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 (mitoK(ATP)) channel openers protect the piglet brain against ischemic stress. Effects of mitoKNI-p channel agonists on isolated mitochondria, however, have not been directly examined. We investigated the effects of K-ATP 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 initoK(ATP), decreased the mitochondrial membrane potential (Delta Psi(m)). On a inolar 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 Delta Psi(m) but increased ROS production. Inhibitors of K-ATP channels did not affect resting Delta Psi(M) or ROS production, but glibenclamide and 5-hydroxydecanoate (5-HD) blocked effects of diazoxide and BMS-191095 on Delta Psi(m) and diazoxide effects on ROS production. We Conclude that BN4S-191095 has selective effects on mitolK(ATP) channels while diazoxide also increases ROS production probably via inhibition of SDH. (c) 2005 Elsevier Inc. All rights reserved.