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J Mol Cell Cardiol. 2010 Apr;48(4):673-9. doi: 10.1016/j.yjmcc.2009.11.011. Epub 2009 Dec 3.

Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization.

Author information

1
Department of Physiology, Brody School of Medicine, Brody School of Medicine East Carolina University, Greenville, NC 27834, USA.

Abstract

We have previously proposed that the heterogeneous collapse of mitochondrial inner membrane potential (DeltaPsi(m)) during ischemia and reperfusion contributes to arrhythmogenesis through the formation of metabolic sinks in the myocardium, wherein clusters of myocytes with uncoupled mitochondria and high K(ATP) current levels alter electrical propagation to promote reentry. Single myocyte studies have also shown that cell-wide DeltaPsi(m) depolarization, through a reactive oxygen species (ROS)-induced ROS release mechanism, can be triggered by global depletion of the antioxidant pool with diamide, a glutathione oxidant. Here we examine whether diamide causes mitochondrial depolarization and promotes arrhythmias in normoxic isolated perfused guinea pig hearts. We also investigate whether stabilization of DeltaPsi(m) with a ligand of the mitochondrial benzodiazepine receptor (4'-chlorodiazepam; 4-ClDzp) prevents the formation of metabolic sinks and, consequently, precludes arrhythmias. Oxidation of the GSH pool was initiated by treatment with 200 microM diamide for 35 min, followed by washout. This treatment increased GSSG and decreased both total GSH and the GSH/GSSG ratio. All hearts receiving diamide transitioned from sinus rhythm into ventricular tachycardia and/or ventricular fibrillation during the diamide exposure: arrhythmia scores were 5.5+/-0.5; n=6 hearts. These arrhythmias and impaired LV function were significantly inhibited by co-administration of 4-ClDzp (64 microM): arrhythmia scores with diamide+4-ClDzp were 0.4+/-0.2 (n=5; P<0.05 vs. diamide alone). Imaging DeltaPsi(m) in intact hearts revealed the heterogeneous collapse of DeltaPsi(m) beginning 20 min into diamide, paralleling the timeframe for the onset of arrhythmias. Loss of DeltaPsi(m) was prevented by 4-ClDzp treatment, as was the increase in myocardial GSSG. These findings show that oxidative stress induced by oxidation of GSH with diamide can cause electromechanical dysfunction under normoxic conditions. Analogous to ischemia-reperfusion injury, the dysfunction depends on the mitochondrial energy state. Targeting the mitochondrial benzodiazepine receptor can prevent electrical and mechanical dysfunction in both models of oxidative stress.

PMID:
19962380
PMCID:
PMC2837795
DOI:
10.1016/j.yjmcc.2009.11.011
[Indexed for MEDLINE]
Free PMC Article

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