Larger rate dependence of late sodium current in cardiac Purkinje cells: A potential link to arrhythmogenesis

Background Purkinje cells (PCs) have a steeper rate dependence of repolarization and are more susceptible to arrhythmic activity than do ventricular myocytes (VMs). Late sodium current (INaL ) is rate dependent and contributes to rate dependence of repolarization. Objective This study sought to test our hypothesis that PCs have a larger rate dependence of INaL , contributing to their steeper rate dependence of repolarization and higher susceptibility to arrhythmic activity, than do VMs. Methods INaL was recorded in isolated rabbit PCs and VMs with the whole-cell patch clamp technique. Action potential was examined using the microelectrode technique. Results Compared with VMs, PCs exhibited a significantly larger rate dependence of INaL with a larger INaL to basic cycle length (BCL) slope. Moreover, PCs had a larger rate dependence of INaL decay and slower recovery kinetics. Interestingly, the larger rate dependence of INaL matched to a steeper rate dependence of action potential duration (APD) in PCs. The INaL blocker tetrodotoxin significantly blunted, while the INaL enhancer anemone toxin (ATX-II) significantly increased, the rate dependence of INaL and APD in PCs and VMs. In the presence of ATX-II, the rate dependence of INaL in PCs was markedly larger than that in VMs, causing a much steeper rate dependence of APD in PCs. Accordingly, PCs exhibited greater rate-dependent electrical instability and were more prone to ATX-II–induced early afterdepolarizations, which were completely inhibited by the INaL inhibitor ranolazine. Conclusion PCs have a significantly larger rate dependence of INaL than do VMs because of distinctive INaL decay and recovery kinetics, which contributes to their larger rate adaptation, and simultaneously predisposes them to a higher risk of arrhythmogenesis.