Lidoflazine is a high affinity blocker of the HERG K +channel

Abstract

Lidoflazine is an antianginal calcium channel blocker that carries a significant risk of QT interval prolongation and ventricular arrhythmia. We investigated whether or not lidoflazine inhibits current through the rapid delayed rectifier K + channel α subunit (encoded by HERG – human ether-a-go-go-related gene), since this channel has been widely linked to drug-induced QT-prolongation. Lidoflazine inhibited potently HERG current (I HERG) recorded from HEK 293 cells stably expressing wild-type HERG (IC 50 of ~16 nM). It was ~13-fold more potent against HERG than was verapamil under similar conditions. On membrane depolarization, I HERG inhibition developed gradually, ruling out closed-channel state dependent inhibition. The effect of command voltage on the drug’s action suggested that lidoflazine preferentially inhibits activated/open HERG channels. The S6 mutation Y652A largely eliminated the inhibitory action of lidoflazine, whilst the F656A mutation also reduced blocking potency. We conclude: first, that lidoflazine produces high affinity blockade of the α subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and, second, that this is likely to represent the molecular mechanism of QT interval prolongation by this drug.