In this study, the pharmacological activity of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphtaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, was compared with that of naproxen in a model of acute ischemia (40 min) and reperfusion (20 min) of the rabbit heart. HTC-3012 (3-100 microM), in spite of inhibition of 6-keto-prostaglandin F(1alpha) generation by the cardiac tissues, brought about a dose-dependent normalization of coronary perfusion pressure, associated with a reduction of ventricular contracture during ischemia with remarkable improvement of left ventricular developed pressure at reperfusion. These beneficial effects were accompanied by a substantial release of nitrite/nitrate in the heart perfusates, indicating that NO has been released by HCT-3012 and donated to the cardiac tissue. These events were paralleled by a significant reduction of creatine kinase activity in heart perfusates during reperfusion. Naproxen (10-100 microM) aggravated the myocardial damage in ischemic reperfused hearts, severely depressing the postischemic ventricular dysfunction. Perfusion of the heart with N(G)-monomethyl-l-arginine (10 microM) caused a marked aggravation of myocardial damage of the reperfused hearts, and this effect was dose dependently prevented by HCT-3012 but not by naproxen. The results of the present experiments clearly indicate that HCT-3012, by donating NO, displays a noticeable anti-ischemic effect in reperfused ischemic rabbit hearts. The safer gastrointestinal profile of HCT-3012 and its ability to control experimental hypertension, suggest that this compound may have therapeutical potential in cardiovascular disease, namely in the prevention of myocardial ischemic events, and may represent a better alternative to conventional nonsteroidal anti-inflammatory drugs.