Teerlink J R, Löffler B M, Hess P, Maire J P, Clozel M, Clozel J P
Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Circulation. 1994 Nov;90(5):2510-8. doi: 10.1161/01.cir.90.5.2510.
Endothelin (ET) is a potent vasoconstrictor, and its concentration is increased in patients with heart failure. The purpose of this study was to investigate the role of endothelin in heart failure by use of a rat model.
Experiments were performed on rats at 1 through 16 weeks after sham operation or coronary artery ligation. Rats with left ventricular end-diastolic pressures > 15 mm Hg were considered to have chronic heart failure (CHF), while the others were considered to have uncomplicated myocardial infarction (MI). There were increased ET-1 concentrations in CHF rats at weeks 1 to 16 (Sham, 20 +/- 0.5 pg/mL, n = 45; CHF, 31 +/- 2 pg/mL, n = 50; P < .001) and transient increases in ET-3 concentrations at week 1 in both the MI and CHF groups. There were no significant increases in big ET-1 concentrations, suggesting an increased conversion of ET-1 from big ET-1 in the CHF group. At weeks 2 through 8, oral administration of the mixed (ETA and ETB) endothelin receptor antagonist bosentan significantly decreased mean arterial pressure in conscious CHF rats, an effect that increased over time. Furthermore, bosentan had an additive effect to the angiotensin-converting enzyme inhibitor cilazapril.
Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan. Therefore, endothelin antagonists may be useful therapeutic agents in the treatment of CHF.
内皮素（ET）是一种强效血管收缩剂，心力衰竭患者体内其浓度会升高。本研究旨在通过大鼠模型探讨内皮素在心力衰竭中的作用。
对假手术或冠状动脉结扎术后1至16周的大鼠进行实验。左心室舒张末压>15 mmHg的大鼠被认为患有慢性心力衰竭（CHF），而其他大鼠被认为患有单纯性心肌梗死（MI）。CHF大鼠在第1至16周时ET-1浓度升高（假手术组，20±0.5 pg/mL，n = 45；CHF组，31±2 pg/mL，n = 50；P <.001），MI组和CHF组在第1周时ET-3浓度短暂升高。大ET-1浓度无显著升高，提示CHF组中ET-1从大ET-1的转化增加。在第2至8周，口服混合（ETA和ETB）内皮素受体拮抗剂波生坦可显著降低清醒CHF大鼠的平均动脉压，且该作用随时间增强。此外，波生坦对血管紧张素转换酶抑制剂西拉普利有相加作用。
口服波生坦后平均动脉压显著降低，证明内皮素在维持CHF大鼠血压中起作用。因此，内皮素拮抗剂可能是治疗CHF的有用治疗药物。
