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

为探讨血管紧张素转换酶和中性内肽酶的联合抑制剂BMS-182657对慢性心力衰竭大鼠心功能的影响，选用体重220~240g雄性Wistar大鼠。结扎左冠状动脉造成大鼠心力衰竭，造成约45%的左心室梗死。术后8周左室舒张末压(LVEDP)升高，提示CHF的发生。术后6~8周，每日灌胃BMS 3 mg/kg体重1次。冠状动脉结扎(CAL)大鼠术后[-+]dp/dt降低，LVEDP升高。BMS治疗显著减轻LVEDP的增加，但不影响[-+]dp/dt的变化。在本研究中，CAL大鼠的梗塞面积从左心室总面积的40%到49%不等。假手术组大鼠左室无梗死，CAL和假手术组大鼠右室无梗死灶。BMS治疗不能改变CHF动物的心肌梗死面积。因此，BMS治疗能有效改善CHF动物的心功能不全。我们以前的研究表明，BMS具有明显的降压作用，可以降低血压。该药的降压作用强度与本研究结果一致，提示该药的降压作用有助于改善CHF大鼠的血流动力学。

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.