Adenine nucleotide translocase mediates the K(ATP)-channel-openers-induced proton and potassium flux to the mitochondrial matrix.
KATP channel openers have been shown to protect ischemic-reperfused myocardium by mimicking ischemic preconditioning, although their mechanisms of action have not been fully clarified. In this study we investigated the influence of the adenine nucleotide translocase (ANT) inhibitors--carboxyatractyloside (CAT) and bongkrekic acid (BA)--on the diazoxide- and pinacidil-induced uncoupling of isolated rat heart mitochondria respiring on pyruvate and malate (6 + 6 mM). We found that both CAT (1.3 microM) and BA (20 microM) markedly reduced the uncoupling of mitochondrial oxidative phosphorylation induced by the K(ATP) channel openers. Thus, the uncoupling effect of diazoxide and pinacidil is evident only when ANT is not fixed by inhibitors in neither the C- nor the M-conformation. Moreover, the uncoupling effect of diazoxide and pinacidil was diminished in the presence of ADP or ATP, indicating a competition of K(ATP) channel openers with adenine nucleotides. CAT also abolished K+-dependent mitochondrial respiratory changes. Thus ANT could also be involved in the regulation of K(ATP)-channel-openers-induced K+ flux through the inner mitochondrial membrane.
Kopustinskiene
Dalia M
DM
Institute for Biomedical Research, Kaunas University of Medicine, Eiveniu Street 4, LT-3007, Kaunas, Lithuania. daliammk@mail.lt
Toleikis
Adolfas
A
Saris
Nils-Erik L
NE
D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives* / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D020110:Pinacidil / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels; D017494:Proton Pumps / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D008565:Membrane Proteins; D015221:Potassium Channels; D017494:Proton Pumps; C117780:mitochondrial K(ATP) channel; D001865:Bongkrekic Acid; D001278:Atractyloside; D020110:Pinacidil; D000226:Mitochondrial ADP, ATP Translocases; D003981:Diazoxide; D011188:Potassium; C003853:carboxyatractyloside