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.