Effects of Na+ channel blocker, pilsicainide, on HERG current expressed in HEK-293 cells

Purpose: Pilsicainide, classified as a relatively pure Na+ channel blocker, occasionally causes QT prolongation, suggesting inhibitory actions on K+ currents. We studied effects of pilsicainide on the K+ channel current of the human ether-a-go-go-related gene (HERG) in heterologous expression system. Methods: The Patch-clamp technique in whole-cell configuration was used to record the channel current of HERG stably expressed in HEK293 cells. Results: Pilsicamide suppressed peak currents of HERG channel during depolarizing pulses and tail currents upon repolarization. Pilsicainide blocked HERG current with IC50 = 20.4 muM and Hill coefficient = 0.98. Voltage-dependent activation was shifted in a negative direction by similar to10 mV by 10 to 20 muM pilsicainide. Block increased with depolarization to voltages between -20 and 0 mV and reached the maximum level at positive voltages to 0 mV without further increase. Following drug equilibration for 10 minutes (holding potential at -100 mV), the peak outward current upon the first depolarization showed time-dependent block; tail current block was maximal. Frequency-dependent block evaluated from tail current was absent with pulse frequencies of 1.33, 0.5, and 0.2 Hz. After a steady state block was achieved, time course of current activation and deactivation was slowed by pilsicainide, and steady-state inactivation and time course of fast inactivation were mildly affected. Conclusions: Pilsicainide blocks HERG current with a preferential affinity, at least, to the open state of the channels with a fast access to binding sites.