NCX 4016, a nitro-
ester of
aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic
ventricular dysfunction and to reduce
myocardial infarct size in the rabbit. The cardioprotection conferred by
NCX 4016 (10, 30, and 100 mg/kg) and
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). Drugs 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 tachycardia and fibrillation; they were reduced dose dependently and correlated with 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 cardiac
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 arrhythmias, 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 from the NO moiety, which modulates a number of cellular events leading to
inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial
necrosis.