Introduction Necrosis of skeletal muscle following ischemia reperfusion (IR) injury is a major problem in plastic and reconstructive surgery, particularly in replantation and free tissue transfer. Nitric oxide (NO) has been shown to decrease muscle necrosis and preserve muscle viability after ischemia reperfusion injury. L-arginine, a substrate for NO synthase, has also been shown to decrease muscle necrosis as well as neutrophil adhesion post IR injury. NO is produced by three isozymes: neuronal (nNOS), epithelial (eNOS), and inducible (iNOS). nNOS and eNOS are constitutive isoforms and produce NO in pmol quantities post ischemia and are thought to play a protective role. iNOS is induced by endotoxins and inflammatory cytokines following IR injury and produces NO in nmol quantities causing NO cytotoxicity. Our previous research has shown that iNOS knockout mice had ≥70% decrease in muscle necrosis when the gracilis muscle was subjected to four hours of ischemia compared to wild type. 1400w (N-[3-(aminomethyl)benzyl] acetamidine) is a highly selective iNOS inhibitor only binding the other constitutive isoforms weakly and reversibly. 1400w may be as effective in reducing skeletal muscle necrosis post ischemia reperfusion injury as an iNOS knockout mutation, and L-arginine may further reduce muscle necrosis when iNOS is selectively inhibited.
Methods The gracillis muscle of 80 Sprague-Dawley rats was dissected free and based on its vascular pedicle. Half of the subjects were subjected to IR injury by clamping the vascular pedicle for four hours. All subjects were given a subcutaneous injection of 1400w or saline directly after muscle dissection or three hours and 50 minutes into ischemia time. All subjects then received L-arginine or saline perfusion into the contralateral femoral vein for 40 minutes. Muscle flaps were harvested 24 hours after perfusion, sectioned and placed in nitroblue tetrazolium to assess muscle preservation.
Results In our control groups without ischemia 1400w and L-arginine showed no effect on muscle viability. In our ischemic groups, L-arginine alone, 1400w alone, and both in combination made significant improvements in muscle viability.
Conclusion We hope to pursue direct therapeutic actions and decrease the morbidity seen in tissue replantation and free flap transfers exposed to IR injury using 1400w inhibition of iNOS and L-arginine.
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