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

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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=1.4μmol/L), and the inactivated state (Kd_I= 1.4μmol/L), of WT Na^+ channels than that for the resting state (Kd_R= 102.6μmol/L). Conclusions These experimental and simulation studies suggest that azimilide blocks the human cardiac Na^+ channel in both the activated and inactivated states.
社団法人日本循環器学会の論文
2004-06-20