Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury

We investigated the influences of the K+ channel opening drugs cromakalim a nd diazoxide and their blocker, glibenclamide, in indomethacin-induced gast ric injury in rats. Cromaknlim (0.1 and 0.3 mg/kg) and diazoxide (10 and 30 mg/kg) produced dose-dependent gastroprotection at doses that were also ef fective on the cardiovascular system. Glibenclamide reversed their gastropr otective effects and aggravated indomethacin-induced gastric damage by its own. Cromakalim (10(-9)-10(-5) M) and diazoxide (10(-9)-10(-4) M) relaxed n oradrenaline pre-contracted gastric arteries (94.59 +/- 1.58% and 93.86 +/- 2.99%, respectively). Their relaxant effects were inhibited by glibenclami de (10(-5) M) but not by indomethacin (10(-5) M) and L-G-nitro-L-arginine ( 10(-4) M). Cromakalim (0.1 and 0.3 mg/kg) did not change gastric mucosal bl ood flow but increased the gastric mucosal vascular conductance in anaesthe tized rats as measured by the hydrogen gas clearance technique. Indomethaci n increased myeloperoxidase activity in the gastric mucose, an effect which was reversed by cromakalim and diazoxide. Glibenclamide abolished their ef fects on myeloperoxidase activity and, alone, increased this parameter. Add itionally, indomethacin caused infiltration of neutrophils which was reduce d by cromakalim and diazoxide in a glibenclamide sensitive manner. The effe cts of cromakalim and diazoxide on mucosal myeloperoxidase activity, neutro phil infiltration and gastric injury correlated with each other. The effect s of diazoxide (30 mg/kg) and glibenclamide (10 mg/kg) on blood glucose lev el were not correlated with their effects on gastric injury. Taken together , K+ channel opening drugs show misoprostol-like protective effects in indo methacin-induced gastric injury which seems to be related to modulation of neutrophil function. (C) 1999 Elsevier Science B.V. All rights reserved.