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Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.
Biochem Biophys Res Commun. 2001 Feb 09; 280(5):1243-50.BB

Abstract

The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'acquired' prolongation of the QT interval of the electrocardiogram (ECG). This potentially proarrhythmic effect is likely to reflect drug actions on ion channels involved in ventricular action potential repolarisation. In this study, we examined the effects of DISO on potassium channels encoded by HERG, as this K channel type has been implicated in both congenital and acquired long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently transfected with HERG cDNA for subsequent whole cell patch clamp recording. HERG tail currents recorded at -40 mV following test pulses to +30 mV were inhibited in a dose-dependent fashion by DISO concentrations within the clinical range (IC50 = 7.23 +/- 0.72 microM; mean +/- SEM). Experiments with 10 microM DISO indicated that the degree of HERG blockade showed some voltage dependence. Further data obtained using an 'envelope of tails' protocol (pulse potential +40 mV) were consistent with a significant role for open-channel blockade at lower drug concentrations. At higher concentrations it is possible that blockade may have involved drug binding to both resting and open channels. Inhibition of the inactivation-deficient mutant HERG-S631A was comparable to that seen for wild-type HERG. Therefore, channel inactivation was not obligatory for DISO to exert its effect. Native delayed rectifier tail currents from rabbit isolated ventricular myocytes were also inhibited by DISO. We conclude (a) that DISO inhibits HERG encoded potassium channels at clinically relevant concentrations and (b) that this action may constitute the molecular basis for acquired LQTS associated with this drug.

Authors+Show Affiliations

Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD, United Kingdom.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11162661

Citation

Paul, A A., et al. "Inhibition of HERG Potassium Channel Current By the Class 1a Antiarrhythmic Agent Disopyramide." Biochemical and Biophysical Research Communications, vol. 280, no. 5, 2001, pp. 1243-50.
Paul AA, Witchel HJ, Hancox JC. Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide. Biochem Biophys Res Commun. 2001;280(5):1243-50.
Paul, A. A., Witchel, H. J., & Hancox, J. C. (2001). Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide. Biochemical and Biophysical Research Communications, 280(5), 1243-50.
Paul AA, Witchel HJ, Hancox JC. Inhibition of HERG Potassium Channel Current By the Class 1a Antiarrhythmic Agent Disopyramide. Biochem Biophys Res Commun. 2001 Feb 9;280(5):1243-50. PubMed PMID: 11162661.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide. AU - Paul,A A, AU - Witchel,H J, AU - Hancox,J C, PY - 2001/2/13/pubmed PY - 2001/3/17/medline PY - 2001/2/13/entrez SP - 1243 EP - 50 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 280 IS - 5 N2 - The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'acquired' prolongation of the QT interval of the electrocardiogram (ECG). This potentially proarrhythmic effect is likely to reflect drug actions on ion channels involved in ventricular action potential repolarisation. In this study, we examined the effects of DISO on potassium channels encoded by HERG, as this K channel type has been implicated in both congenital and acquired long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently transfected with HERG cDNA for subsequent whole cell patch clamp recording. HERG tail currents recorded at -40 mV following test pulses to +30 mV were inhibited in a dose-dependent fashion by DISO concentrations within the clinical range (IC50 = 7.23 +/- 0.72 microM; mean +/- SEM). Experiments with 10 microM DISO indicated that the degree of HERG blockade showed some voltage dependence. Further data obtained using an 'envelope of tails' protocol (pulse potential +40 mV) were consistent with a significant role for open-channel blockade at lower drug concentrations. At higher concentrations it is possible that blockade may have involved drug binding to both resting and open channels. Inhibition of the inactivation-deficient mutant HERG-S631A was comparable to that seen for wild-type HERG. Therefore, channel inactivation was not obligatory for DISO to exert its effect. Native delayed rectifier tail currents from rabbit isolated ventricular myocytes were also inhibited by DISO. We conclude (a) that DISO inhibits HERG encoded potassium channels at clinically relevant concentrations and (b) that this action may constitute the molecular basis for acquired LQTS associated with this drug. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/11162661/Inhibition_of_HERG_potassium_channel_current_by_the_class_1a_antiarrhythmic_agent_disopyramide_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(01)94269-X DB - PRIME DP - Unbound Medicine ER -