Effect of nitric oxide and nitroxide SOD-mimic on the recovery of isolated rat heart following ischemia and reperfusion.
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 O(2)z*(-) of peroxynitrite and its downstream toxic products, such as *OH, *NO(2) and CO(3)*(-), 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 O(2)*(-). Hence, nitroxides by virtue of catalytic removal of O(2)*(-) 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 x 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 CO(3)z.rad;(-) and *NO(2) radicals formed during the decomposition of peroxynitrite in the presence of bicarbonate, thus promoting cardioprotection following post-ischemic reperfusion.
D000818:Animals; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007700:Kinetics; D017202:Myocardial Ischemia; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000627:therapeutic use; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D015424:Reperfusion; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D009589:Nitrogen Oxides; D009569:Nitric Oxide; D014443:Tyrosine; C007543:dityrosine; D013482:Superoxide Dismutase; C039900:nitroxyl