title: Inhibition of iNOS attenuates skeletal muscle reperfusion injury in extracellular superoxide dismutase knockout mice.
abstract: 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 1400 W on the reperfused cremaster muscle in extracellular super-oxide 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 1400 W or the same amount of phosphate-buffered saline (PBS, as a control) subcutaneously at 10 min before the start of reperfusion. 1400 W 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 peroxi-nitrate (ONOO(-)) level) in 1400 W-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 super-oxide anion (O(2) (-)). Thus, inhibition of iNOS appears to be a treatment strategy for reducing clinical I/R injury.
authors.affiliation: Department of Orthopaedic Surgery, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Jong Woong
authors.initials: JW
authors.lastname: Park
authors.forename: Wen-Ning
authors.initials: WN
authors.lastname: Qi
authors.forename: John Q
authors.initials: JQ
authors.lastname: Liu
authors.forename: James R
authors.initials: JR
authors.lastname: Urbaniak
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Folz
authors.forename: Long-En
authors.initials: LE
authors.lastname: Chen
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase