Inactivation block of the HERG human cardiac K + channels by RP58866

RP58866 possesses a unique electrophysiological property: highly effective against various types of arrhythmias including ventricular fibrillation in animal models, noticeably those occurring during ischaemia with depolarized membrane due to elevated extracellular K + concentrations. To understand the potential ionic mechanisms, we performed detailed studies on the effects of RP58866 on the HERG channels expressed in Xenopus oocytes, which are believed to be important compositions of the rapid component of delayed rectifier K + current in the hearts. RP58866 significantly inhibited the HERG channels in a concentration‐dependent manner, with ∼50% decrease in the current amplitude at a concentration of 1 μ M . RP58866 produced more pronounced inhibition with voltage protocols which favoured inactivation of the HERG channels. It caused substantial negative shift of the inactivation curves but did not alter the activation properties. The inhibition was considerably relieved by elevating [K + ] o from 5–20 m M , which weakened the channel inactivation. More importantly, the potency was reduced by ∼100 fold on the mutated HERG channels (S631A) in which the C‐type inactivation was substantially weakened. We conclude that blockade of the HERG channels by RP58866 is mainly associated with the binding of the drugs to the inactivated channels. This unique property of HERG blockade might explain some previously reported but unexplained observations: RP58866 maintains its efficacy in APD prolongation with depolarized membrane potential and in arrhythmias during ischaemia with manifested membrane depolarization.British Journal of Pharmacology (1999) 127 , 1899–1907; doi: 10.1038/sj.bjp.0702741