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ALTERING EXTRACELLULAR POTASSIUM CONCENTRATION DOES NOT MODULATE DRUG BLOCK OF HUMAN ETHER‐A‐GO‐GO ‐RELATED GENE (hERG) CHANNELS
Author(s) -
Limberis James T,
Su Zhi,
Cox Bryan F,
Gintant Gary A,
Martin Ruth L
Publication year - 2006
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2006.04487.x
Subject(s) - herg , quinidine , potassium channel , pharmacology , torsades de pointes , dofetilide , potassium channel blocker , chemistry , patch clamp , hek 293 cells , terfenadine , long qt syndrome , medicine , electrophysiology , qt interval , biochemistry , gene
SUMMARY1 Drug‐induced block of the rapidly activating delayed rectifier K + current (I Kr ), encoded by human ether‐a‐go‐go ‐related gene (hERG), has been linked to acquired long QT syndrome (aLQTS). Hypokalaemia is a recognized risk factor in aLQTS. To further understand why hypokalaemia is a risk factor in aLQTS, we examined the effect of [K + ] o on drug block of the hERG potassium channel stably expressed in human embryonic kidney (HEK‐293) cells using whole‐cell voltage‐clamp techniques. 2 The effects of selected [K + ] o (1–20 mmol/L) on hERG block with four structurally diverse compounds (dofetilide, mesoridazine, quinidine and terfenadine) from different therapeutic classes were evaluated. Reducing [K + ] o from 20 to 1 mmol/L had little effect on IC 50 values for hERG current block for all four compounds. For example, evaluating quinidine in external potassium concentrations of 20, 10, 5 and 1 mmol/L resulted in IC 50 values of 1.82 ± 0.33, 2.04 ± 0.28, 1.57 ± 0.52 and 1.14 ± 0.21 mmol/L, respectively. No statistically significant difference ( P > 0.35, anova ) was observed between drug block of hERG in different external potassium concentrations. These data are in contrast with previously reported results examining hERG channel modulation expressed in AT‐1 cells under similar experimental conditions. 3 These results demonstrate that [K + ] o does not directly modulate drug block of hERG channels expressed in an HEK‐293 cell line. The enhanced risk of Torsades de Pointes associated with hypokalaemia in aLQTS may be due to reduction of other (non‐hERG) potassium currents, further reducing the repolarization reserve, and not due to direct modulation of hERG block by [K + ] o .