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Inhibition by Imipramine of the Voltage-Dependent K+ Channel in Rabbit Coronary Arterial Smooth Muscle Cells.

Toxicological sciences : an official journal of the Society of Toxicology (2020-10-04)
Jin Ryeol An, Mi Seon Seo, Hee Seok Jung, Ryeon Heo, Minji Kang, Eun-Taek Han, Hongzoo Park, Won-Kyo Jung, Il-Whan Choi, Won Sun Park
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Diphenylphosphine, 98%
Sigma-Aldrich
Linopirdine, ≥98% (HPLC)
Sigma-Aldrich
DPO-1, needles, >97% (NMR)