Chapter 3 L‐arginine + 3/2 NADPH + H+ +2O2NOScitrulline + NO + 3/2 NADPH+ Figure 3.1 These contradictory events may be a result of the effect of different isoforms of NOS during IR injury. Three isoforms of human NOS are described—endothelial (eNOS) and neuronal (nNOS)—which are both calcium ion dependent, and inducible (iNOS), which is calcium ion independent. eNOS is expressed in the endothelium and is a significant contributor for maintenance of basal vascular tone. The two isoforms, eNOS and nNOS, are constitutive, continuously synthesizing NO in small amounts (picomolar range). nNOS is quantitatively and physiologically of little significance and is not addressed in NO flap studies. L‐arginine, a NO donor, is converted by the eNOS in the endothelial cells to produce NO as a paracrine signal molecule for the smooth muscle cells in the vessel wall, causing vasodilation via the NO‐cGMP pathway. eNOS is expressed and upregulated by shear stress, growth factors (e.g. VEGF), and hormones (e.g. bradykinin, endothelin‐1). eNOS is also active in platelets where it contributes as an opposing agent for platelet aggregation and thrombosis.7 NO itself also inhibits platelet aggregation and adhesion by affecting both the platelets and the neighboring endothelial cells. NO thereby prevents thrombus formation and stimulates vasodilation and promotes blood flow.8 iNOS requires de novo synthesis after induction by proinflammatory cytokines (e.g. interleukins, tumor necrosis factor, interferons) or endotoxins (e.g. bacterial lipopolysaccharides). iNOS is not only predominantly expressed in inflammatory mechanisms such as macrophages, neutrophils, mast cells, and platelets but also in muscle and endothelial cells. It is activated by response to inflammatory mediators, bacterial toxins, and ischemia. Once activated, iNOS produces NO at high concentrations (nanomolar range). iNOS activity has been shown to possess both detrimental effects by producing peroxynitrate during IR and beneficial effects through mast cell activation, which releases vascular endothelial growth factor (VEGF).6,9,10 VEGF not only promotes angiogenesis in wound healing but also acts as a vasodilator by upregulation of endothelial eNOS, which has shown to reduce IR injury.11 The trigger: Free flap surgery During surgery, ischemia is induced whenever free tissue transfers are used in autologous reconstruction. If flap elevation and primary ischemia is within the ischemic tolerance level of the tissue, blood flow after the anastomosis will reverse the transient derangement in the flap during the ischemia period. 40
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