Inflammatory mediators may contribute to the diarrhea associated with colitis. Although the secretory action of such mediators is reported in normal tissue, there is little information regarding their effects on inflamed tissue. We examined the short-circuit current response (Isc) to these mediators, in mitomycin-C (MC)-induced colitis, a model with histological similarities to colitis in man. Rats were injected once with MC (3.25 mg/kg, intraperitoneally) or vehicle. The colons were removed three and seven days later and mounted, devoid of muscularis, in Ussing chambers for measurement of Isc, potential difference (PD), and resistance (Rt). MC-treated rats had diarrhea after three days, and microscopic studies revealed colonic inflammation. There were no significant differences in Rt, PD, and Isc between control and MC-treated tissues at three and seven days. Maximal increases in Isc to bradykinin, prostaglandin E1, carbachol, substance P, and serotonin were depressed at three and/or seven days after MC. The Isc response to theophylline was not affected. Theophylline activates secretion through an intracellular mechanism; the other agonists act by interaction with epithelial cell membranes. Therefore, the mechanism for the decreased Isc may result from uncoupling of receptors to second-messenger systems or desensitization of receptor-linked secretory mechanisms.