Effects of Na+ channel blocker, pilsicainide, on HERG current expressed in HEK-293 cells.
OBJECTIVE
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
Pilsicainide suppressed peak currents of HERG channel during depolarizing pulses and tail currents upon repolarization. Pilsicainide blocked HERG current with IC50 = 20.4 microM and Hill coefficient = 0.98. Voltage-dependent activation was shifted in a negative direction by approximately 10 mV by 10 to 20 microM 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.
Wu
Long-Mei
LM
Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Japan.
Orikabe
Minako
M
Hirano
Yuji
Y
Kawano
Seiko
S
Hiraoka
Masayasu
M
D000200:Action Potentials / Q000187:drug effects; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D026941:Sodium Channel Blockers; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D008012:Lidocaine; C042288:pilsicainide