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Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels

Delphine S Dupuis1, Dan A Klaerke, Søren-Peter Olesen

  • 1Department of Medical Physiology and Copenhagen Heart Arrhythmia Research Center, University of Copenhagen, Panum Institute, 3 Blegdamsvej, DK 2200 Copenhagen N and NeuroSearch, DK-2750 Ballerup, Denmark. delphine.dupuis@pharma.novartis.com

Basic & Clinical Pharmacology & Toxicology
|February 1, 2005
PubMed

Insights

Beta-blockers like propranolol can block cardiac HERG potassium channels, potentially causing arrhythmias. However, this effect occurs at high concentrations, suggesting safety for congenital long QT syndrome patients.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Cardiology
  • Ion Channel Physiology

Background:

  • Congenital long QT syndrome (LQTS) patients are susceptible to arrhythmias, particularly with increased sympathetic tone.
  • Beta-adrenoceptor blockers are crucial for preventing LQTS-related arrhythmias.
  • A potential concern is whether these beta-blockers might inadvertently block cardiac HERG potassium channels, exacerbating the condition.

Purpose of the Study:

  • To investigate if commonly used beta-adrenoceptor blockers directly inhibit cardiac HERG potassium channels.
  • To determine the concentration-dependent effects and affinities of specific beta-blockers on HERG channel function.
  • To assess the clinical relevance of observed HERG channel blockade in the context of established safety margins.

Main Methods:

  • Heterologous expression of HERG potassium channels in Xenopus oocytes and HEK293 cells.
  • Two-electrode voltage-clamp technique to measure HERG channel currents.
  • Concentration-response analysis to determine IC50 values and assess voltage-dependency.

Main Results:

  • Propranolol demonstrated concentration-dependent inhibition of HERG current (IC50 = 81 µM), with enhanced block when co-expressed with KCNE2 (IC50 = 52 µM).
  • ICI118551 showed similar HERG channel blocking affinity, while metoprolol and atenolol exhibited weak effects.
  • HERG channel blockade by these compounds occurred at high micromolar concentrations, exceeding the safe margin of 100 µM.

Conclusions:

  • Certain beta-adrenoceptor blockers, notably propranolol, can inhibit cardiac HERG potassium channels.
  • The observed HERG channel blockade occurs at concentrations significantly higher than those considered safe for clinical use in LQTS.
  • These findings suggest that the direct HERG channel blocking effect of these beta-blockers is unlikely to pose an additional risk for arrhythmia development in LQTS patients.

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