Inhibition of HERG potassium channel current by the Class 1a antiarrhythmic agent disopyramide

The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'ac quired' prolongation of the QT interval of the electrocardiogram (ECG). Thi s 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 HER G, as this K channel type has been implicated in both congenital and acquir ed long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently t ransfected 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 cli nical range (IC50 = 7.23 +/- 0.72 muM; mean +/- SEM), Experiments with 10 m uM DISO indicated that the degree of HERG blockade showed some voltage depe ndence. 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 possi ble that blockade may have involved drug binding to both resting and open c hannels. Inhibition of the inactivation-deficient mutant HERG-S631A was com parable to that seen for wild-type HERG. Therefore, channel inactivation wa s not obligatory for DISO to exert its effect. Native delayed rectifier tai l currents from rabbit isolated ventricular myocytes were also inhibited by DISO, We conclude (a) that DISO inhibits HERG encoded potassium channels a t clinically relevant concentrations and (b) that this action may constitut e the molecular basis for acquired LQTS associated with this drug. (C) 2001 Academic Press.