Department of Physiology.
Department of Medical Environmental Biology and Tropical Medicine.
Toxicol Sci. 2020 Dec 1;178(2):302-310. doi: 10.1093/toxsci/kfaa149.
Imipramine, a tricyclic antidepressant, is used in the treatment of depressive disorders. However, the effect of imipramine on vascular ion channels is unclear. Therefore, using a patch-clamp technique we examined the effect of imipramine on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Kv channels were inhibited by imipramine in a concentration-dependent manner, with an IC50 value of 5.55 ± 1.24 µM and a Hill coefficient of 0.73 ± 0.1. Application of imipramine shifted the steady-state activation curve in the positive direction, indicating that imipramine-induced inhibition of Kv channels was mediated by influencing the voltage sensors of the channels. The recovery time constants from Kv-channel inactivation were increased in the presence of imipramine. Furthermore, the application of train pulses (of 1 or 2 Hz) progressively augmented the imipramine-induced inhibition of Kv channels, suggesting that the inhibitory effect of imipramine is use (state) dependent. The magnitude of Kv current inhibition by imipramine was similar during the first, second, and third depolarizing pulses. These results indicate that imipramine-induced inhibition of Kv channels mainly occurs in the closed state. The imipramine-mediated inhibition of Kv channels was associated with the Kv1.5 channel, not the Kv2.1 or Kv7 channel. Inhibition of Kv channels by imipramine caused vasoconstriction. From these results, we conclude that imipramine inhibits vascular Kv channels in a concentration- and use (closed-state)-dependent manner by changing their gating properties regardless of its own function.
丙咪嗪是一种三环类抗抑郁药，用于治疗抑郁障碍。然而，丙咪嗪对血管离子通道的作用尚不清楚。因此，我们使用膜片钳技术研究了丙咪嗪对新鲜分离的兔冠状动脉血管平滑肌细胞电压依赖性钾通道（Kv 通道）的影响。丙咪嗪以浓度依赖性方式抑制 Kv 通道，IC50 值为 5.55±1.24 μM，Hill 系数为 0.73±0.1。丙咪嗪的应用使稳态激活曲线向正方向移动，表明丙咪嗪诱导的 Kv 通道抑制是通过影响通道的电压传感器介导的。在丙咪嗪存在下，Kv 通道失活的恢复时间常数增加。此外，应用串脉冲（1 或 2 Hz）可逐渐增强丙咪嗪对 Kv 通道的抑制作用，表明丙咪嗪的抑制作用是使用（状态）依赖性的。在第一个、第二个和第三个去极化脉冲期间，丙咪嗪对 Kv 电流的抑制程度相似。这些结果表明，丙咪嗪诱导的 Kv 通道抑制主要发生在关闭状态。丙咪嗪对 Kv 通道的抑制与 Kv1.5 通道有关，而与 Kv2.1 或 Kv7 通道无关。丙咪嗪对 Kv 通道的抑制导致血管收缩。从这些结果中，我们得出结论，丙咪嗪通过改变其门控特性，以浓度和使用（关闭状态）依赖性方式抑制血管 Kv 通道，而与自身功能无关。
