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

1 The class III antiarrhythmic azimilide has previously been shown to inhibit I-Ks and I-Kr in guinea-pig cardiac myocytes and I-Ks (minK) channels expressed in Xenopus oocytes. Because HERG channels underly the conductance I-Kr in human heart, the effects of azimilide on HERG channels expressed in Xenopus oocytes were the focus of the present study. 2 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 mu M and 5.2 mu M respectively. 3 In an envelope of tail test, HERG channel blockade increased with increasing channel activation, indicating binding of azimilide to open channels. 4 Azimilide blockade of HERG channels expressed in Xenopus oocytes and I-Kr in mouse AT-1 cells was decreased under conditions of high [K+](e), whereas block of slowly activating I-Ks channels was not affected by changes in [K+](e). 5 In summary, azimilide is a blocker of cardiac delayed rectifier channels, I-Ks and HERG. Because of the distinct effects of stimulation frequency and [K+](e) on azimilide block of I-Kr and I-Ks,, 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.