Prolonged colonic epithelial hyporesponsiveness after colitis: role of inducible nitric oxide synthase

Colonic;epithelial secretion is an important host defense mechanism. We exa mined whether a bout of colitis would produce long-lasting changes in epith elial function that persisted after resolution of mucosal inflammation. Col itis was induced in rats with intracolonic trinitrobenzenesulfonic acid. Si x weeks later, colonic damage and inducible nitric oxide synthase (iNOS) mR NA expression and activity were measured. Segments of distal colon were mou nted in Ussing chambers for measurement of permeability and responsiveness to secretory stimuli. Basal electrolyte transport parameters and permeabili ty were not different from untreated controls. Despite normal macroscopic a nd histological appearance, secretory responses to electrical field stimula tion (EFS), isobutylmethylxanthine (IBMX), and carbachol were significantly depressed (by 60-70%) relative to controls. (iNOS) mRNA expression and enz yme activity were significantly elevated. Dexamethasone reversed epithelial hyporesponsiveness and significantly reduced iNOS mRNA expression. A selec tive iNOS inhibitor normalized the secretory responses to EFS and IBMX but not to carbachol. These data suggest that ongoing synthesis of nitric oxide by iNOS contributes to chronic suppression of epithelial secretory functio n after episodes of colitis.