Development of the dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase as the drugs of chronic heart failure

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The present study was undertaken to examine the effect of long-term treatment with BMS-182657 (BMS), a combined inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), on cardiac function in rats with chronic heart failure (CHF).Male Wistar rats weighting 220 - 240 g were used in the present study. CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Left ventricular end-diastric pressure (LVEDP) was increased 8 weeks after the operation, suggesting the development of CHF.Rats were treated orally with 3 mg/kg body weight of BMS once daily from 6th to 8th week after the operation. The coronary artery-ligated (CAL) rats showed decreases in 【minus-plus】dP/dt and an increase in LVEDP after the operation. Treatment with BMS significantly attenuated the increase in LVEDP, but not the changes in 【minus-plus】dP/dt. The infarct areas of the CAL rat ranged from 40 to 49% of the total left ventricle in the present study. There was no infarction in the left ventricles of sham-operated rats and in the right ventricle of CAL and sham-operated rats. The infarct size was not altered by treatment with BMS.Thus, treatment of BMS is effective in improving cardiac dysfunction of the animals with CHF. Our previous studies have shown a marked hypotensive effect of BMS decreased blood pressure. The magnitude of the hypotensive effects of this agent is in good agreement with that in the present study, suggesting that the hypotensive effects contribute to the improvement of hemodynamics in rats with CHF.