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, but recent studies have indicated that this compound may also have physiologic activity and induces vascular relaxation as well as inhibition of platelet aggregation and neutrophil adhesion. The present experiment was designed to determine whether ONOO(-) may exert different effects on postischemic myocardial injury in a crystalloid perfusion environment versus a blood perfusion environment and, if it does, to clarify the mechanisms causing any differences. In Krebs-Henseleit buffer-perfused rabbit hearts, administration of ONOO(-) at the onset of reperfusion enhanced myocardial injury in a concentration-dependent fashion with a significant effective concentration of 30 microM. In contrast, in blood-perfused hearts, administration of ONOO(-) (1 to 30 microM) significantly attenuated postmyocardial injury as evidenced by improved cardiac function recovery, preserved endothelial function, decreased myocardial creatine kinase loss, and reduced necrotic size. The minimal and maximal protective concentrations were determined to be 1 and 3 microM, respectively. When a high concentration of ONOO(-) (i.e., 100 microM) was administered, a detrimental effect was observed. Administration of ONOO(-) decreased neutrophil accumulation in the ischemic-reperfused myocardial tissue in a concentration-dependent manner in blood-perfused hearts and inhibited neutrophil 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 toxic to the cardiac tissue at a relatively high concentration, but it can indirectly protect myocardial cells from neutrophil-induced injury at a much lower concentration.
Ma
X L
XL
Division of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Xin.Ma@mail.tju.edu
Gao
F
F
Lopez
B L
BL
Christopher
T A
TA
Vinten-Johansen
J
J
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000494:pharmacology* / Q000627:therapeutic use; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits
D009566:Nitrates; C039642:peroxynitric acid; D009195:Peroxidase