Effects of new class III antiarrhythmic drug niferidil on electrical activity in murine ventricular myocardium and their ionic mechanisms

摘要

A new class III antiarrhythmic drug niferidil has been recently introduced as a highly effective therapy cure for cases of persistent atrial fibrillation, but ionic mechanisms of its action are still unknown. Effects of niferidil on action potential (AP) waveform and major ionic currents were studied in mouse ventricular myocardium. APs were recorded with glass microelectrodes in multicellular preparations of right ventricular wall. Whole-cell patch-clamp technique was used to measure K+, Ca2+, and Na+ currents in isolated mouse ventricular myocytes. While 10(-7) M niferidil failed to alter the AP configuration, 10(-6) M tended to prolong APs (by 12.05 +/- A 1.8 % at 50 % of repolarization) and 10(-5) M induced significant slowing of repolarization (32.1 +/- A 4.9 % at 50 % of repolarization). Among the potassium currents responsible for AP repolarization phase, I (K1) was found to be almost insensitive to niferidil. I (to) demonstrated low sensitivity to niferidil with IC50 = 2.03 x 10(-4) M. I (Kur), which was previously hypothesized to be the main target of the drug, was more sensitive with IC50 = 6 x 10(-5) M. However, sustained delayed rectifier potassium current I (ss) was inhibited with even lower IC50 = 2.8 x 10(-5) M. Therefore, suppression of I (ss) and, second, I (Kur) by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in I (CaL) peak amplitude (IC50a parts per thousand 10(-4) M), but failed to alter I (Na) significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting I (ss) and I (Kur) K+ currents, but not exclusively I (Kur), as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where I (Kr) is strongly expressed instead of I (ss).