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.

Links

Publisher Full Text

Authors

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

Institution

School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, The University of Bristol, Bristol, UK.

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