2. Academic Validation
  3. Suppression of voltage-gated K+ channels by darifenacin in coronary arterial smooth muscle cells

Suppression of voltage-gated K+ channels by darifenacin in coronary arterial smooth muscle cells

  • Eur J Pharmacol. 2021 Jan 15:891:173707. doi: 10.1016/j.ejphar.2020.173707.
Mi Seon Seo 1,  Jin Ryeol An 1,  Hee Seok Jung 1,  Minji Kang 1,  Ryeon Heo 1,  Eun-Taek Han 2,  Se-Ran Yang 3,  Hongzoo Park 4,  Won-Kyo Jung 5,  Il-Whan Choi 6,  Young Min Bae 7,  Sung Hun Na 8,  Won Sun Park 9
Affiliations

Affiliations

  • 1 Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea.
  • 2 Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea.
  • 3 Department of Thoracic and Cardiovascular Surgery, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea.
  • 4 Department of Urology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea.
  • 5 Department of Biomedical Engineering, and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan, 48513, South Korea.
  • 6 Department of Microbiology, College of Medicine, Inje University, Busan, 48516, South Korea.
  • 7 Department of Physiology, Konkuk University School of Medicine, Chungju, 27478, South Korea.
  • 8 Department of Obstetrics and Gynecology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea. Electronic address: lahun@kangwon.ac.kr.
  • 9 Department of Physiology, Kangwon National University School of Medicine, Chuncheon, 24341, South Korea. Electronic address: parkws@kangwon.ac.kr.
PMID: 33137332 DOI: 10.1016/j.ejphar.2020.173707
Abstract

Darifenacin, an anticholinergic agent, has been used to treat overactive bladder syndrome. Despite its extensive clinical use, there is little information about the effect of darifenacin on vascular ion channels, specifically K+ channels. This study aimed to investigate the effect of the anti-muscarinic drug darifenacin on voltage-gated K+ (Kv) channels, vascular contractility, and coronary blood flow in rabbit coronary arteries. We used the whole-cell patch-clamp technique to evaluate the effect of darifenacin on Kv channels. Darifenacin inhibited the Kv current in a concentration-dependent manner. Applying 1 μM darifenacin shifted the activation and inactivation curves toward a more positive and negative potential, respectively. Darifenacin slowed the time constants of recovery from inactivation. Furthermore, blockade of the Kv current with darifenacin was increased gradually by applying a train of pulses, indicating that darifenacin inhibited Kv currents in a use- (state)-dependent manner. The darifenacin-mediated inhibition of Kv currents was associated with the Kv1.5 subtype, not the Kv2.1 or Kv7 subtype. Applying another anti-muscarinic drug atropine or ipratropium did not affect the Kv current or change the inhibitory effect of darifenacin. Isometric organ bath experiments using isolated coronary arteries were applied to evaluate whether darifenacin-induced inhibition of the Kv channel causes vasocontraction. Darifenacin substantially induced vasocontraction. Furthermore, darifenacin caused membrane depolarization and decreased coronary blood flow. From these results, we concluded that darifenacin inhibits the Kv currents in concentration- and use- (state)-dependent manners. Inhibition of the Kv current with darifenacin occurred by shifting the steady-state activation and inactivation curves regardless of its anti-muscarinic effect.

Keywords

Coronary arterial smooth muscle cell; Darifenacin; Patch-clamp; Voltage-gated K(+) channel.

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