Clozel Martine, Qiu Changbin, Qiu Chang-Shen, Hess Patrick, Clozel Jean-Paul
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
J Am Coll Cardiol. 2002 Jan 2;39(1):142-7. doi: 10.1016/s0735-1097(01)01692-8.
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).
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.
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.
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).
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.
我们在心肌梗死（MI）大鼠模型中研究了短期使用替唑生坦治疗对心脏功能、肺水肿及心力衰竭（HF）长期演变的影响。
内皮素（ET）可能在从MI进展至HF的过程中起主要作用。替唑生坦是一种新型的双重ET（A）/ET（B）受体拮抗剂。
大鼠接受冠状动脉结扎，并在MI后1小时和24小时接受载体或替唑生坦（10mg/kg静脉推注）治疗。在MI后48小时测量心脏血流动力学和肺重量。在五个月的时间内评估生存率。
结扎后48小时，接受载体治疗的大鼠出现HF，表现为左心室舒张末期压力（LVEDP）显著升高、dP/dt（max）和平均动脉压（MAP）降低以及肺水肿的发生。替唑生坦治疗减轻了LVEDP和肺重量的增加，并轻微降低了MAP，而不影响dP/dt（max）。替唑生坦未改变梗死面积。尽管替唑生坦治疗在24小时后停止，但最初给予替唑生坦显著降低了心脏肥大（22%），并使五个月时的死亡率降低了51%（替唑生坦治疗组生存率为50%，载体治疗组生存率为19%，p<0.001）。
在大鼠MI后的第一天给予替唑生坦，除了能急性改善血流动力学状况外，还能显著提高长期生存率。这种提高与肺水肿的减轻和心脏肥大的预防有关。替唑生坦可能是预防和治疗缺血性HF的一种安全有效的治疗药物。
