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J Am Coll Cardiol, 2002; 39:142-147
© 2002 by the American College of Cardiology Foundation
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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*{dagger}, Chang-Shen Qiu*{dagger}, Patrick Hess* and Jean-Paul Clozel, MD*

* Actelion Ltd., Allschwil, Switzerland
{dagger} 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 ETA/ETB 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/dtmax 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/dtmax. 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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