Inhibitory effects of the atypical antipsychotic, clozapine, on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells
Minji Kang1, Ryeon Heo1, Seojin Park1, Seo-Yeong Mun1, Minju Park1, Eun-Taek Han2, Jin-Hee Han2, Wanjoo Chun3, Kwon-Soo Ha4, Hongzoo Park5, Won-Kyo Jung6, Il-Whan Choi7, and Won Sun Park1,*
1Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, 2Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, 3Department of Pharmacology, Kangwon National University School of Medicine, 4Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, 5Institute of Medical Sciences, Department of Urology, Kangwon National University School of Medicine, Chuncheon 24341, 6Department of Biomedical Engineering and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan 48513, 7Department of Microbiology, College of Medicine, Inje University, Busan 48516, Korea
Author contributions: Conceptualization: M.K., R.H., I.C., and W.S.P. Writing – original draft: M.K., R.H., and W.J. Data curation: S.P. and J.H. Software: S.P., S.M., J.H., K.H., and H.P. Methodology: S.M., M.P., and W.C. Validation: M.P. Investigation: E.H., W.C., and K.H. Visualization: E.H. Supervision: W.C. Formal analysis: K.H. and H.P. Writing – review & editing: I.C. and W.S.P. Funding acquisition: I.C. and W.S.P.
Received: April 15, 2022; Revised: May 10, 2022; Accepted: May 16, 2022
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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 concentrationand 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.