The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia-reperfusion in the anesthetized rat

NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, ap pears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postisch emic ventricular dysfunction and to reduce myocardial infarct size in the r abbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) a nd aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Dr ugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachyca rdia and fibrillation; they were reduced dose dependently and correlated wi th survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardi ac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N-G-nitro-L-arginine methyl ester ( L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arr hythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L -NAME. The beneficial effects of NCX 4016 appear to derive in large part fr om the NO moiety, which modulates a number of cellular events leading to in flammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.