and 1 mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1 mg/kg), und er condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac o utput, and LV dilatation. E-3174 at 0.3 and 1 mg/kg reduced pulmonary arter y pressure (-13+/-6% and -22+/-3% from baseline, respectively, p<0.05), pul monary capillary wedge pressure (-18+/-4% and -36+/-10%, p<0.05) and mean a rterial 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 o f left ventricular pressure(dP/dt/P) or the time constant for relaxation. E ffects of losartan at 1 mg/kg were similar to those of 0.3 mg/kg of E-3174. Enalapril at 1 mg/kg caused changes comparable to those seen after E-3174 administration (1 mg/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 1 mg /kg and E-3174 at 0.3 and 1 mg/kg increased fractional shortening to a simi lar extent (FS: +52+/-12%, +47+/-8% and +56+/-8%), while enalapril at 0.3 a nd 1 mg/kg had no significant effects on FS. Reflex elevation of plasma ren in activity induced by 1 mg/kg of E-3174 was similar to that caused by 1 mg /kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that ac ute blockade of the AT1 receptor with E-3174 reduced elevated pre- and afte r-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these elects of E-3174 were comp arable to those produced by enalapril, and were 3 times stronger than those by losartan.