Abramochkin Denis V, Kuzmin Vladislav S, Rosenshtraukh Leonid V
Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskije gory, 1, 12, 119991, Moscow, Russia,
Naunyn Schmiedebergs Arch Pharmacol. 2015 Oct;388(10):1105-12. doi: 10.1007/s00210-015-1146-x. Epub 2015 Jun 24.
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(+), Ca(2+), 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 ± 1.8% at 50% of repolarization) and 10(-5) M induced significant slowing of repolarization (32.1 ± 4.9% at 50% of repolarization). Among the potassium currents responsible for AP repolarization phase, IK1 was found to be almost insensitive to niferidil. Ito demonstrated low sensitivity to niferidil with IC50 = 2.03 × 10(-4) M. IKur, which was previously hypothesized to be the main target of the drug, was more sensitive with IC50 = 6 × 10(-5) M. However, sustained delayed rectifier potassium current Iss was inhibited with even lower IC50 = 2.8 × 10(-5) M. Therefore, suppression of Iss and, second, IKur by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in ICaL peak amplitude (IC50≈10(-4) M), but failed to alter INa significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting Iss and IKur K(+) currents, but not exclusively IKur, as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where IKr is strongly expressed instead of Iss.
一种新型III类抗心律失常药物尼非地尔最近被引入，作为持续性心房颤动病例的高效治疗药物，但它的作用离子机制仍不清楚。研究了尼非地尔对小鼠心室肌动作电位（AP）波形和主要离子电流的影响。在右心室壁的多细胞标本中用玻璃微电极记录动作电位。采用全细胞膜片钳技术测量分离的小鼠心室肌细胞中的钾离子、钙离子和钠离子电流。虽然10^(-7)M的尼非地尔未能改变动作电位的形态，但10^(-6)M的尼非地尔倾向于延长动作电位（在复极化50%时延长12.05±1.8%），而10^(-5)M的尼非地尔则导致复极化明显减慢（在复极化50%时减慢32.1±4.9%）。在负责动作电位复极化阶段的钾电流中，发现IK1对尼非地尔几乎不敏感。Ito对尼非地尔的敏感性较低，IC50 = 2.03×10^(-4)M。先前推测为该药物主要靶点的IKur对尼非地尔更敏感，IC50 = 6×10^(-5)M。然而，持续延迟整流钾电流Iss受到抑制，IC50甚至更低，为2.8×10^(-5)M。因此，尼非地尔对Iss以及其次对IKur的抑制似乎是小鼠心室组织中动作电位延长的基础。尼非地尔还使L型钙电流峰值幅度适度降低（IC50≈10^(-4)M），但对钠离子电流没有明显影响。尼非地尔延长小鼠心室肌动作电位主要是通过抑制Iss和IKur钾电流，但并不像之前所提出的那样仅仅是IKur。需要进一步研究以揭示尼非地尔在人类心肌中的作用机制，在人类心肌中强烈表达的是IKr而不是Iss。
