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Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels.
Br J Pharmacol. 2003 Nov; 140(5):996-1002.BJ

Abstract

Dronedarone is a noniodinated benzofuran derivative that has been synthesized to overcome the limiting iodine-associated adverse effects of the potent antiarrhythmic drug amiodarone. In this study, the acute electrophysiological effects of dronedarone on repolarizing potassium channels were investigated to determine the class III antiarrhythmic action of this compound. HERG and KvLQT1/minK potassium channels conduct the delayed rectifier potassium current IK in human heart, being a primary target for class III antiarrhythmic therapy. HERG and KvLQT1/minK were expressed heterologously in Xenopus laevis oocytes, and the respective potassium currents were recorded using the two-microelectrode voltage-clamp technique. Dronedarone blocked HERG channels with an IC50 value of 9.2 microM and a maximum tail current reduction of 85.2%. HERG channels were blocked in the closed, open, and inactivated states. The half-maximal activation voltage was shifted by -6.1 mV, and HERG current block by dronedarone was voltage-dependent, but not use-dependent. Dronedarone exhibited a weaker block of KvLQT1/minK currents (33.2% at 100 microM drug concentration), without causing significant changes in the corresponding current-voltage relationships. In conclusion, these data demonstrate that dronedarone is an antagonist of cloned HERG potassium channels, with additional inhibitory effects on KvLQT1/minK currents at higher drug concentrations, providing a molecular mechanism for the class III antiarrhythmic action of the drug.

Authors+Show Affiliations

Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, Heidelberg D-69115, Germany. Dierk_Thomas@med.uni-heidelberg.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

14517175

Citation

Thomas, Dierk, et al. "Acute Effects of Dronedarone On Both Components of the Cardiac Delayed Rectifier K+ Current, HERG and KvLQT1/minK Potassium Channels." British Journal of Pharmacology, vol. 140, no. 5, 2003, pp. 996-1002.
Thomas D, Kathofer S, Zhang W, et al. Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels. Br J Pharmacol. 2003;140(5):996-1002.
Thomas, D., Kathofer, S., Zhang, W., Wu, K., Wimmer, A. B., Zitron, E., Kreye, V. A., Katus, H. A., Schoels, W., Karle, C. A., & Kiehn, J. (2003). Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels. British Journal of Pharmacology, 140(5), 996-1002.
Thomas D, et al. Acute Effects of Dronedarone On Both Components of the Cardiac Delayed Rectifier K+ Current, HERG and KvLQT1/minK Potassium Channels. Br J Pharmacol. 2003;140(5):996-1002. PubMed PMID: 14517175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels. AU - Thomas,Dierk, AU - Kathofer,Sven, AU - Zhang,Wei, AU - Wu,Kezhong, AU - Wimmer,Anna-Britt, AU - Zitron,Edgar, AU - Kreye,Volker A W, AU - Katus,Hugo A, AU - Schoels,Wolfgang, AU - Karle,Christoph A, AU - Kiehn,Johann, Y1 - 2003/09/29/ PY - 2003/10/1/pubmed PY - 2004/8/17/medline PY - 2003/10/1/entrez SP - 996 EP - 1002 JF - British journal of pharmacology JO - Br J Pharmacol VL - 140 IS - 5 N2 - Dronedarone is a noniodinated benzofuran derivative that has been synthesized to overcome the limiting iodine-associated adverse effects of the potent antiarrhythmic drug amiodarone. In this study, the acute electrophysiological effects of dronedarone on repolarizing potassium channels were investigated to determine the class III antiarrhythmic action of this compound. HERG and KvLQT1/minK potassium channels conduct the delayed rectifier potassium current IK in human heart, being a primary target for class III antiarrhythmic therapy. HERG and KvLQT1/minK were expressed heterologously in Xenopus laevis oocytes, and the respective potassium currents were recorded using the two-microelectrode voltage-clamp technique. Dronedarone blocked HERG channels with an IC50 value of 9.2 microM and a maximum tail current reduction of 85.2%. HERG channels were blocked in the closed, open, and inactivated states. The half-maximal activation voltage was shifted by -6.1 mV, and HERG current block by dronedarone was voltage-dependent, but not use-dependent. Dronedarone exhibited a weaker block of KvLQT1/minK currents (33.2% at 100 microM drug concentration), without causing significant changes in the corresponding current-voltage relationships. In conclusion, these data demonstrate that dronedarone is an antagonist of cloned HERG potassium channels, with additional inhibitory effects on KvLQT1/minK currents at higher drug concentrations, providing a molecular mechanism for the class III antiarrhythmic action of the drug. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/14517175/Acute_effects_of_dronedarone_on_both_components_of_the_cardiac_delayed_rectifier_K+_current_HERG_and_KvLQT1/minK_potassium_channels_ L2 - https://doi.org/10.1038/sj.bjp.0705502 DB - PRIME DP - Unbound Medicine ER -