BLOCKADE OF HUMAN I-SK CHANNELS EXPRESSED IN XENOPUS OOCYTES BY THE NOVEL CLASS-III ANTIARRHYTHMIC NE-10064

cRNA encoding the human I-sK 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 fdr its ability to block these channels. The compound displayed potent inhibitory effects with an EC(50) of 5.4 mu M. 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 I-sK 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 I-sK channels and suggest that such effects could be involved in its antiarrhythmic action.