Blockade of human IsK channels expressed in Xenopus oocytes by the novel class III antiarrhythmic NE-10064.
cRNA encoding the human IsK protein was injected into Xenopus oocytes and the expressed channels were investigated using the two-microelectrode voltage-clamp method. The novel class III antiarrhythmic NE-10064 (1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3- [4-(4-methyl-1-piperazinyl)-butyl]-2,4-imidazolidinedione dihydrochloride) was tested for its ability to block these channels. The compound displayed potent inhibitory effects with an EC50 of 5.4 microM. The block caused by NE-10064 was use-dependent, i.e. channels had to be activated for the inhibition to occur. Further, the reversal of the inhibition during the wash-out period was use-dependent. Finally, the blockade of human IsK channels by NE-10064 appeared to be voltage-dependent, being more pronounced at depolarized potentials. We conclude that this novel class III antiarrhythmic is a potent inhibitor of human IsK channels and suggest that such effects could be involved in its antiarrhythmic action.
Busch
A E
AE
Physiologisches Institut I, Eberhard-Karls-Universität Tübingen, Germany.
Herzer
T
T
Takumi
T
T
Krippeit-Drews
P
P
Waldegger
S
S
Lang
F
F
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D018118:Chloride Channels / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008564:Membrane Potentials; D008839:Microelectrodes; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D018118:Chloride Channels; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; C059983:potassium channel protein I(sk); C086123:azimilide; D011188:Potassium; D002118:Calcium