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

Author:

Mikio Hiramatsu   Long-Mei Wu   Yuji Hirano   Seiko Kawano   Tetsushi Furukawa   Masayasu Hiraoka  

Journal:

Heart and Vessels

Issue Date:

2004

Abstract(summary):

A Na+-channel blocker, cibenzoline, blocks the delayed rectifier potassium current (Ik), but its detailed action on the rapidly activating component (Ikr) of Ik 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 muM 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 dollar sign8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the Ikr-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.

Page:

137-143