title: Mitochondrial uncoupling agents trigger ventricular fibrillation in isolated rat hearts.
abstract: Sudden cardiac death resulting from ventricular fibrillation (VF) remains a major cause of mortality. The purpose of this study was to investigate the roles of loss of oxidative phosphorylation and activation of the mitochondrial ATP-sensitive K+ channel and permeability transition pore in VF development during myocardial ischemia by using mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenylhydrazone and 2,4-dinitrophenol) and channel blockers (5-hydroxydecanoate and cyclosporine A) at concentrations that have been demonstrated to block the intended targets selectively. Isolated rat hearts (n = 8 per group) were perfused with 0.3 μM carbonyl cyanide m-chlorophenylhydrazone, 100 μM 2,4-dinitrophenol, 0.2 μM cyclosporine A, 100 μM 5-hydroxydecanoate, or vehicle solution and regional ischemia induced after 10 minutes. Carbonyl cyanide m-chlorophenylhydrazone and 2,4 dinitrophenol caused profound QT shortening and triggered VF in 100% of hearts before ischemia. During ischemia, neither cyclosporine A (88%) nor 5-hydroxydecanoate (100%) reduced VF incidence compared with control (100% VF). In separate hearts, carbonyl cyanide m-chlorophenylhydrazone decreased tissue ATP content, and glibenclamide or glimepiride delayed the QT shortening and onset of VF triggered by carbonyl cyanide m-chlorophenylhydrazone. In conclusion, mitochondrial uncoupling agents trigger VF, likely as a result of ATP depletion with subsequent activation of sarcolemmal ATP-sensitive K+ currents. The mechanism of VF in ischemia does not involve activation of the mitochondrial ATP-sensitive K+ channel or permeability transition pore.
authors.affiliation: West Virginia School of Osteopathic Medicine, Lewisburg, WV 24901, USA.
authors.forename: A Shea
authors.initials: AS
authors.lastname: Hatcher
authors.forename: Julie M
authors.initials: JM
authors.lastname: Alderson
authors.forename: Hugh
authors.initials: H
authors.lastname: Clements-Jewery
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000150:complications*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000209:etiology*
chemical_list: D003652:Decanoic Acids; D006880:Hydroxy Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C052853:5-hydroxydecanoic acid; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D019297:2,4-Dinitrophenol