Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

1 We have examined the role of nitric oxide (NO) in a model of functional a ngiogenesis in which survival of a skin flap depends entirely on angiogenes is to provide an arterial blood supply to maintain tissue viability. 2 The different effects of nitric oxide synthase (NOS) inhibitors on rat sk in flap survival appeared to be explained on the basis of their NOS isoform selectivity. Skin flap survival was decreased by iNOS-selective (inducible NOS) inhibitors, S-methyl-isothiourea, aminoguanidine and amino-ethylthior ea; unaffected by the non-selective inhibitor nitro-imino-L-ornithine; and enhanced by the cNOS (constitutive NOS, that is endothelial NOS (eNOS) and neuronal NOS (nNOS)) inhibitor, nitro-L-arginine methyl ester. 3 Skin flap survival was reduced in mice with targeted disruption of the iN OS gene (iNOS knockout mice), and the administration of nitro-L-arginine me thyl ester significantly increased flap survival in iNOS knockout mice (P < 0.05). 4 iNOS immunoreactivity was identified in mast cells in the angiogenic regi on. Immunoreactive vascular endothelial growth factor (VEGF) and basic fibr oblast growth factor were also localized to mast cells. 5 The combination of interferon-<gamma> and tumour necrosis factor-alpha in duced NO production and increased VEGF levels in mast cells cultured from b one marrow of wild-type, but not iNOS KO mice. 6 The increased tissue survival associated with the capacity for iNOS expre ssion may be related to iNOS-dependent enhancement of VEGF levels and an en suing angiogenic response. Our results provide both pharmacological and gen etic evidence that iNOS activity promotes survival of ischaemic tissue.