Mechanisms of cardioprotection by peroxynitrite in myocardial ischemia and reperfusion injury

Abstract

Peroxynitrite (ONOO−), an intermediate formed from the equimolar interaction of nitric oxide (NO) and superoxide, is thought to be an important mediator of tissue injury in myocardial ischemia-reperfusion. However, physiologically relevant (i.e., maximally achievable) concentrations of ONOO− significantly decreased neutrophil-endothelium interactions in the rat mesentery. We therefore examined the dose-response relationship of infusion of different concentrations of ONOO− in a feline model of myocardial ischemia-reperfusion and provide data on the cellular mechanisms responsible for these observed effects. Cats subjected to 90 min of ischemia followed by 270 min of reperfusion were infused with different concentrations of ONOO− 10 min before reperfusion and continuing throughout reperfusion. We observed that infusion of 2 μM ONOO−provided significant cardioprotection, whereas either 0.2 or 20 μM ONOO− did not protect. ONOO− at 2 μM also preserved coronary endothelial function, decreased P-selectin expression, and attenuated polymorphonuclear leukocyte (PMN) adherence to the vascular endothelium. ONOO− did not exert its cardioprotective effects by acting as a direct NO donor in solution. However, in vitro, ONOO− can react with glutathione to form S-nitrosoglutathione, which can act as an NO carrier and exert beneficial effects. Thus only maximally achievable concentrations of ONOO− exert significant cardioprotective effects, in part by decreasing surface expression of P-selectin and decreasing PMN-endothelium interactions.

Potential Benefits of Peroxynitrite

“…These data suggest that the maximally effective concentrations of PN were in the lower micromolar range (2 M) and the cardioprotective effects were not due to changes in hemodynamic, electrophysiological or hematologic variables [279]. In regard to endothelial injury, a significant decrease in response to acetylcholine, and the calcium ionophore, A23187, in animals receiving the cardiac insult, but in animals infused with the middle dose of PN (2 M) endothelial function was preserved, whereas in animals receiving either the low or high dose of PN (0.2 M or 20 M), endothelial dysfunction was comparable to that observed in animals subjected to myocardial ischemia/reper-fusion [279]. The extent of neutrophil adherence to coronary artery segments obtained at the conclusion of these experiments was examined, and again in those animals receiving the middle dose of PN (2 M), LAD segments exhibited a significantly lower neutrophil adherence that in those animals receiving the ischemia/reperfusion insult alone [279].…”

“…The infusions of PN were assessed in their ability to limit the progression of myocardial necrosis following reperfusion. Interestingly, only the middle dose (2 M) statistically protected the myocardium from developing a substantial amount of necrosis [279]. These data suggest that the maximally effective concentrations of PN were in the lower micromolar range (2 M) and the cardioprotective effects were not due to changes in hemodynamic, electrophysiological or hematologic variables [279].…”

“…In regard to endothelial injury, a significant decrease in response to acetylcholine, and the calcium ionophore, A23187, in animals receiving the cardiac insult, but in animals infused with the middle dose of PN (2 M) endothelial function was preserved, whereas in animals receiving either the low or high dose of PN (0.2 M or 20 M), endothelial dysfunction was comparable to that observed in animals subjected to myocardial ischemia/reper-fusion [279]. The extent of neutrophil adherence to coronary artery segments obtained at the conclusion of these experiments was examined, and again in those animals receiving the middle dose of PN (2 M), LAD segments exhibited a significantly lower neutrophil adherence that in those animals receiving the ischemia/reperfusion insult alone [279]. The role of surface expression of P-selectin was examined in this model, and the percentage of expression in the coronary microvasculature was significantly attenuated only with the infusion of PN at the 2 M dose [279].…”

“…Interestingly, only the middle dose (2 M) statistically protected the myocardium from developing a substantial amount of necrosis [279]. These data suggest that the maximally effective concentrations of PN were in the lower micromolar range (2 M) and the cardioprotective effects were not due to changes in hemodynamic, electrophysiological or hematologic variables [279]. In regard to endothelial injury, a significant decrease in response to acetylcholine, and the calcium ionophore, A23187, in animals receiving the cardiac insult, but in animals infused with the middle dose of PN (2 M) endothelial function was preserved, whereas in animals receiving either the low or high dose of PN (0.2 M or 20 M), endothelial dysfunction was comparable to that observed in animals subjected to myocardial ischemia/reper-fusion [279].…”

“…Moreover, the beneficial actions of PN may be due to the formation of S-nitrosothiols and PN may act as a NO carrier or PN can act as a direct NO donor. Nossuli, Hayward et al 1998 examined the dose-response relationships following different concentrations of PN infusion in a model of myocardial ischemia/reperfusion and also investigated with the mechanisms responsible for these beneficial effects [279]. Animals were subjected to myocardial ischemia followed by reperfusion and were administered with different concentrations of PN (0.2 M, 2 M, or 20 M) directly infused into the left ventricle beginning 10 min before and continued throughout the reperfusion period [279].…”