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.