Mulder P, Richard V, Derumeaux G, Hogie M, Henry J P, Lallemand F, Compagnon P, Macé B, Comoy E, Letac B, Thuillez C
VACOMED, Department of Pharmacology, Rouen University Medical School and Rouen University Hospital, France.
Circulation. 1997 Sep 16;96(6):1976-82. doi: 10.1161/01.cir.96.6.1976.
Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.
Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.
Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
慢性心力衰竭（CHF）患者血浆中血管收缩肽内皮素（ET）水平升高，ET水平是该疾病死亡率的主要预测指标。因此，ET可能在CHF中起有害作用。本研究的目的是评估ET受体拮抗剂波生坦长期治疗对CHF大鼠模型的影响。
对大鼠进行冠状动脉结扎，并给予安慰剂或波生坦（30或100mg·kg⁻¹·d⁻¹）治疗2或9个月。波生坦100mg·kg⁻¹显著提高了生存率（9个月后：未治疗组为47%；波生坦组为65%；P<0.01）。在整个9个月的治疗期间，波生坦显著降低了动脉压和心率。治疗2或9个月后，ET拮抗剂降低了中心静脉压和左心室（LV）舒张末期压力以及血浆儿茶酚胺、尿cGMP和LV室胶原密度。波生坦还减少了LV扩张（2个月时通过体外压力/容积关系的变化证明）。2个月后进行的超声心动图研究表明，ET拮抗剂减少了非梗死LV壁的肥厚并增加了收缩力。较低剂量的波生坦（30mg·kg⁻¹）没有主要的血流动力学或结构效应，对生存率也没有影响。
ET拮抗剂长期治疗可显著提高该CHF大鼠模型的生存率。生存率的提高与前负荷和后负荷的降低、心输出量的增加以及LV肥厚、LV扩张和心脏纤维化的减少有关。因此，用波生坦等ET拮抗剂进行长期治疗可能对人类CHF有益，并可能提高该疾病的长期生存率。
