REDUCTION OF REPERFUSION INJURY BY THIOL PROTEASE INHIBITION

Abstract

The effect of intravenous infusion of NCO-700, a new synthetic inhibitor of thiol protease, on infarct size and regional myocardial blood flow was studied in 36 anesthetized open-chest dogs. Dogs underwent either 1 hr or 3 hr of left anterior descending artery occlusion followed by reperfusion. Animals in the treated groups received a single bolus intravenous injection of NCO-700 (20mg/kg) before reperfusion followed by a 2-hour infusion of the same dose. Regional myocardial blood flow was determined serially by the hydrogen clearance method. At 12 hr after starting reperfusion, the zone at risk was defined by dye injection and the Zone of necrosis was subsequently determined by triphenyltetrazolium chloride staining of left ventricular slices. There were no major hemodynamic differences between control and treated groups. In the 1-hour occlusion groups, infarct size (as a percentage of the zone at risk) was markedly reduced in NCO-700 treated animals (n=10) compared with control animals (n=10) (9±3% vs 39±7%, p<0.01) (mean ± SEM). Regional myocardial blood flow in the ischemic region was significantly increased in treated animals at 1 hr after reperfusion (94±12% of baseline vs 59±5%, p<;0.01). Light and electron microscopy of the ischemic zone demonstrated a decrease in hemorrhage and relative preservation of the endothelial structure of the microvasculature in treated animals. In the 3-hour occlusion groups, there were no significant differences between control and treated animals in infarct size or regional myocardial blood flow. These observations suggested that intravenous administration of NCO-700 at reperfusion reduced infarct size and increased regional blood flow in the ischemic region after reperfusion.