The aim of this study was to investigate the role of inducible
nitric oxide (
NO) synthase (iNOS) and NO on the modulation of the inflammatory response caused by splanchnic
ischemia and reperfusion. A severe model of
mesenteric ischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of the superior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with
GW274150 (5 mg/kg i.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS 'knock-out', iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study, using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, we evaluated the survival rate. Under these conditions, wild-type mice treated with
GW274150 and iNOS-KO mice showed a significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated with
GW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesenteric injury, upregulation of
P-selectin and
intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significant inhibition of the degree of oxidative and nitrosative damage, indicated by
malondialdehyde levels, formation of
nitrotyrosine and
poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory
cytokines tumour
necrosis factor-alpha,
interleukin (IL) 6, and IL-1beta were also significantly reduced in iNOS-KO mice in comparison with control wild-type mice. Wild-type mice treated with
GW274150 and iNOS-KO mice were also found to have reduced activation of the transcriptional factor
nuclear factor-kappaB in the ileum. These results suggest that the induction of iNOS and NO production are essential for the upregulation of the inflammatory response in splanchnic
ischemia/reperfusion and participate in end organ damage under these conditions.