INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE AMELIORATES ENDOTOXIN-INDUCED GUT MUCOSAL BARRIER DYSFUNCTION IN RATS

Background & Aims: The permeability of intestinal epithelial monolayer s increases after exposure to nitric oxide. The aim of this study was to investigate the role of excessive NO production on intestinal barri er function in rats injected with lipopolysaccharide (LPS), Methods: R ats were injected with saline or IFS (5 mg/kg), Bacterial translocatio n to mesenteric lymph nodes, liver, and spleen was assessed 24 hours a fter LPS injection, Mucosal permeability was determined by loading flu orescein-labeled dextran (mel wt, 4000 daltons) into an intestinal seg ment and measuring its appearance in plasma. intestinal mucosal mitoch ondrial respiration was assessed using (4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide. Results; intestinal tissue from LPS-chall enged rats showed upregulation of inducible NO synthase (iNOS) messeng er RNA expression and subsequent up-regulation of iNOS enzymatic activ ity. Plasma concentrations of nitrite plus nitrate (NO2-/NO3-) were in creased for at least 24 hours after injection of LPS. Treatment with t he selective iNOS inhibitor, aminoguanidine, inhibited iNOS enzymatic activity and overproduction of NO2-/NO3-, LPS-induced bacterial transl ocation was reduced by aminoguanidine. LPS-induced intestinal hyperper meability was ameliorated by both aminoguanidine and another selective iNOS inhibitor, S-methylisothiourea. LPS depressed intestinal mucosal mitochondrial function, and this effect was ameliorated by aminoguani dine, Conclusions: Overproduction of NO may contribute to intestinal b arrier dysfunction in LPS challenged rats, possibly by Interfering wit h mitochondrial oxidative metabolism.