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) c hannels expressed in Xenopus oocytes. Because HERG channels underly th e conductance I-Kr in human heart, the effects of azimilide on HERG ch annels expressed in Xenopus oocytes were the focus of the present stud y. 2 In contrast to other well characterized HERG channel blockers, az imilide blockade was reverse use-dependent, i.e., the relative block a nd apparent affinity of azimilide decreased with an increase in channe l activation frequency. Azimilide blocked HERG channels at 0.1 and 1 H z 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 Azimil ide blockade of HERG channels expressed in Xenopus oocytes and I-Kr in mouse AT-1 cells was decreased under conditions of high [K+](e), wher eas block of slowly activating I-Ks channels was not affected by chang es 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 ea ch of these cardiac delayed rectifier channels depends on heart freque ncy. [K+](e) and regulatory status of the respective channels.