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

Abstract

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).