Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action

The class III antiarrhythmic azimilide has previously been shown to inhibit IKs and IKr in guinea‐pig cardiac myocytes and IKs (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance IKr in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. In contrast to other well characterized HERG channel blockers, azimilide blockade was reverse use‐dependent, i.e., the relative block and apparent affinity of azimilide decreased with an increase in channel activation frequency. Azimilide blocked HERG channels at 0.1 and 1 Hz with IC50 s of 1.4 μM and 5.2 μM respectively. In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. Azimilide blockade of HERG channels expressed in Xenopus oocytes and IKr in mouse AT‐1 cells was decreased under conditions of high [K+]e, whereas block of slowly activating IKs channels was not affected by changes in [K+]e. In summary, azimilide is a blocker of cardiac delayed rectifier channels, IKs and HERG. Because of the distinct effects of stimulation frequency and [K+]e on azimilide block of IKr and IKs channels, we conclude that the relative contribution of block of each of these cardiac delayed rectifier channels depends on heart frequency. [K+]e and regulatory status of the respective channels. British Journal of Pharmacology (1998) 123, 23–30; doi:10.1038/sj.bjp.0701575