State-Dependent Blocking Actions of Azimilide Dihydrochlo-ride (NE-10064) on Human Cardiac Na⁺ Channels

Abstract

Background Azimilide reportedly blocks Na⁺ channels, although its mechanism remains unclear. Methods and Results The kinetic properties of the azimilide block of the wild-type human Na⁺ channels (WT: hH1) and mutant ΔKPQ Na⁺ channels (ΔKPQ) expressed in COS7 cells were investigated using the whole-cell patch clamp technique and a Markovian state model. Azimilide induced tonic block of WT currents by shifting the h∞ curve in the hyperpolarizing direction and caused phasic block of WT currents with intermediate recovery time constant. The peak and steady-state ΔKPQ currents were blocked by azimilide, although with only a slight shift in the h∞ curve. The phasic block of peak and steady-state ΔKPQ currents by azimilide was significantly larger than the blocking of the peak WT current. The affinity of azimilide predicted by a Markovian state model was higher for both the activated state (Kd_A =1.4 μmol/L), and the inactivated state (Kd_I =1.4 μmol/L), of WT Na⁺ channels than that for the resting state (Kd_R =102.6 μmol/L). Conclusions These experimental and simulation studies suggest that azimilide blocks the human cardiac Na⁺ channel in both the activated and inactivated states. (Circ J 2004; 68: 703 - 711)