Effects of channel modulation and pH on IsK inhibition by the novel class III antiarrhythmic azimilide (NE-10064)

Inhibition of human I_sK channels expressed in Xenopus oocytes by the novel class III antiarrhythmic azimilide was studied under distinct treatments known to increase I_sK (hypotonic solution, A23187 and isoproterenol). Azimilide inhibited I_sK under all conditions with similar potency. Reduction of ionic strength or pH changes from pH 6.5 to 8.5 did not alter I_sK amplitude. However, inhibition of I_sK by azimilide was decreased by reduced pH, but not by reduced ionic strength. Further, the apparent affinity of azimilide was increased more than tenfold by increasing pH from 6.5 to 8.5. The data suggest that the neutral form of azimilide, a weak base, inhibits I_sK via a lipophilic protein-drug interaction. pH-dependence of azimilide may significantly alter its effects on I_sK under distinct pathophysiological conditions (acidosis vs. alkalosis) and in distinct locations (heart vs. kidney).