Diazoxide attenuates indomethacin-induced small intestinal damage in the rat

ATP-sensitive potassium (KATP) 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 KATP channel opener diazoxide on small intestinal injury induced in rats by indomethacin administration. The effect of glibenclamide, a KATP 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 KATP 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.