Block of HERG current expressed in HEK293 cells by the Na+-channel blocker cibenzoline.
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 IC(50) = 3.7 +/- 0.963 micro M 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 approximately 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 IC(50) 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.
Hiramatsu
Mikio
M
Department of Cardiovascular Disease, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Wu
Long-Mei
LM
Hirano
Yuji
Y
Kawano
Seiko
S
Furukawa
Tetsushi
T
Hiraoka
Masayasu
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C000606913:KCNH2 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers; C032151:cifenline