Numerous studies have shown that production of reactive oxygen and nitrogen species (ROS and RNS) during reperfusion causes tissue damage due in part to inactivation of mitochondrial electron transport chain proteins. The damage is paradoxical as the vasodilator, nitric oxide (NO), produced from sheer-stressed endothelial cells is a protective species that should increase blood flow. Likewise, superoxide dismutase (SOD) can convert the superoxide to hydrogen peroxide that should then also trigger vasodilation via activation of protein kinase G. It has been hypothesized that, instead, NO and superoxide react with each other to give peroxynitrite. The peroxynitrite is a potent oxidant that is known to inactivate mitochondrial proteins. It has been difficult to validate this chain of events in vivo due to the short half-lives and limited detection modalities for ROS and RNS. In this issue, the article by Xu et al. provides compelling support for this mechanistic scenario via the clever use of endothelial NOS-/- mice, blood flow measurements, SOD mimetics, and in vivo electron paramagnetic resonance oximetry. In the untreated control mice, there is considerable tissue damage, loss of contractile function, and damage to mitochondrial proteins. The SOD mimetic agents efficiently trap the burst phase superoxide via rapid conversion to hydrogen peroxide to produce increased blood flow, improved contractile functional recovery, and suppressed inactivation of mitochondrial proteins. Much of the protection is lost when the mice are also treated with glibenclamide, suggesting that the primary vasodilatory effect of NO and hydrogen peroxide is via activation of sarcolemmal ATP-sensitive potassium channels. Collectively, these results confirm the proposed mechanisms that underlie oxidative stress following ischemic reperfusion and suggest therapeutic options that can be used to ameliorate the subsequent tissue damage.
Footnotes
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See article at J Pharmacol Exp Ther 2008, 327:402-410.
- The American Society for Pharmacology and Experimental Therapeutics