A ligand to the mitochondrial benzodiazepine receptor prevents ventricular arrhythmias and LV dysfunction after ischemia or glutathione depletion

We examined how instability of mitochondrial membrane potential (ΔΨ m ) contributed to arrhythmogenesis and left ventricular dysfunction in intact hearts subjected to metabolic challenge. In isolated myocytes, oxidative stress was previously shown to elicit oscillations in ΔΨ m which were stabilized by 4′‐chlorodiazepam (4‐ClDzp), a ligand to the mitochondrial benzodiazepine receptor. Guinea pig hearts were stressed either with global ischemia/reperfusion (I/R) or normoxic perfusion with diamide (to deplete the reduced glutathione pool). In both groups, overwhelming the anti‐oxidant defenses led to severe electrical and contractile dysfunction. Hearts exposed to I/R had high propensity for arrhythmias (score of 6.0 ± 0.7) and contractile dysfunction (LV developed pressure (LVDP) and LV minimum pressure at end of I/R: 10 ± 3 mmHg and 58 ± 1 mmHg, respectively). Stabilizing ΔΨ m with 4‐ClDzp reduced arrhythmias (score 1.25 ± 0.25; P < 0.01) and contractile dysfunction (LVDP and LVP min were 23 ± 1 and 18 ± 3 mmHg at the end of I/R, respectively; P < 0.01). Similarly, diamide induced arrhythmias (score of 6.0 ± 1.1) that were prevented by co‐treatment with 4‐ClDzp (score of 1.0 ± 0.6; P < 0.01). LVDP also recovered significantly in diamide‐treated hearts plus 4‐Cldzp. These data provide further evidence that stabilizing ΔΨ m in the face of oxidative stress has significant clinical implications for myocardial I/R injury.