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

血管紧张素转换酶和中性内肽酶双重抑制剂治疗慢性心力衰竭药物的研制

• 批准号: 10557226
• 负责人: YOSHIDA Makoto
• 金额: $ 2.24万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557226/
• 关键词: chronic heart failure; angiotensin-conversing enzyme; neutral endopeptidase; dual inhibitor; BMS-182657; 変換酵素; ニュートラルエンドペプチダーゼ; ANP

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.

本研究旨在观察BMS-182657（BMS）（一种血管紧张素转换酶（ACE）和中性内肽酶（NEP）的联合抑制剂）长期治疗对慢性心力衰竭（CHF）大鼠心功能的影响。CHF通过大鼠左冠状动脉结扎诱导，这导致约45%的左心室梗死。术后8周左室舒张末压（LVEDP）明显升高，提示CHF的发生。术后6 ~ 8周每天口服BMS 3 mg/kg体重。冠状动脉结扎（CAL）大鼠术后dP/dt降低，LVEDP增加。BMS治疗显著减弱了LVEDP的增加，但未减弱[负-正]dP/dt的变化。在本研究中，CAL大鼠的梗死面积占左心室总面积的40%至49%。假手术组大鼠左心室、CAL组和假手术组大鼠右心室均无梗死。BMS治疗对心肌梗死面积无明显影响，因此BMS治疗对改善CHF动物心功能障碍是有效的。我们以前的研究表明BMS具有显著的降压作用。该药物的扩张作用的大小与本研究的结果一致，表明该扩张作用有助于改善CHF大鼠的血流动力学。