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

Abstract

We have previously proposed that the heterogeneous collapse of mitochondrial inner membrane potential (ΔΨ 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 ΔΨ 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 ΔΨ 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 200μM diamide for 35 minutes, 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 (64μM): arrhythmia scores with diamide + 4-ClDzp were 0.4± 0.2 (n=5; P < 0.05 vs. diamide alone). Imaging ΔΨ m in intact hearts revealed the heterogeneous collapse of ΔΨ m beginning 20 minutes into diamide, paralleling the timeframe for the onset of arrhythmias. Loss of ΔΨ 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.

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

“…Under physiological conditions, Ͼ90% of energy production required for heart function comes from mitochondria and is dependent on activity of the multisubunit complexes forming the ETC (complexes I-IV) that generates the proton-motive force driving ATP synthesis through complex V. The activities of the ETC and ATP synthesis are tightly regulated to match ATP supply and demand in the heart during physiological workload (22). Any alteration in mitochondrial function is therefore expected to reduce the energetic reserves and disturb homeostatic balance during stress, resulting in impairment of cardiac electrical and mechanical functions (1,5,10,11,48,59) and, Fig. 2.…”

Pyruvate-fortified resuscitation stabilizes cardiac electrical activity and energy metabolism during hypovolemia

“…Oxidative stress is potentially arrhythmogenic [4,40] . The lipid peroxide 8-isoprostane is a marker of oxidative stress and antioxidant deficiency [7,38] .…”

“…Tourniquets impose ischemia on the distal tissue; reintroduction of oxygenated blood upon tourniquet removal triggers massive production of ROS which provoke systemic inflammation [2,3] . In myocardium, ROS can destabilize electrophysiological function by decreasing mitochondrial membrane potential [4] , disrupting ATP production [5,6] and increasing K + flux through sarcolemmal ATP-sensitive potassium (KATP) channels [4,5] . Creatine kinase (CK), which catalyzes high energy phosphate shuttling from the mitochondria to the cytosol, can be reversibly inactivated by ROS [6][7][8] , potentially producing a pro-arrhythmic state [7] .…”

“…ROS have been implicated in the pathogenesis of arrhythmias, and it has been suggested that the antioxidative properties of certain medications could suppress ROS-mediated arrhythmogenesis [40] . Several studies have identified K + channels that are sensitive to oxyradical attack [4,51] . Zhang et al [52] elegantly demonstrated that ROS could dampen the delayed rectifier and HERG K + channel activities, thereby prolonging the action potential.…”

Cardioprotective Effects of Pravastatin Against Lethal Ventricular Arrhythmias Induced by Reperfusion in the Rat Heart

“…[16][17][18] in the present study, to examine the effects of pravastatin on H2O2-induced ∆Ψm loss, confocal microscopy was performed using cells loaded with TMRE. Time-lapse scanning began immediately after the application of H2O2.…”