Contribution of endogenous endothelin to the extension of myocardial infarct size in rats.

Pathophysiological roles of endogenous endothelin have been studied from the viewpoint of its contribution to the extension of myocardial infarct size. A monoclonal antibody against endothelin 1 (AwETN40) suppressed changes induced by endothelin 1 and endothelin 2 but did not modify those by endothelin 3 in vivo or in vitro. Effects of AwETN40 on myocardial infarct size were investigated. Coronary ligation (1 hour) and reperfusion (24 hours) in rats caused infarction in 35% of the left ventricle. Repetitive or single administration of AwETN40 reduced the infarct size; an intravenous injection of 22.5 mg/kg of the antibody 5 minutes after coronary occlusion or 5 minutes before reperfusion reduced the size by 38% or 31% of the control, respectively. Plasma and tissue endothelin 1 and plasma big endothelin 1 in rats were measured at various stages after occlusion. Plasma endothelin 1 showed a fourfold increase 10 minutes after reperfusion (from 1.02 to 3.96 pg/ml) and had returned to the control value after 8 hours. Plasma big endothelin 1 showed changes similar to those of plasma endothelin 1. No significant changes in plasma endothelin 2 and endothelin 3 were observed. Cardiac tissue contained seven times as much endothelin 1 as the control value 1 hour after reperfusion (4.59 versus 33.1 pg/g tissue), and a high concentration (13.2 pg/g tissue) was maintained even after 48 hours. We concluded that an increase in endogenous endothelin 1 plays an important role in the extension of myocardial infarct size.

从内源性内皮素对心肌梗死面积扩大的作用这一角度，对其病理生理作用进行了研究。一种抗内皮素1的单克隆抗体（AwETN40）可抑制内皮素1和内皮素2所诱导的变化，但在体内或体外均不改变内皮素3所引起的变化。研究了AwETN40对心肌梗死面积的影响。大鼠冠状动脉结扎（1小时）再灌注（24小时）导致左心室35%发生梗死。重复或单次给予AwETN40可减小梗死面积；冠状动脉闭塞5分钟后或再灌注前5分钟静脉注射22.5mg/kg该抗体，梗死面积分别比对照组减小38%或31%。在闭塞后的不同阶段测量大鼠血浆和组织中的内皮素1以及血浆中的大内皮素1。血浆内皮素1在再灌注10分钟时增加了4倍（从1.02 pg/ml增加到3.96 pg/ml），8小时后恢复到对照值。血浆大内皮素1的变化与血浆内皮素1相似。未观察到血浆内皮素2和内皮素3有显著变化。再灌注1小时后，心脏组织中的内皮素1含量是对照值的7倍（4.59 pg/g组织对33.1 pg/g组织），即使在48小时后仍维持较高浓度（13.2 pg/g组织）。我们得出结论，内源性内皮素1的增加在心肌梗死面积扩大中起重要作用。