Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.
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.
Paul
A A
AA
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD, United Kingdom.
Witchel
H J
HJ
Hancox
J C
JC
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016466:CHO Cells; D027682:Cation Transport Proteins; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004206:Disopyramide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D049452:Green Fluorescent Proteins; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D008164:Luminescent Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D049452:Green Fluorescent Proteins; D004206:Disopyramide