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Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis.
J Cardiovasc Electrophysiol. 2011 Oct; 22(10):1163-70.JC

Abstract

INTRODUCTION

Human ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K(+) channel current (I(Kr)), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (I(hERG)) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C.

METHODS AND RESULTS

Whole-cell patch-clamp recordings of I(hERG) were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC(50)) values for I(hERG) tail inhibition at -40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither I(hERG) kinetics nor the extent of observed I(hERG) blockade by any of these drugs.

CONCLUSION

Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification.

Authors+Show Affiliations

School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, The University of Bristol, Bristol, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21489024

Citation

DU, C Y., et al. "Pharmacological Inhibition of the hERG Potassium Channel Is Modulated By Extracellular but Not Intracellular Acidosis." Journal of Cardiovascular Electrophysiology, vol. 22, no. 10, 2011, pp. 1163-70.
DU CY, El Harchi A, Zhang YH, et al. Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis. J Cardiovasc Electrophysiol. 2011;22(10):1163-70.
DU, C. Y., El Harchi, A., Zhang, Y. H., Orchard, C. H., & Hancox, J. C. (2011). Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis. Journal of Cardiovascular Electrophysiology, 22(10), 1163-70. https://doi.org/10.1111/j.1540-8167.2011.02060.x
DU CY, et al. Pharmacological Inhibition of the hERG Potassium Channel Is Modulated By Extracellular but Not Intracellular Acidosis. J Cardiovasc Electrophysiol. 2011;22(10):1163-70. PubMed PMID: 21489024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological inhibition of the hERG potassium channel is modulated by extracellular but not intracellular acidosis. AU - DU,C Y, AU - El Harchi,A, AU - Zhang,Y H, AU - Orchard,C H, AU - Hancox,J C, Y1 - 2011/04/13/ PY - 2011/4/15/entrez PY - 2011/4/15/pubmed PY - 2012/2/7/medline SP - 1163 EP - 70 JF - Journal of cardiovascular electrophysiology JO - J Cardiovasc Electrophysiol VL - 22 IS - 10 N2 - INTRODUCTION: Human ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K(+) channel current (I(Kr)), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (I(hERG)) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C. METHODS AND RESULTS: Whole-cell patch-clamp recordings of I(hERG) were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC(50)) values for I(hERG) tail inhibition at -40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither I(hERG) kinetics nor the extent of observed I(hERG) blockade by any of these drugs. CONCLUSION: Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification. SN - 1540-8167 UR - https://www.unboundmedicine.com/medline/citation/21489024/Pharmacological_inhibition_of_the_hERG_potassium_channel_is_modulated_by_extracellular_but_not_intracellular_acidosis_ L2 - https://doi.org/10.1111/j.1540-8167.2011.02060.x DB - PRIME DP - Unbound Medicine ER -