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Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels.
Clin Exp Pharmacol Physiol. 2006 Nov; 33(11):1059-65.CE

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 IC50 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 IC50 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.

Authors+Show Affiliations

Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. james.limberis@abbott.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17042915

Citation

Limberis, James T., et al. "Altering Extracellular Potassium Concentration Does Not Modulate Drug Block of Human Ether-a-go-go-related Gene (hERG) Channels." Clinical and Experimental Pharmacology & Physiology, vol. 33, no. 11, 2006, pp. 1059-65.
Limberis JT, Su Z, Cox BF, et al. Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels. Clin Exp Pharmacol Physiol. 2006;33(11):1059-65.
Limberis, J. T., Su, Z., Cox, B. F., Gintant, G. A., & Martin, R. L. (2006). Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels. Clinical and Experimental Pharmacology & Physiology, 33(11), 1059-65.
Limberis JT, et al. Altering Extracellular Potassium Concentration Does Not Modulate Drug Block of Human Ether-a-go-go-related Gene (hERG) Channels. Clin Exp Pharmacol Physiol. 2006;33(11):1059-65. PubMed PMID: 17042915.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altering extracellular potassium concentration does not modulate drug block of human ether-a-go-go-related gene (hERG) channels. AU - Limberis,James T, AU - Su,Zhi, AU - Cox,Bryan F, AU - Gintant,Gary A, AU - Martin,Ruth L, PY - 2006/10/18/pubmed PY - 2007/2/3/medline PY - 2006/10/18/entrez SP - 1059 EP - 65 JF - Clinical and experimental pharmacology & physiology JO - Clin. Exp. Pharmacol. Physiol. VL - 33 IS - 11 N2 - 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 IC50 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 IC50 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. SN - 0305-1870 UR - https://www.unboundmedicine.com/medline/citation/17042915/Altering_extracellular_potassium_concentration_does_not_modulate_drug_block_of_human_ether_a_go_go_related_gene__hERG__channels_ L2 - https://doi.org/10.1111/j.1440-1681.2006.04487.x DB - PRIME DP - Unbound Medicine ER -