Protective Effect of Elastase Inhibition Against Myocardial Dysfunction and Injury Induced by Ischemia and Reperfusion in Isolated Rat Hearts

BACKGROUND: Elastase release has been incriminated in the genesis of reperfusion-induced myocardial dysfunction and injury, and elastase inhibitors have been reported to reduce myocardial dysfunction in dogs subjected to coronary artery occlusion and reperfusion. METHODS AND RESULTS: To examine if elastase inhibition will modify myocardial dysfunction and injured induced by ischemia and reperfusion in isolated hearts, hearts from male Sprague Dawley rats were subjected to 30 minutes of total ischemia followed by 30 minutes of reperfusion. Ischemia-reperfusion resulted in myocardial dysfunction (increase in coronary perfusion pressure and decrease in myocardial contraction), injury (measured as creatine kinase release), and lipid peroxidation (myocardial malondialdehyde). Perfusion of hearts with an elastase inhibitor, ICI200,880, protected against myocardial dysfunction, injury and lipid peroxidation following ischemia-reperfusion. As expected, perfusion with superoxide dismutase protected the hearts against hemodynamic deterioration following ischemia-reperfusion. In in vitro studies, there was no direct effect of ICI200,880 on superoxide anion generation. CONCLUSIONS: ICI200,880 seems to exert cardioprotective effects against ischemia-reperfusion-induced injury and myocardial dysfunction in isolated buffer-perfused hearts, most likely by an elastase-like protease inhibitory activity.