Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria

Mitochondrial ATP-sensitive potassium (mitoKATP) channel openers protect the piglet brain against ischemic stress. Effects of mitoKATP channel agonists on isolated mitochondria, however, have not been directly examined. We investigated the effects of KATP channel openers and blockers on membrane potential and on the production of reactive oxygen species (ROS) in isolated piglet mitochondria. Diazoxide and BMS-191095, putative selective openers of mitoKATP, decreased the mitochondrial membrane potential (ΔΨm). On a molar basis, diazoxide was less effective than BMS-191095. In contrast, diazoxide but not BMS-191095 increased ROS production by mitochondria. Since diazoxide also inhibits succinate dehydrogenase (SDH), we examined the effects of 3-nitropropionic acid (3-NPA), an inhibitor of SDH. 3-NPA failed to change the ΔΨm but increased ROS production. Inhibitors of KATP channels did not affect resting ΔΨm or ROS production, but glibenclamide and 5-hydroxydecanoate (5-HD) blocked effects of diazoxide and BMS-191095 on ΔΨm and diazoxide effects on ROS production. We conclude that BMS-191095 has selective effects on mitoKATP channels while diazoxide also increases ROS production probably via inhibition of SDH.