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Acidosis Impairs the Protective Role of hERG K + Channels Against Premature Stimulation
Author(s) -
DU CHUN YUN,
ADENIRAN ISMAIL,
CHENG HONGWEI,
ZHANG YI HONG,
EL HARCHI AZIZA,
MCPATE MARK J.,
ZHANG HENGGUI,
ORCHARD CLIVE H.,
HANCOX JULES C.
Publication year - 2010
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/j.1540-8167.2010.01772.x
Subject(s) - herg , repolarization , pharmacology , medicine , potassium channel , patch clamp , cardiac action potential , biophysics , ventricular action potential , chemistry , electrophysiology , biology
Acidosis and the hERG K + Channel . Introduction: Potassium channels encoded by human ether‐à‐go‐go‐related gene ( hERG ) underlie the cardiac rapid delayed rectifier K + channel current (I Kr ). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including I Kr . The aim of this study was to characterize effects of extracellular acidosis on hERG current (I hERG ), with particular reference to quantifying effects on I hERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli. Methods and Results: I hERG recordings were made from hERG‐expressing Chinese Hamster Ovary cells using whole‐cell patch‐clamp at 37°C. I hERG during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state I hERG activation were shifted by ∼+6 mV; maximal I hERG conductance was reduced. The voltage‐dependence of I hERG inactivation was little‐altered. Fast and slow time‐constants of I hERG deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time‐course of recovery of I hERG from inactivation was observed, but time‐course of activation was unaffected. The amplitude of outward I hERG transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3. Conclusion: During acidosis the contribution of I hERG to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1160‐1169)