SEARCH

SEARCH BY CITATION

Keywords:

  • acidosis;
  • arrhythmia;
  • action potential;
  • hERG;
  • potassium channel

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 (IKr). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including IKr. The aim of this study was to characterize effects of extracellular acidosis on hERG current (IhERG), with particular reference to quantifying effects on IhERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli.

Methods and Results: IhERG recordings were made from hERG-expressing Chinese Hamster Ovary cells using whole-cell patch-clamp at 37°C. IhERG during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state IhERG activation were shifted by ∼+6 mV; maximal IhERG conductance was reduced. The voltage-dependence of IhERG inactivation was little-altered. Fast and slow time-constants of IhERG 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 IhERG from inactivation was observed, but time-course of activation was unaffected. The amplitude of outward IhERG 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 IhERG 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)