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Published on: February 8, 2011

State dependent dissociation of HERG channel inhibitors

D Stork1, E N Timin, S Berjukow

  • 1Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, Vienna 1090, Austria.

British Journal of Pharmacology
|June 27, 2007
PubMed

Insights

Drug block of HERG channels, crucial for cardiac rhythm, varies with cell pulsing rate. Some drugs show frequency-dependent block, while others appear trapped, impacting QT interval risk.

Area of Science:

  • Pharmacology
  • Cardiology
  • Molecular Biology

Background:

  • Inhibition of the human ether-à-go-go-related gene (hERG) channel prolongs the QT interval, increasing the risk of fatal torsades de pointes arrhythmias.
  • Many hERG channel blockers exhibit increased potency at higher stimulation frequencies, a phenomenon known as frequency-dependent block.
  • This frequency dependence can complicate the accurate assessment of drug-induced hERG channel block and associated cardiac risks.

Purpose of the Study:

  • To systematically compare the kinetics of hERG channel inhibition and recovery from block by eight different drug compounds.
  • To investigate the influence of varying stimulation frequencies on the IC(50) values of hERG channel blockers.
  • To elucidate the mechanisms underlying frequency-dependent block and drug dissociation from hERG channels.

Main Methods:

  • Heterologous expression of hERG channels in Xenopus oocytes.
  • Measurement of hERG channel currents using the two-electrode voltage clamp technique.
  • Systematic assessment of drug block and recovery kinetics at different stimulation frequencies.

Main Results:

  • Four compounds (amiodarone, cisapride, droperidol, haloperidol) demonstrated frequency-dependent block (Group 1).
  • Four compounds (bepridil, domperidone, E-4031, terfenadine) showed similar block across frequencies, with limited recovery from block (Group 2).
  • Frequent pulsing enhanced the washout of Group 2 compounds, and a specific mutation (D540K) facilitated recovery from block by these agents.

Conclusions:

  • Drug dissociation rates from open and closed hERG channels differ, leading to 'use-dependent' block.
  • Group 1 drugs dissociate from both open and resting states, while Group 2 drugs appear to dissociate primarily from the open state, leading to 'trapped' kinetics.
Abstract

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