Block of HERG current expressed in HEK293 cells by the Na⁺-channel blocker cibenzoline

Abstract

A Na⁺-channel blocker, cibenzoline, blocks the delayed rectifier potassium current (I _k), but its detailed action on the rapidly activating component (I _kr) of I _k encoded by the human ether-a-go-go-related gene (HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC₅₀ = 3.7 ± 0.963 µM and Hill coefficient = 0.74 ± 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of −40 to −30 mV, and the block increased with depolarization reaching a plateau at 0 mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2 Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by ∼8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I _kr-like current reconstituted by HERG clone transfection with an IC₅₀ value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.