Peroxynitrite, a two-edged sword in post-ischemic myocardial injury - Dichotomy of action in crystalloid-versus blood-perfused hearts

Peroxynitrite (ONOO-) is widely recognized as a mediator of NO. toxicity, b ut recent studies have indicated that this compound may also have physiolog ic activity and induces vascular relaxation as well as inhibition of platel et aggregation and neutrophil adhesion. The present experiment was designed to determine whether ONOO- may exert different effects on postischemic myo cardial injury in a crystalloid perfusion environment versus a blood perfus ion environment and, if it does, to clarify the mechanisms causing any diff erences. In Krebs-Henseleit buffer-perfused rabbit hearts, administration o f ONOO- at the onset of reperfusion enhanced myocardial injury in a concent ration-dependent fashion with a significant effective concentration of 30 m u M. In contrast, in blood-perfused hearts, administration of ONOO- (1 to 3 0 mu M) significantly attenuated postmyocardial injury as evidenced by impr oved cardiac function recovery, preserved endothelial function, decreased m yocardial creatine kinase loss, and reduced necrotic size. The minimal and maximal protective concentrations were determined to be 1 and 3 mu M, respe ctively. When a high concentration of ONOO- (i.e., 100 mu M) was administer ed, a detrimental effect was observed. Administration of ONOO- decreased ne utrophil accumulation in the ischemic-reperfused myocardial tissue in a con centration-dependent manner in blood-perfused hearts and inhibited neutroph il adhesion to cultured endothelial cells exposed to hypoxia/reoxygenation. Taken together, these results demonstrate that ONOO- may act as a "double- edged sword" in postischemic myocardial injury. This compound is directly t oxic to the cardiac tissue at a relatively high concentration, but it can i ndirectly protect myocardial cells from neutrophil-induced injury at a much lower concentration.