Premium
Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival
Author(s) -
Kane Anthony J,
Barker Jane E,
Mitchell Geraldine M,
Theile David R B,
Romero Rosalind,
Messina Aurora,
Wagh Milind,
Fraulin Frankie O G,
Morrison Wayne A,
Stewart Alastair G
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703944
Subject(s) - nitric oxide synthase , endothelial nos , angiogenesis , nitric oxide , vascular endothelial growth factor , medicine , endocrinology , neovascularization , enos , chemistry , biology , pharmacology , vegf receptors
We have examined the role of nitric oxide (NO) in a model of functional angiogenesis in which survival of a skin flap depends entirely on angiogenesis to provide an arterial blood supply to maintain tissue viability. The different effects of nitric oxide synthase (NOS) inhibitors on rat skin 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 aminoethylthiorea; 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. Skin flap survival was reduced in mice with targeted disruption of the iNOS gene (iNOS knockout mice), and the administration of nitro‐ L ‐arginine methyl ester significantly increased flap survival in iNOS knockout mice ( P <0.05). iNOS immunoreactivity was identified in mast cells in the angiogenic region. Immunoreactive vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were also localized to mast cells. The combination of interferon‐γ and tumour necrosis factor‐α induced NO production and increased VEGF levels in mast cells cultured from bone marrow of wild‐type, but not iNOS KO mice. The increased tissue survival associated with the capacity for iNOS expression may be related to iNOS‐dependent enhancement of VEGF levels and an ensuing angiogenic response. Our results provide both pharmacological and genetic evidence that iNOS activity promotes survival of ischaemic tissue.British Journal of Pharmacology (2001) 132 , 1631–1638; doi: 10.1038/sj.bjp.0703944