Chapter 3 Numerous studies followed in which L‐NAME has shown to increase,10,74,75 decrease,3,57,58,66,70 or have no effect63 on IR injury and flap survival. Three studies using various IR models have compared L‐arginine with L‐NAME. Two of these studies showed a decreased flap survival compared with arginine and also a decreased flap survival compared with the sham group.66,70 One study by Meldrum et al. revealed a similar flap survival in L‐NAME compared with the sham group but an increase in flap survival in the arginine group.63 Cordeiro compared L‐arginine with L‐arginine + L‐NAME in a rat and a pig IR injury flap model. The protective effect of L‐arginine was completely negated by the addition of L‐NAME in both studies.57,58 Evidence from studies using iNOS knock‐out mice is conflicting, showing both beneficial and deleterious effects after IR injury.76,77 Discussion IR injury remains a problem in reconstructive surgery and can result in (partial) loss of a free tissue transfer. Free radicals and neutrophils act as major contributors to IR‐ induced microvascular dysfunction. NO appears to play a pivotal role in attenuating the severity of IR injury, and its role has been investigated in numerous organ IR studies and surgical flap models.78 Using NOS substrate, L‐arginine, or direct NO donors to stimulate NO production has shown to protect tissue from IR injury in numerous studies. Studies with NOS inhibition or knock‐out mouse models show the dual role of NO during IR injury. The most obvious and most used argumentation for this is that NO, continuously produced by eNOS in the endothelium, is believed to be tissue protective by maintaining blood flow and preventing aggregation and activation of leucocytes and platelets. In contrast, NO, produced in large amounts by iNOS, is thought to be tissue damaging through a direct toxic effect by the formation of free radicals such as peroxynitrite. The reason for conflicting results in relation to NOS inhibition and iNOS expression may be attributed to different experiment protocols and different arginine supplementation regimens. Arginine supplementation has been the focus of debate because of the “arginine paradox.” The arginine paradox is the fact that, despite intracellular physiological concentration of arginine being several hundred micromoles per liter, far exceeding the ≈μM Km of eNOS, the acute supplementation of L‐arginine still increases NO production. This is demonstrated in several studies as discussed above.79 There are some possible explanations of the arginine paradox. The endothelial uptake of arginine is mediated by the cationic amino acid transporter 1 (CAT‐1). eNOS and CAT‐1 are physically associated in the endothelial cells; therefore, extracellular arginine is directly delivered to eNOS. Intracellular NO production may thus be (partially) dependent on 48
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