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27.04.2019

Inhibitory Effect of Tricyclic Antidepressant Doxepin on Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

Zeitschrift:
Cardiovascular Toxicology
Autoren:
Hongliang Li, Hojung Kang, Jin Ryeol An, Mi Seon Seo, Won-Kyo Jung, Dae-Sung Lee, Grace Choi, Mi-Jin Yim, Jeong Min Lee, Young Min Bae, Youn Kyoung Son, Il-Whan Choi, Won Sun Park
Wichtige Hinweise
Handling Editor:Rajiv Janardhanan.

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s12012-019-09519-8) contains supplementary material, which is available to authorized users.
Hongliang Li and Hojung Kang contributed equally to this work.

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Abstract

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 (IC50) 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.

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