The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Inhibitory effects of the atypical antipsychotic, clozapine, on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells

  • Kang, Minji (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • Heo, Ryeon (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • Park, Seojin (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • Mun, Seo-Yeong (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • Park, Minju (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • Han, Eun-Taek (Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine) ;
  • Han, Jin-Hee (Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine) ;
  • Chun, Wanjoo (Department of Pharmacology, Kangwon National University School of Medicine) ;
  • Ha, Kwon-Soo (Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicin) ;
  • Park, Hongzoo (Institute of Medical Sciences, Department of Urology, Kangwon National University School of Medicine) ;
  • Jung, Won-Kyo (Department of Biomedical Engineering and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University) ;
  • Choi, Il-Whan (Department of Microbiology, College of Medicine, Inje University) ;
  • Park, Won Sun (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine)
  • Received : 2022.04.15
  • Accepted : 2022.05.16
  • Published : 2022.07.01
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Abstract

To investigate the adverse effects of clozapine on cardiovascular ion channels, we examined the inhibitory effect of clozapine on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Clozapine-induced inhibition of Kv channels occurred in a concentration-dependent manner with an half-inhibitory concentration value of 7.84 ± 4.86 µM and a Hill coefficient of 0.47 ± 0.06. Clozapine did not shift the steady-state activation or inactivation curves, suggesting that it inhibited Kv channels regardless of gating properties. Application of train pulses (1 and 2 Hz) progressively augmented the clozapine-induced inhibition of Kv channels in the presence of the drug. Furthermore, the recovery time constant from inactivation was increased in the presence of clozapine, suggesting that clozapine-induced inhibition of Kv channels is use (state)-dependent. Pretreatment of a Kv1.5 subtype inhibitor decreased the Kv current amplitudes, but additional application of clozapine did not further inhibit the Kv current. Pretreatment with Kv2.1 or Kv7 subtype inhibitors partially blocked the inhibitory effect of clozapine. Based on these results, we conclude that clozapine inhibits arterial Kv channels in a concentration-and use (state)-dependent manner. Kv1.5 is the major subtype involved in clozapine-induced inhibition of Kv channels, and Kv2.1 and Kv7 subtypes are partially involved.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2021-R1F1A1045544, 2021-R1A4A1031574).

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