| Title | ALTERING EXTRACELLULAR POTASSIUM CONCENTRATION DOES NOT MODULATE DRUG BLOCK OF HUMAN ETHER-A-GO-GO-RELATED GENE (hERG) CHANNELS. | | Author(s) | Limberis JT, Su Z, Cox BF, Gintant GA, Martin RL | | Institution | Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA. | | Source | Clin Exp Pharmacol Physiol 2006 Nov; 33(11):1059-65. | | Abstract | 1. 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). | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 17042915 |
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