Inhibitory effects of the atypical antipsychotic, clozapine, on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells
10.4196/kjpp.2022.26.4.277
- Author:
Minji KANG
1
;
Ryeon HEO
;
Seojin PARK
;
Seo-Yeong MUN
;
Minju PARK
;
Eun-Taek HAN
;
Jin-Hee HAN
;
Wanjoo CHUN
;
Kwon-Soo HA
;
Hongzoo PARK
;
Won-Kyo JUNG
;
Il-Whan CHOI
;
Won Sun PARK
Author Information
1. Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Korea
- Publication Type:Original Article
- From:The Korean Journal of Physiology and Pharmacology
2022;26(4):277-285
- CountryRepublic of Korea
- Language:English
-
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 halfinhibitory 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 clozapineinduced 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 clozapineinduced inhibition of Kv channels, and Kv2.1 and Kv7 subtypes are partially involved.
