Temporary salvage of ischemic myocardium by the protease inhibitor bis[ethyl(2R,3R)-3-[(S)-methyl-1-[4-(2,3,4-trimethoxyphenyl-methyl) piperazin-1-ylcarbonyl]butyl-carbonyl]oxiran-2-carbo xylate]sulfate.
The administration (i.v., 20, 40 and 60 mg/kg) of the thiol protease inhibitor bis[ethyl(2R, 3R)-3-[(S)-methyl-1-[4-(2,3,4-trimethoxyphenyl-methyl) piperazin-1-ylcarbonyl] butyl-carbonyl] oxiran-2-carboxylate]sulfate (NCO-700), before and/or after the coronary ligation significantly reduced the necrotic mass in the rabbit left ventricle and also prevented the creatine phosphokinase loss in the ischemic myocardium up to 3 h and not at 6 h after the ligation. The activities of both calcium-activated neutral protease and cathepsin B in the subendo- and subepicardial layers of the ischemic, marginal or control myocardium of dog were inhibited by the NCO-700 administration (20 mg/kg i.v.) after the coronary ligation. A hemodynamic study using heart-lung preparation of the dog demonstrated a dose-dependent coronary dilatation with weak and transient negative ino- and chronotropic effects. These data suggested that NCO-700 sensitive protease(s) is(are) included in the step of myocardial cell degradation and that NCO-700 temporarily salvages it, as is important for the recent PTCR (percutaneous transluminal coronary reperfusion) therapy.