Mitochondrial Uncoupling Agents Trigger Ventricular Fibrillation in Isolated Rat Hearts

作者：Hatcher A Shea; Alderson Julie M; Clements Jewery Hugh^*

来源：Journal of Cardiovascular Pharmacology, 2011, 57(4): 439-446.

DOI：10.1097/FJC.0b013e31820d5342

• ventricular fibrillation
• rat
• ischemia
• ATP
• mitochondria
• KATP channel

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 mu M carbonyl cyanide m-chlorophenylhydrazone, 100 mu M 2,4-dinitrophenol, 0.2 mu M cyclosporine A, 100 mu M 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.

• 出版日期2011-4