Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction

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• 作者：Martine Clozel ; Changbin Qiu ; Chang-Shen Qiu ; Patrick Hess ; Jean-Paul Clozel
• 关键词：ACC/AHA Scientific Statements ; coronary disease ; electrocardiography ; exercise ; tests
• 刊名：Journal of the American College of Cardiology
• 出版年：2002
• 出版时间：2 January 2002
• 年：2002
• 卷：39
• 期：1
• 页码：142-147
• 全文大小：178 K

文摘

We investigated the effects of short-term tezosentan treatment on cardiac function, pulmonary edema and long-term evolution of heart failure (HF) in a rat model of myocardial infarction (MI).

Background

Endothelin (ET) may play a major role in the progression from MI to HF. Tezosentan is a new dual ET_A/ET_B receptor antagonist.

Methods

Rats were subjected to coronary artery ligation and were treated with either vehicle or tezosentan (10 mg/kg IV bolus) at 1 h and 24 h after MI. Cardiac hemodynamics and lung weight were measured at 48 h after MI. Survival was assessed over a five-month period.

Results

At 48 h after ligation, vehicle-treated rats developed HF, as evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP), reduction in dP/dt_max and mean arterial pressure (MAP), and development of pulmonary edema. Tezosentan treatment attenuated the increase in LVEDP and in lung weight and slightly reduced MAP without affecting dP/dt_max. Infarct size was not modified by tezosentan. Despite the fact that treatment with tezosentan was stopped after 24 h, the initial tezosentan administration significantly reduced cardiac hypertrophy (22 % ) and decreased mortality by 51 % at five months (50 % survival vs. 19 % survival in vehicle-treated rats, p < 0.001).

Conclusions

Tezosentan administered during the first day after MI in rats, in addition to improving acutely hemodynamic conditions, markedly increases long-term survival. This increase is associated with a decrease of pulmonary edema and prevention of cardiac hypertrophy. Tezosentan could be a safe and useful therapeutic agent in the prevention and treatment of ischemic HF.