Endothelin (ET) levels are elevated in congestive heart failure secondary to myocardial infarction (MI) and correlate well with the severity of pulmonary hypertension (PH), suggesting that the ET peptide could contribute to the pathophysiology of venous PH. Alterations of pulmonary vasoreactivity to ET after MI and the respective roles of the ETA and ETB receptors (ETA-R and ETB-R) have never been evaluated, to our knowledge. MI was induced in rats. Three weeks later, small pulmonary resistance arteries were mounted on a microvascular myograph. Cumulative concentration-response curves to ET-1 and sarafo-toxin 6c (S6c) were performed. Response to ET was also assessed in the presence of ET-R antagonists. Heterodimeriza-tion of receptors was evaluated by immunoprecipitation of the ETB-R, followed by western blotting for the expression of the ETA-R. Maximal vasoconstriction and sensitivity to ET-1 were similar in sham and MI with values of 88 ± 3.9% and 80 ± 3.8%, respectively. The response to S6c was similarly less in both sham (67 ± 5.7%) and MI groups (60 ± 6.6%). When administered alone, the ETA-R antagonist (10 n M A-147627.1) and the ETB-R antagonist (1 μ M A-192621.1) had no significant effect. However, their combination markedly reduced vaso-constriction (52 ± 5.3%; P < 0.001). The endothelial and medial distribution of ET-Rs was similar in sham and MI groups. In vitro studies demonstrated co-immunoprecipitation of the ETA-R and ETB-R. Vasoconstriction of isolated resistance pulmonary arteries to ET agonists is not altered after MI. Dual antagonism results in optimal blockade of vasoconstriction, possibly because the ETA-R and ETB-R can form functional heterodimers.

中文翻译：

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心肌梗死后内皮素-1 诱导的肺血管收缩的评估

心肌梗死 (MI) 继发的充血性心力衰竭中内皮素 (ET) 水平升高，并且与肺动脉高压 (PH) 的严重程度密切相关，表明 ET 肽可能有助于静脉 PH 的病理生理学。MI后肺血管对ET的反应性变化以及ET各自的作用A和ET乙受体（ETA-R和ET乙-R）据我们所知从未被评估过。在大鼠中诱导心肌梗死。三周后，将小的肺阻力动脉安装在微血管肌动描记器上。绘制了 ET-1 和 sarafo-toxin 6c (S6c) 的累积浓度-响应曲线。还在 ET-R 拮抗剂存在的情况下评估了对 ET 的反应。通过 ET 的免疫沉淀评估受体的异二聚化乙-R，然后通过蛋白质印迹法检测 ET 的表达A-R。假手术和 MI 组中的最大血管收缩和对 ET-1 的敏感性相似，分别为 88 ± 3.9% 和 80 ± 3.8%。假手术组 (67 ± 5.7%) 和 MI 组 (60 ± 6.6%) 对 S6c 的反应同样较低。当单独给药时，ETA-R 拮抗剂 (10 n MA-147627.1) 和 ET乙-R拮抗剂(1μMA-192621.1)没有显着效果。然而，它们的组合显着减少了血管收缩（52 ± 5.3%；P < 0.001）。假手术组和 MI 组中 ET-R 的内皮和内侧分布相似。体外研究证明了 ET 的免疫共沉淀A-R和ET乙-R。MI 后，孤立性肺动脉对 ET 激动剂的血管收缩不会改变。双重拮抗作用导致血管收缩的最佳阻断，可能是因为 ETA-R和ET乙-R可以形成功能性异二聚体。