The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Inhibition of voltage-dependent K+ channels by antimuscarinic drug fesoterodine in coronary arterial smooth muscle cells

  • Park, Seojin (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine) ;
  • 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) ;
  • 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) ;
  • Park, Hongzoo (Institute of Medical Sciences, Department of Urology, Kangwon National University School of Medicine) ;
  • Park, Won Sun (Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine)
  • Received : 2022.07.18
  • Accepted : 2022.08.08
  • Published : 2022.09.01
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Abstract

Fesoterodine, an antimuscarinic drug, is widely used to treat overactive bladder syndrome. However, there is little information about its effects on vascular K+ channels. In this study, voltage-dependent K+ (Kv) channel inhibition by fesoterodine was investigated using the patch-clamp technique in rabbit coronary artery. In whole-cell patches, the addition of fesoterodine to the bath inhibited the Kv currents in a concentration-dependent manner, with an IC50 value of 3.19 ± 0.91 μM and a Hill coefficient of 0.56 ± 0.03. Although the drug did not alter the voltage-dependence of steady-state activation, it shifted the steady-state inactivation curve to a more negative potential, suggesting that fesoterodine affects the voltage-sensor of the Kv channel. Inhibition by fesoterodine was significantly enhanced by repetitive train pulses (1 or 2 Hz). Furthermore, it significantly increased the recovery time constant from inactivation, suggesting that the Kv channel inhibition by fesoterodine is use (state)-dependent. Its inhibitory effect disappeared by pretreatment with a Kv 1.5 inhibitor. However, pretreatment with Kv2.1 or Kv7 inhibitors did not affect the inhibitory effects on Kv channels. Based on these results, we conclude that fesoterodine inhibits vascular Kv channels (mainly the Kv1.5 subtype) in a concentration- and use (state)-dependent manner, independent of muscarinic receptor antagonism.

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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