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EXPERIMENTAL STUDY

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

Martine Clozel, MD^*,*, Changbin Qiu, MD, PhD^*, Chang-Shen Qiu^*, Patrick Hess^* and Jean-Paul Clozel, MD^*

^* Actelion Ltd., Allschwil, Switzerland
Department of Pharmacology, Shanghai Institute of Materia Medica, Shanghai, China

Manuscript received February 22, 2001; revised manuscript received September 10, 2001, accepted September 10, 2001.

^* Reprint requests and correspondence: Dr. Martine Clozel, Actelion Pharmaceuticals Ltd., Innovation Center, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
martine.clozel{at}actelion.com

OBJECTIVES: 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.

Abbreviations and Acronyms   BW   body weight   CHF   chronic heart failure   ET   endothelin   HF   heart failure   HR   heart rate   LV   left ventricle   LVdP/dtmax+   maximal rate of positive rise of left ventricular pressure   LVEDP   left ventricle end-diastolic pressure   MAP   mean arterial pressure   MI   myocardial infarction   RV   right ventricle, right ventricular

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