Nitric oxide synthase inhibition can initiate or prevent gut inflammation: Role of enzyme source

Abstract

The role of nitric oxide in gut inflammation was evaluated by comparing the effects of selective or nonselective inhibitors of nitric oxide synthase (NOS). Aminoguanidine, a selective inducible NOS (iNOS) inhibitor, or NG-nitro-l-arginine methyl ester (l-NAME) were administered via the drinking water to normal guinea pigs or following induction of ileitis with trinitrobenzene sulfonic acid (TNBS 30 mg/kg). Aminoguanidine had no detectable effect in normal animals. In contrast,l-NAME caused a time and dose-dependent increase in ileal myeloperoxidase activity and circulating leukocyte numbers. Only the ileum was inflamed withl-NAME treatment. In TNBS ileitis, both NOS inhibitors were protective, inhibiting in a dose-dependent manner granulocyte infiltration and submucosal fibrosis, with concurrent reductions in substance P immunoreactivity, epithelial protein leak and bowel wall thickening. Aminoguanidine was remarkably potent with an EC50 value of 100 ng/ml (drinking water concentration).l-NAME was approximately 100-fold less potent than aminoguanidine. We conclude from this pharmacological profile, that a lack of cNOS activity or an excess of iNOS activity can lead to gut inflammation. Aminoguanidine is the most potent inhibitor of experimental inflammatory bowel disease yet reported.