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 mitoK(ATP) 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 mitoK(ATP), decreased the mitochondrial membrane potential (delta psi(m)). 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 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 BMS-191095 has selective effects on mitoK(ATP) channels while diazoxide also increases ROS production probably via inhibition of SDH.
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. dbusija@wfubmc.edu
David W
DW
Busija
Prasad
P
Katakam
Nishadi C
NC
Rajapakse
Bela
B
Kis
Gary
G
Grover
Ferenc
F
Domoki
Ferenc
F
Bari
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001578:Benzopyrans / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009942:Organometallic Compounds / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013552:Swine; D013997:Time Factors
C428117:BMS 191095; D001578:Benzopyrans; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007093:Imidazoles; D009942:Organometallic Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C110932:tetramethyl rhodamine ethyl ester; C052853:5-hydroxydecanoic acid; C037102:naphthoyl-ATP; D000255:Adenosine Triphosphate; D003981:Diazoxide; D005905:Glyburide