Allosteric Modulation of K(v)11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

作者：Yu Zhiyi; Liu Jia; van Veldhoven Jacobus P D; IJzerman Adriaan P; Schalij Martin J; Pijnappels Daniel A; Heitman Laura H^*; de Vries Antoine A F^*

来源：Circulation-Arrhythmia and Electrophysiology, 2016, 9(4): e003439.

DOI：10.1161/CIRCEP.115.003439

• arrhythmias
• cardiac
• cardiotoxicity
• cell culture techniques
• myocytes
• cardiac
• potassium voltage-gated channel
• subfamily H
• member 2
• radioligand assay
• voltage-sensitive dye imaging

Background Ventricular arrhythmias as a result of unintentional blockade of the K(v)11.1 (hERG [human ether-a-go-go-related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by K(v)11.1 allosteric modulators.
Methods and Results Using [H-3]dofetilide-binding assays with membranes of human K(v)11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the K(v)11.1 channel, with LUF7244 showing the strongest effect at 10 mol/L. The K(v)11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays.
Conclusions Allosteric modulation of the K(v)11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended K(v)11.1 blockers via pharmacological combination therapy.

• 出版日期2016-4