Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels

The human ether-a-go-go-related gene (HERG) encodes a K+ channel with bioph ysical properties nearly identical to the rapid component of the cardiac-de layed rectifier K+ current (I-Kr). HERG channels are one primary target for the pharmacological management of arrhythmias. In this study, we investiga ted the acute effects of the class III antiarrhythmic drug amiodarone on HE RG channels expressed heterologously in Xenopus oocytes by use of the two-m icroelectrode voltage clamp technique. Amiodarone blocked HERG channels wit h an IC50, of 9.8 mu M with a maximum outward tail current reduction of 62. 8%. The block consisted of two main components, a closed channel block that could not be reversed within the time of experiments and an open channel b lock with a slow unblock, having a recovery time constant of 73 s at -80 mV . Inactivation of the HERG channel at very positive potentials could not pr event amiodarone block. These results indicate that HERG channels can be bl ocked by amiodarone in closed, open and inactivated states. The block of op en channels was cumulative, use-dependent and voltage-dependent. In summary , our data suggest that the strong class III antiarrhythmic action of amiod arone is at least partially based upon its acute inhibitory effects on HERG potassium channels.