Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide

A novel pure class III antiarrhythmic agent, 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphen-ethyl)-N-methylamino]ethane hydrochloride (KCB-328) prolongs action potential duration (APD) by blocking the rapid component delayed rectifier K+ current (IKr). However, KCB-328 manifests little of the reverse frequency dependence (RFD) that is a general characteristic of class III antiarrhythmic agents. We have studied the onset and recovery kinetics of KCB-328 and dofetilide on APD in guinea-pig papillary muscle and on human ether-a-go-go-related gene (HERG) channel, which encodes IKr, expressed in Xenopus oocytes. KCB-328 (1 microM) and dofetilide (0.1 microM) progressively increased the duration of post-rest AP at 1-Hz stimulation, with onset time constants of 6.4 +/- 0.6 seconds and 20.7 +/- 1.8 seconds, respectively. With a 100-second resting period, the effect of KCB-328 recovered by 70% with a time constant of 13.2 +/- 4.2 seconds, whereas that of dofetilide recovered only by 25%. Both drugs blocked activated HERG channels in a biexponential decay fashion, with faster time constants for KCB-328 (3 microM) than for dofetilide (0.3 microM). After a 300-second resting period, HERG current inhibited by KCB-328 was recovered more at depolarized membrane potentials than at hyperpolarized ones, with a time constant of 179.9 seconds during the rest at -60 mV. In contrast, recovery after dofetilide was negligible at all voltages tested. These results suggest that KCB-328 binds to IKr at a preferentially open state in a use-dependent manner, but that KCB-328 unbinds from the resting state more readily than dofetilide. The less striking RFD of KCB-328 than of dofetilide might be related to the faster recovery from its effect on IKr.