阻断内皮素受体和抑制血管紧张素转化酶在慢性心衰大鼠中的相加作用

目的:评价一种新的内皮素受体拮抗剂tezosentan对慢性心衰大鼠血流动力学的急性作用,并进一步研究该药与血管紧张素转化酶(ACE)抑制剂依那普利合用是否有相加作用。方法:在结扎左侧冠状动脉所致的慢性心衰大鼠中测量血流动力学的指标。结果:心肌梗死3-5周后,大鼠产生慢性心衰,与假手术大鼠相比,慢性心衰大鼠左心室舒张末期压(LVEDP)显著升高,其均值为23-26mmHg,心肌收缩力(左心室dp/dt_(max))降低30％-40％,平均动脉压(MAP)降低大于10％。在慢性心衰大鼠中,静脉注射tezosentan(10mg·kg~(-1))或依那普利(1mg·kg~(-1))显著降低其MAP和LVEDP,并对其心率或dp/dt_(max)无影响。与tezosentan或依那普利单用组相 比,两者合用对慢性心衰大鼠的MAP和LVEDP具有相加作用,对其心率或dp/dt_(max)无显著性作用。结论:急性静脉注射tezosentan改善慢性心衰大鼠心脏血流动力学,降低其LVEDP和后负荷(MAP),其心率和心肌收缩性(dp/dt_(max))并不受影响。Tezosentan的这些有利作用与依那普利相似。而且在抑制ACE作用的基础上,Tezosentan的这些有益作用也是很明显的。因此,tezosentan有望成为急性治疗心衰的有效新药。

Additional effects of endothelin receptor blockade and angiotensin converting enzyme inhibition in rats with chronic heart failure

AIM: To evaluate the acute effects of tezosentan, a new dual parenteral endothelin receptor antagonist, on hemodynamics in a rat model of chronic heart failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had additive hemodynamic effect. METHODS: Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery. RESULTS: At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean values of 23 to 26 mmHg, by a 30 % to 40 % reduction in left ventricular dp/dt(max) and by a more than 10 % decrease in mean arterial pressure (MAP) as compared to sham-operated rats. In CHF rats, acute intravenous administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats. CONCLUSION: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. These favorable effects of tezosentan are similar to those of enalapril. Furthermore, the benefits of tezosentan are apparent in addition to ACE inhibition. Thus, tezosentan could be a useful therapeutic agent in the acute treatment of heart failure.