Role of NO in IR‐injury in surgical flaps NO has been found to have a dual role during IR injury. On the one hand, it seems to be tissue protective; on the other hand, it can have a destructive capacity. NO increases blood flow and prevents leucocyte and platelet activation, thereby reducing inflammation and thrombus formation. Endothelial cells are crucial in the maintenance of homeostasis in the microcirculation. In anoxic states, endothelial cells lose their ability to synthesize NO and to degrade vasoconstrictors. This is evidenced by the fading of endothelium‐dependent vasodilatation to acetylcholine, which under homeostatic conditions leads to NO production in endothelial cells.49 During IR injury, eNOS expression is reduced, and iNOS is upregulated.50,51 The beneficial effects attributed to NO are caused by the constitutive eNOS and increasing NO production by upregulation of eNOS, has proven to ameliorate IR injury52‐54. On the other hand, NO insufficiency due to diminished eNOS could be a factor in the no‐reflow phenomenon in ischemia‐affected tissue. Huk et al demonstrated that, L‐arginine, a NOS substrate, decreased superoxide generation by eNOS while increasing NO accumulation, leading to protection from vasoconstriction and reduction of edema after reperfusion.55 Flap perfusion with a NO donor demonstrated significant improved flap survival and a decrease of neutrophil accumulation after IR injury in several models using several sources of exogenous NO.56‐ 58 Nitrosoglutathione (GSNO), a NO donor administered before reperfusion, increases NO plasma levels and increases expression of eNOS and suppressed iNOS with positive effect on flap survival.3 These effects are observed not solely in flap‐related surgery but also in other organ systems (e.g., myocardium and liver).59,60 In contrast, NO produced by the iNOS during inflammation, mainly in activated leucocytes can also lead to tissue destruction by formation of free radicals as described above.61 However, the overall effect of NO on IR appears to be beneficial. Analysis of NO and IR in Relation to Surgical Flaps Viability In the past two decades, research on the role of NO in flap tissue has arrived with conflicting results, displaying the dual role of NO on IR injury. Using PubMed with Mesh terms “nitric oxide” and “surgical flaps,” all relevant data were collected in relation to NO and surgical flap viability. Studies of therapeutic addition of NO, through direct NO donors or NOS substrates, describe a generally positive role for NO on flap survival. Studies focused on NOS enzyme regulation using (selective) inhibitors reveal more conflicting details regarding the role of iNOS and eNOS and NO in flap viability. An list of various direct NO donors used in flap studies is given in Table 3.1.62 45
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