Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. Am J Physiol Heart Circ Physiol 293: H1545-H1552, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00064.2007.-In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), and NO-aspirin (56 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n ϭ 23), aspirin (n ϭ 22), and NO-aspirin groups (n ϭ 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 Ϯ 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin-and NOaspirin-pretreated groups, 36.7 Ϯ 1.8 and 22.9 Ϯ 4.3%, respectively (both P Ͻ 0.05 compared with vehicle group; P Ͻ 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P Ͻ 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P Ͻ 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N G -nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion. nitroaspirin; aspirin; cardioprotection; ischemia-reperfusion; infarct size ISCHEMIC MYOCARDIAL TISSUE will inevitably induce necrosis if blood flow is not restored immediately. Early reperfusion after coronary obstruction is well established to recover injured myocardium; nevertheless, reperfusion itself is believed to bring about additional cellular injury (25,30). During the last two decades, numerous studies have been done that focus on the roles of nitric oxide (NO) in the pathogenesis progress and pharmacological intervention of myocardial ischemia and reperfusion. Of them, exogenous NO donors may provide therapeutic benefit and are also a recent conceptual advance in the management of reperfusion damage (1,17,19,39). However, conventional NO donors (e.g., organic nitrates) frequently result in unwanted hemodynamic effects due to the ...