Department of Physiology, Kangwon National University School of Medicine, 1 Kangwondaehak-gil, Chuncheon, 24341, South Korea.
Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea.
Cardiovasc Toxicol. 2019 Oct;19(5):465-473. doi: 10.1007/s12012-019-09519-8.
Doxepin, tricyclic antidepressant, is widely used for the treatment of depressive disorders. Our present study determined the inhibitory effect of doxepin on voltage-dependent K (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Vascular Kv currents were inhibited by doxepin in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC) value of 6.52 ± 1.35 μM and a Hill coefficient of 0.72 ± 0.03. Doxepin did not change the steady-state activation curve or inactivation curve, suggesting that doxepin does not alter the gating properties of Kv channels. Application of train pulses (1 or 2 Hz) slightly reduced the amplitude of Kv currents. However, the inhibition of Kv channels by train pulses were not changed in the presence of doxepin. Pretreatment with Kv1.5 inhibitor, DPO-1, effectively reduced the doxepin-induced inhibition of the Kv current. However, pretreatment with Kv2.1 inhibitor (guangxitoxin) or Kv7 inhibitor (linopirdine) did not change the inhibitory effect of doxepin on Kv currents. Inhibition of Kv channels by doxepin caused vasoconstriction and membrane depolarization. Therefore, our present study suggests that doxepin inhibits Kv channels in a concentration-dependent, but not use-, and state-dependent manners, irrespective of its own function.
多塞平，三环类抗抑郁药，广泛用于治疗抑郁障碍。本研究采用全细胞膜片钳技术，研究了多塞平对新鲜分离的兔冠状动脉血管平滑肌细胞电压依赖性钾（Kv）通道的抑制作用。多塞平呈浓度依赖性抑制血管 Kv 电流，半数抑制浓度（IC）值为 6.52±1.35 μM，Hill 系数为 0.72±0.03。多塞平不改变 Kv 通道的稳态激活曲线或失活曲线，表明多塞平不改变 Kv 通道的门控特性。应用串脉冲（1 或 2 Hz）可轻微减小 Kv 电流的幅度。然而，在多塞平存在的情况下，串脉冲对 Kv 通道的抑制作用没有改变。Kv1.5 抑制剂 DPO-1 的预处理可有效降低多塞平诱导的 Kv 电流抑制。然而，Kv2.1 抑制剂（广息痛）或 Kv7 抑制剂（利诺吡啶）的预处理不能改变多塞平对 Kv 电流的抑制作用。多塞平抑制 Kv 通道引起血管收缩和膜去极化。因此，本研究表明，多塞平以浓度依赖性而非使用依赖性和状态依赖性方式抑制 Kv 通道，与其自身功能无关。
