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KMID : 0811720220260050397
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Korean Journal of Physiology & Pharmacology
2022 Volume.26 No. 5 p.397 ~ p.404
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Inhibition of voltage-dependent K+ channels by antimuscarinic drug fesoterodine in coronary arterial smooth muscle cells
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Park Seo-Jin
Kang Min-Ji
Heo Ryeon
Mun Seo-Yeong
Park Min-Ju
Han Eun-Taek
Han Jin-Hee
Chun Wan-Joo
Park Hong-Zoo
Park Won-Sun
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Abstract
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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.
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KEYWORD
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Coronary artery, Fesoterodine, Kv potassium channel, Kv1.5 potassium channel, Use-dependence
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