Diazoxide attenuates indomethacin-induced small intestinal damage in the rat

ATP-sensitive potassium (K(ATP)) channel openers have been shown to protect against cellular damage in neurons cardiac muscle and kidney and to effectively reduce nonsteroidal anti inflammatory drug (NSAID)-induced gastric damage in rats We investigated the effects of K(ATP) channel opener diazoxide on small intestinal injury Induced in rats by indomethacin administration The effect of glibenclamide a K(ATP) channel blocker was also evaluated Diazoxide (15 45 and 135 mg/kg) or glibenclamide (18 mg/kg) were given by oral gavage 1 h before and 6 h after indomethacin treatment (20 mg/kg p o) After 24 h macroscopic and histologic lesions myeloperoxidase (MPO) activity and lipid peroxidation levels were evaluated Diazoxide at 15 mg/kg was ineffective while at doses of 45 mg/kg and 135 mg/kg was able to significantly improve all damage parameters Glibenclamide administration enhanced intestinal injury These results show for the first time a beneficial effect of diazoxide in Indomethacin-Induced enteritis in the rat Several mechanisms such as oxidative phosphorylation uncoupling and hypermotility seem particularly important in NSAID induced intestinal injury Such events lead to increased mucosal permeability and to penetration of noxious lumen components which ignite the inflammatory response Since K(ATP) channel openers were shown to protect against mitochondrial damage to reduce Intercellular permeability and to relax smooth muscle we suggest that diazoxide could exert its beneficial effects by one or more of these actions