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: A Shea Hatcher, Julie M Alderson, Hugh Clements-Jewery
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 57 Issue 4 Pg. 439-46 (Apr 2011) ISSN: 1533-4023 [Electronic] United States
• PMID: 21283023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Decanoic Acids
• Hydroxy Acids
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Potassium Channels
• mitochondrial K(ATP) channel
• Carbonyl Cyanide m-Chlorophenyl Hydrazone
• 5-hydroxydecanoic acid
• Cyclosporine
• Adenosine Triphosphate
• 2,4-Dinitrophenol

Topics

• 2,4-Dinitrophenol (pharmacology)
• Adenosine Triphosphate (metabolism)
• Animals
• Carbonyl Cyanide m-Chlorophenyl Hydrazone (pharmacology)
• Cyclosporine (pharmacology)
• Decanoic Acids (pharmacology)
• Hydroxy Acids (pharmacology)
• Male
• Mitochondrial Membrane Transport Proteins (drug effects, metabolism)
• Mitochondrial Permeability Transition Pore
• Myocardial Ischemia (complications)
• Oxidative Phosphorylation (drug effects)
• Potassium Channels (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sarcolemma (drug effects, metabolism)
• Ventricular Fibrillation (etiology)