Sato R, Hisatome I, Tanaka Y, Sasaki N, Kotake H, Mashiba H, Katori R
1st Department of Medicine, Kinki University, Osaka, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 1991 Sep;344(3):331-6. doi: 10.1007/BF00183008.
Aprindine is a class Ib antiarrhythmic agent. We studied effects of aprindine (3 mumol/l) on the Na+ current using whole cell voltage clamp (tip resistance = 0.5 M omega, [Na]i ando = 10 mmol/l at 18 degrees C). Aprindine revealed tonic block (Kdrest = 37.7 mumol/l, Kdi = 0.74 mumol/l; n = 4). Aprindine, shifted inactivation curve to hyperpolarizing direction by 11.4 +/- 3.5 mV (n = 4) without changes in slope factor. In the presence of 3 mumol/l aprindine, aprindine showed phasic block, i.e., duration-dependent block at 2 Hz (64% +/- 3% at 1.5 ms, 82% +/- 6% at 20 ms, 93% +/- 7% at 200 ms; n = 4). Short single prepulse also produced aprindine-induced phasic block (12% at 1.5 ms, 22% at 100 ms; n = 2). After removal of fast inactivation of Na+ current by 3 mmol/l tosylchloramide sodium, aprindine revealed phasic block, independent of holding potential. The recovery time constant from aprindine-induced phasic block was 4.8 s at holding potential = -100 mV and 5.0 s at holding potential = -140 mV. This use-dependent block of aprindine had pH dependency. Under acidic condition (pH 6.0), 3 mumol/l aprindine showed smaller use-dependent block (14% +/- 7% at 2 Hz; n = 4) comparing with either at pH 7.4 (68% +/- 13%; n = 4) or at pH 8.0 (90% +/- 12%; n = 4). The results suggest that aprindine could bind to the receptor via activation process through channel pore, resulting in decrease of Na+ current, and egress from the receptor through the lipid bilayer. These effects might be attenuated under acidic condition due to changes in intracellular ratio of charged to neutralized form of drug molecule.
阿普林定是一种Ib类抗心律失常药物。我们使用全细胞膜片钳技术（在18℃时，尖端电阻 = 0.5 MΩ，细胞内和细胞外[Na⁺] = 10 mmol/L）研究了阿普林定（3 μmol/L）对Na⁺电流的影响。阿普林定表现出持续性阻滞（静息解离常数Kdrest = 37.7 μmol/L，内向解离常数Kdi = 0.74 μmol/L；n = 4）。阿普林定使失活曲线向超极化方向移动11.4 ± 3.5 mV（n = 4），斜率因子无变化。在存在3 μmol/L阿普林定的情况下，阿普林定表现出时相性阻滞，即在2 Hz时呈时间依赖性阻滞（在1.5 ms时为64% ± 3%，在20 ms时为82% ± 6%，在200 ms时为93% ± 7%；n = 4）。短的单个预脉冲也会产生阿普林定诱导的时相性阻滞（在1.5 ms时为12%，在100 ms时为22%；n = 2）。在用3 mmol/L对甲苯磺酰氯胺钠消除Na⁺电流的快速失活后，阿普林定表现出时相性阻滞，与钳制电位无关。从阿普林定诱导的时相性阻滞中恢复的时间常数在钳制电位为 -100 mV时为4.8 s，在钳制电位为 -140 mV时为5.0 s。阿普林定的这种使用依赖性阻滞具有pH依赖性。在酸性条件（pH 6.0）下，3 μmol/L阿普林定与在pH 7.4（68% ± 13%；n = 4）或pH 8.0（90% ± 12%；n = 4）时相比，表现出较小的使用依赖性阻滞（在2 Hz时为14% ± 7%；n = 4）。结果表明，阿普林定可通过通道孔的激活过程与受体结合，导致Na⁺电流降低，并通过脂质双层从受体中逸出。由于药物分子带电形式与中和形式的细胞内比例变化，这些效应在酸性条件下可能会减弱。
