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Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells

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Abstract

We describe the effect of a tricyclic antidepressant drug desipramine on voltage-dependent K+ (Kv) currents in freshly isolated rabbit coronary arterial smooth muscle cells using a conventional whole-cell patch clamp technique. Application of desipramine rapidly decreased the Kv current amplitude in a concentration-dependent manner, with an IC50 value of 5.91 ± 0.18 μM and a Hill coefficient of 0.61 ± 0.09. The steady-state inactivation curves of the Kv channels were not affected by desipramine. However, desipramine shifted the steady-state inactivation curves toward a more negative potential. Application of train pulses (1 or 2 Hz) slightly reduced the Kv current amplitude. Such reduction in the Kv current amplitude by train pulses increased in the presence of desipramine. Furthermore, the inactivation recovery time constant was also increased in the presence of desipramine, suggesting that desipramine-induced inhibition of the Kv current was use-dependent. Application of a Kv1.5 inhibitor (DPO-1) and/or a Kv2.1 inhibitor (guangxitoxin) did not change the inhibitory effect of desipramine on Kv currents. Based on these results, we concluded that desipramine directly inhibited the Kv channels in a dose- and state-dependent manner, but the effect was independent of norepinephrine/serotonin reuptake inhibition.

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References

  1. DeVane, C. L. (1998). Differential pharmacology of newer antidepressants. Journal of Clinical Psychiatry, 59, 85–93.

    Article  PubMed  CAS  Google Scholar 

  2. Von Wolff, A., Hölzel, L. P., Westphal, A., Härter, M., & Kriston, L. (2013). Selective serotonin reuptake inhibitors and tricyclic antidepressants in the acute treatment of chronic depression and dysthymia: A systematic review and meta-analysis. Journal of Affective Disorders, 144, 7–15.

    Article  CAS  Google Scholar 

  3. Luo, L., Xie, Y., Wang, A., Liu, X., Xiao, F., Zhong, X., et al. (2014). Desipramine ameliorates Cr(VI)-induced hepatocellular apoptosis via the inhibition of ceramide channel formation and mitochondrial PTP opening. Cellular Physiology and Biochemistry, 34, 2128–2136.

    Article  PubMed  CAS  Google Scholar 

  4. Brielmaier, J., Senerth, J. M., Silverman, J. L., Matteson, P. G., Millonig, J. H., DiCicco-Bloom, E., et al. (2014). Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice. Genes, Brain and Behavior, 13, 286–298.

    Article  CAS  Google Scholar 

  5. Mokhber, N., Abdollahian, E., Soltanifar, A., Samadi, R., Saghebi, A., Haghighi, M. B., et al. (2014). Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. Pharmacopsychiatry, 47, 131–140.

    Article  PubMed  CAS  Google Scholar 

  6. Rudorfer, M. V., & Young, R. C. (1980). Anticholinergic effects and plasma desipramine levels. Clinical Pharmacology and Therapeutics, 28, 703–705.

    Article  PubMed  CAS  Google Scholar 

  7. White, N. C., Litovitz, T., & Clancy, C. (2008). Suicidal antidepressant overdoses: A comparative analysis by antidepressant type. Journal of Medical Toxicology, 4, 238–250.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zahradnik, I., Minarovic, I., & Zahradniková, A. (2008). Inhibition of the cardiac L-type calcium channel current by antidepressant drugs. Journal of Pharmacology and Experimental Therapeutics, 324, 977–984.

    Article  PubMed  CAS  Google Scholar 

  9. Staudacher, I., Wang, L., Wan, X., Obers, S., Wenzel, W., Tristram, F., et al. (2011). hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine. Naunyn-Schmiedeberg’s Archives of Pharmacology, 383, 119–139.

    Article  PubMed  CAS  Google Scholar 

  10. Dick, G. M., Bratz, I. Z., Borbouse, L., Payne, G. A., Dincer, U. D., Knudson, J. D., et al. (2008). Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation. American Journal of Physiology Heart and Circulatory Physiology, 294, 2371–2381.

    Article  CAS  Google Scholar 

  11. Li, H., Hong, D. H., Kim, H. S., Kim, H. W., Jung, W. K., Na, S. H., et al. (2015). The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. Toxicology and Applied Pharmacology, 15, 207–213.

    Article  CAS  Google Scholar 

  12. Nelson, M. T., & Quayle, J. M. (1995). Physiological roles and properties of potassium channels in arterial smooth muscle. American Journal of Physiology, 268, 799–822.

    Article  Google Scholar 

  13. Ko, E. A., Han, J., Jung, I. D., & Park, W. S. (2008). Physiological roles of K+ channels in vascular smooth muscle cells. Journal of Smooth Muscle Research, 44, 65–81.

    Article  PubMed  Google Scholar 

  14. Shimoda, L. A., Sylvester, J. T., & Sham, J. S. (1998). Inhibition of voltage-dependent K+ currents in rat intrapulmonary arterial myocytes by endothelin-1. American Journal of Physiology, 274, 842–853.

    Google Scholar 

  15. Bae, Y. M., Kim, A., Kim, J., Park, W. S., Kim, T. K., Lee, Y. R., et al. (2006). Serotonin depolarizes the membrane potential in rat mesenteric artery myocytes by decreasing voltage-gated K+ currents. Biochemical and Biophysical Research Communications, 347, 468–476.

    Article  PubMed  CAS  Google Scholar 

  16. Doyon, G., & Bruemmer, D. (2016). Vascular smooth muscle cell dysfunction in diabetes: Nuclear receptors channel to relaxation. Clinical Science, 130, 1837–1839.

    Article  PubMed  CAS  Google Scholar 

  17. Liu, Y., & Gutterman, D. D. (2002). The coronary circulation in diabetes: Influence of reactive oxygen species on K+ channel-mediated vasodilation. Vascular Pharmacology, 38, 43–49.

    Article  PubMed  CAS  Google Scholar 

  18. Archer, S. L., London, B., Hampl, V., Wu, X., Nsair, A., Puttagunta, L., et al. (2001). Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage-gated potassium channel Kv1.5. The FASEB Journal, 15, 1801–1803.

    Article  PubMed  CAS  Google Scholar 

  19. Cox, R. H., Folander, K., & Swanson, R. (2001). Differential expression of voltage-gated K+ channel genes in arteries from spontaneously hypertensive and Wistar-Kyoto rats. Hypertension, 37, 1315–1322.

    Article  PubMed  CAS  Google Scholar 

  20. Gillman, P. K. (2007). Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology, 151, 737–748.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lin, Z. Y., Chen, L. M., Zhang, J., Pan, X. D., Zhu, Y. G., Ye, Q. Y., et al. (2012). Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons. Acta Pharmacologica Sinica, 33, 438–444.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Wu, S. N., Hsu, M. C., Liao, Y. K., Wu, F. T., Jong, Y. J., & Lo, Y. C. (2012). Evidence for inhibitory effects of flupirtine, a centrally acting analgesic, on delayed rectifier K+ currents in motor neuron-like cells. Evidence-Based Complementary and Alternative Medicine, 2012, 148–403.

    Google Scholar 

  23. Kim, J. M., Park, W. S., Lin, H. Y., Shin, K. C., Sung, D. J., Kim, J. G., et al. (2015). Blockade of voltage-gated K+ currents in rat mesenteric arterial smooth muscle cells by MK801. Journal of Pharmacological Sciences, 127, 92–102.

    Article  PubMed  CAS  Google Scholar 

  24. Kim, H. S., Li, H., Kim, H. W., Shin, S. E., Jung, W. K., Ha, K. S., et al. (2017). The selective serotonin reuptake inhibitor dapoxetine inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. Clinical and Experimental Pharmacology and Physiology, 44, 480–487.

    Article  PubMed  CAS  Google Scholar 

  25. Carignani, C., & Corsi, M. (2002). Inhibition of SK3 channels in the TE671 human medulloblastoma cell line by desipramine and imipramine. European Journal of Pharmacology, 448, 139–142.

    Article  PubMed  CAS  Google Scholar 

  26. Shin, S. E., Li, H., Kim, H. S., Kim, H. W., Seo, M. S., Ha, K. S., et al. (2017). Nortriptyline, a tricyclic antidepressant, inhibits voltage-dependent K+ channels in coronary arterial smooth muscle cells. The Korean Journal of Physiology & Pharmacology, 21, 225–232.

    Article  Google Scholar 

  27. Kim, H. S., Li, H., Kim, H. W., Shin, S. E., Choi, I. W., Firth, A. L., et al. (2016). Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. Journal of Biosciences, 41, 659–666.

    Article  PubMed  CAS  Google Scholar 

  28. Hong, D. H., Li, H., Kim, H. S., Kim, H. W., Shin, S. E., Jung, W. K., et al. (2015). The effects of the selective serotonin reuptake inhibitor fluvoxamine on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. Biological and Pharmaceutical Bulletin, 38, 1208–1213.

    Article  PubMed  CAS  Google Scholar 

  29. Kim, H. S., Li, H., Kim, H. W., Shin, S. E., Seo, M. S., An, J. R., et al. (2017). Escitalopram, a selective serotonin reuptake inhibitor, inhibits voltage-dependent K+ channels in coronary arterial smooth muscle cells. The Korean Journal of Physiology & Pharmacology, 21, 415–421.

    Article  Google Scholar 

  30. Xu, C., Lu, Y., Tang, G., & Wang, R. (1999). Expression of voltage-dependent K+ channel genes in mesenteric artery smooth cells. American Journal of Physiology, 277, 1055–1063.

    Google Scholar 

  31. Yuan, X. J., Wang, J., Juhaszova, M., Golovina, V. A., & Rubin, L. J. (1998). Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells. American Journal of Physiology, 274, 621–635.

    Google Scholar 

  32. Nichols, A. I., Abell, M., Chen, Y., Behrle, J. A., Frick, G., Paul, J., et al. (2013). Effect of desvenlafaxine on the pharmacokinetics of desipramine in healthy adults. International Clinical Psychopharmacology, 28, 99–105.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (Ministry of Education: 2016-R1D1A3B03930169) (Ministry of Science, ICT and Future Planning: 2015-R1A4A1038666).

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Author notes

  1. Sung Eun Shin and Hongliang Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Kangwon National University School of Medicine, 1 Kangwondaehak-gil, Chuncheon, 24341, South Korea

    Sung Eun Shin, Hongliang Li, Jin Ryeol An, Mi Seon Seo & Won Sun Park

  2. Department of Obstetrics and Gynecology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea

    Sung Hun Na

  3. Department of Biomedical Engineering and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea

    Won-Kyo Jung

  4. Department of Pulmonary, Critical Care and Sleep Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, 90033, USA

    Amy L. Firth

  5. Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea

    Kwon-Soo Ha

  6. Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea

    Eun-Taek Han

  7. Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea

    Seok-Ho Hong

  8. Department of Microbiology, College of Medicine, Inje University, Busan, 48516, South Korea

    Il-Whan Choi

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  1. Sung Eun Shin
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Correspondence to Won Sun Park.

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Shin, S.E., Li, H., An, J.R. et al. Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells. Cardiovasc Toxicol 18, 252–260 (2018). https://doi.org/10.1007/s12012-017-9435-x

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