内皮素受体阻断和血管紧张素转换酶抑制对慢性心力衰竭大鼠的附加作用。

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

作者信息

Qiu C B, Qiu C S, Hess P, Clozel J P, Clozel M

机构信息

Department of Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China; Actelion Ltd, CH-4123 Allschwil, Switzerland.

出版信息

Acta Pharmacol Sin. 2001 Jun;22(6):541-8.

PMID:11747762

Abstract

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.

摘要

目的

评估新型双靶点肠外内皮素受体拮抗剂替唑生坦对慢性心力衰竭（CHF）大鼠模型血流动力学的急性影响，并进一步研究替唑生坦与血管紧张素转换酶（ACE）抑制剂依那普利联合使用是否具有相加的血流动力学效应。

方法

通过结扎左冠状动脉诱导大鼠发生CHF，并测量其血流动力学。

结果

在心肌梗死后3至5周，大鼠出现CHF。与假手术大鼠相比，左心室舒张末期压力（LVEDP）显著升高，平均值为23至26 mmHg，左心室dp/dt（max）降低30%至40%，平均动脉压（MAP）降低超过10%，这些均证明了CHF的发生。在CHF大鼠中，急性静脉注射替唑生坦（10 mg·kg）或依那普利（1 mg·kg）均可显著降低MAP和LVEDP，而不影响心率或dp/dtmax。与单独使用替唑生坦（P < 0.05）或依那普利（P < 0.05）相比，替唑生坦与依那普利联合使用时对MAP和LVEDP具有相加效应。与替唑生坦或依那普利治疗的CHF大鼠相比，联合治疗对心率和dp/dtmax无显著影响。