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Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis.

Abstract

INTRODUCTION
Human ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K(+) channel current (I(Kr) ), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (I(hERG)) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C.
METHODS AND RESULTS
Whole-cell patch-clamp recordings of I(hERG) were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC(50)) values for I(hERG) tail inhibition at -40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither I(hERG) kinetics nor the extent of observed I(hERG) blockade by any of these drugs.
CONCLUSION
Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification.

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  • Publisher Full Text
  • Authors

    DU CY, El Harchi A, Zhang YH, Orchard CH, Hancox JC

    Source

    Journal of cardiovascular electrophysiology 22:10 2011 Oct pg 1163-70

    MeSH

    Acidosis
    Amiodarone
    Anti-Arrhythmia Agents
    Dose-Response Relationship, Drug
    Ether-A-Go-Go Potassium Channels
    Flecainide
    HEK293 Cells
    Humans
    Hydrogen-Ion Concentration
    Membrane Potentials
    Patch-Clamp Techniques
    Phenethylamines
    Potassium
    Potassium Channel Blockers
    Sulfonamides
    Time Factors
    Transfection

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21489024