Role of NO in IR‐injury in surgical flaps extracellular arginine concentrations. Supplementation with L‐lysine, a competitive inhibitor for arginine CAT‐1 transport, results in diminished NO production. Increasing extracellular arginine concentration, while arginine transport is determinant in NO production, explains the arginine paradox.80 Another cause of the arginine paradox can be explained by the presence of asymmetric dimethyl‐arginine (ADMA), which is an endogenous competitive inhibitor of NOS. ADMA inhibits NO production and causes local vasoconstriction when infused intra‐ arterially. Elevated ADMA levels are increased in several pathological conditions such as hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, chronic heart failure, and IR injury. Karaaslan et al. have demonstrated increased ADMA levels in the IR flap model.81 A small modification in the ADMA level affects vascular NO production, and ADMA may be considered a novel endothelial dysfunction marker. Since ADMA is a competitive inhibitor of NOS, its inhibitory action can be overcome by L‐arginine supplementation, explaining the arginine paradox.82 NO itself is labile in nature and therefore impractical to supplement. Direct NO donors have provided good results in experimental studies. Their clinical use is appealing; however, NO donors may also have cardiovascular effects, resulting in hypotension, and may therefore also be impractical. Some NO donors such as SNP also contain and release toxic molecules, which limit their clinical use. The use of a NOS substrate, L‐arginine, is relatively simple and tolerated well by patients, with low toxicity, easy administration, and at low cost. L‐arginine appears thus far to be an excellent agent to use for prophylaxis against IR injury. A clinical pilot study using arginine supplementation has shown to increase flap microcirculation.83 The therapeutic possibilities are wide, and efforts to stimulate NO to improve flap survival in a clinical setting are to be encouraged. 49
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