Nitric oxide releasing aspirin derivative reduces myocardial necrosis induced by myocardial ischemia-reperfusion in the rat

NCX 4016, an NO-releasing derivative of aspirin, has been previously shown to improve postischemic ventricular dysfunction and to reduce the mortality rate in rabbit with permanent ligature of left anterior coronary artery. Using anesthetized rats submitted for 30 min. to local myocardial ischemia followed by 120 min. reperfusion (MI/R). The cardioprotection conferred by NCX 4016 (10-30-100 mg/kg) and aspirin (ASA; 54 mg/kg) was investigated. These compounds were administered orally for 5 consecutive days. NCX 4016 provided a marked cardioprotection by reducing dose-dependently cardiac rhythm derangements and the mortality rate. In these animals, the infarct size was also restricted proportionally to the dose used of NCX 4016. This event was accompanied with diminution of plasma creatine kinase and cardiac myeloperoxidase. ASA was almost devoid of cardioprotection activity against MI/R damage. In rats treated with the inhibitor of NO-synthase (L-NAME 100 mg/kg), a further aggravation of myocardial damage with augmentation of mortality rate was observed. NCX 4016 (100 mg/kg) greatly prevented the worsening effect caused by L-NAME. The protecting effects shown by NCX 4016 was in a large part mediated by NO released by the original compound with modulation of a variety of cellular events leading to inflammation, coronary microcirculation obstruction, arrhythmias and progression of myocardial necrosis