| Prevention of mitochondrial fission, a source of mitochondrial dysfunction, through inhibition of dynamin-related protein 1 (DRP1) is an attractive therapeutic strategy for numerous diseases ranging from cardiovascular to neurodegenerative disorders. In this study, we examined the electrophysiological consequences of DRP1 inhibition in ex vivo models of oxidative stress-induced arrhythmias using two distinct blockers, namely Mdivi-1 and Dynasore. Mdivi-1 conferred protection against oxidative stress-related arrhythmias by suppressing endogenous superoxide generation and mitochondrial fragmentation in response to exogenous H2O2 challenge. These favorable effects, however, did not translate to a model of acute ischemia-reperfusion (I/R) injury. Similarly, pretreatment of hearts with 1 muM Dynasore for 120min but not 30min preserved mitochondrial function upon H2O2 challenge. This, in turn, blunted the loss of left ventricular developed pressure (LVDP) and delayed the onset of arrhythmias. Importantly, these favorable effects were retained in the setting of I/R as Dynasore partially suppressed the incidence of reperfusion arrhythmias. Investigation of the electrophysiological substrate revealed marked attenuation of conduction slowing in response to ischemia in Dynasore treated compared to untreated hearts. Surprisingly, treatment with high-dose (5 muM) Dynasore resulted in the rapid elevation of coronary perfusion pressure, Delta&PSgr;m depolarization, and APD instability leading to the onset of arrhythmias even in the absence of exogenous stress. Our findings are consistent with a narrow therapeutic window for improving electrophysiological properties through chemical inhibition of DRP1. |
