Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are closely involved in the mechanism of skeletal muscle ischemia/reperfusion (I/R) injury. This study was designed to determine the effects of inducible nitric oxide synthase (iNOS) inhibitor 1400W on the reperfused cremaster muscle in extracellular superoxide dismutase knockout (EC-SOD-/-) mice. The muscle was exposed to 4.5 h of ischemia, followed by 90 min of reperfusion. Mice received either 3 mg/kg of 1400W or the same amount of phosphate-buered saline (PBS, as a control) subcutaneously at 10 min before the start of reperfusion. 1400W treatment markedly improved the recovery speed of vessel diameter and blood flow in the reperfused cremaster muscle of EC-SOD-/- mice compared to controls. Histological examination showed reduced edema in the interstitial space and muscle fiber, and reduced density of nitrotyrosine (a marker of total peroxinitrite (ONOO-) level) in 1400W-treated muscles compared to controls. Our results suggest that iNOS and ONOO- products are involved in skeletal muscle I/R injury. Reduced I/R injury by using selective inhibition of iNOS perhaps works by limiting cytotoxic ONOO - generation, a reaction product of nitric oxide (NO) and superoxide anion (O2 -). Thus, inhibition of iNOS appears to be a treatment strategy for reducing clinical I/R injury.
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