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Nitric oxide synthesized from L-arginine in cells has important salutary physiological roles, but can also exert deleterious effects. Nitric oxide (NO) can ameliorate post-ischemic reperfusion myocardial injury, yet formation from NO and O2˙− of peroxynitrite and its downstream toxic products, such as ˙OH, ˙NO2 and CO3˙−, can ultimately exacerbate reperfusion damage. Nitroxide stable radicals, such as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL), unlike SOD, readily penetrate cells and catalytically remove intracellular O2˙−. Hence, nitroxides by virtue of catalytic removal of O2˙− would be expected to diminish the adverse effect of NO and lower post-ischemic reperfusion cardiac damage. We show that post-ischemic recovery of hemodynamic functions of isolated perfused rat hearts treated with L-arginine or TPL alone did not differ from that of the control hearts. However, the recovery of hearts treated with the combined regimen of L-arginine and TPL was significantly improved, e.g. the Work Index = (left ventricular developed pressure × heart rate) recovered to 92±1.6% (L-arginine and TPL) vs. 59.4±5.4% (Control), 60±2.9% (L-arginine) and 53.3±4.3% (TPL) of the pre-ischemic value; mean±SEM, N=10, P<0.001. The enhanced recovery of hemodynamic function of hearts treated with L-arginine and TPL was accompanied by an increased recovery of oxygen consumption during the reperfusion. The combined regimen of L-arginine and TPL reduces the negative effects of NO by either inhibiting the production of ONOO− or through reaction with CO3˙− and ˙NO2 radicals formed during the decomposition of peroxynitrite in the presence of bicarbonate, thus promoting cardioprotection following post-ischemic reperfusion.