2. Academic Validation
  3. Norquetiapine blocks the human cardiac sodium channel Nav1.5 in a state-dependent manner

Norquetiapine blocks the human cardiac sodium channel Nav1.5 in a state-dependent manner

  • Eur J Pharmacol. 2020 Oct 15:885:173532. doi: 10.1016/j.ejphar.2020.173532.
Dong-Hyun Kim 1,  Kang-Sik Park 2,  See-Hyoung Park 3,  Sang June Hahn 4,  Jin-Sung Choi 5
Affiliations

Affiliations

  • 1 Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, South Korea; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, South Korea.
  • 2 Department of Physiology, Kyung Hee University School of Medicine, Seoul, 02447, South Korea.
  • 3 Department of Bio and Chemical Engineering, Hongik University, Sejong City, 30016, South Korea.
  • 4 Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
  • 5 Integrated Research Institute of Pharmaceutical Science, College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, South Korea. Electronic address: jinsung.choi@catholic.ac.kr.
PMID: 32882214 DOI: 10.1016/j.ejphar.2020.173532
Abstract

Quetiapine, an atypical antipsychotic drug, is used for the treatment of schizophrenia and acute mania. Although a previous report showed that quetiapine blocked hERG potassium current, quetiapine has been considered relatively safe in terms of cardiovascular side effects. In the present study, we used the whole-cell patch-clamp technique to investigate the effect that quetiapine and its major metabolite norquetiapine can exert on human cardiac sodium channels (hNav1.5). The half-maximal inhibitory concentrations of quetiapine and norquetiapine at a holding potential of -90 mV near the resting potential of cardiomyocytes were 30 and 6 μM, respectively. Norquetiapine as well as quetiapine was preferentially bound in the inactivated state of the hNav1.5 channel. Norquetiapine slowed the recovery from inactivation of hNav1.5 and consequently induced strong use-dependent inhibition. Our results indicate that norquetiapine blocks hNav1.5 current in concentration-, state- and use-dependent manners, suggesting that the blockade of hNav1.5 current by norquetiapine may shorten the cardiac action potential duration and reduce the risk of QT interval prolongation induced by the inhibition of hERG potassium currents.

Keywords

Cardiac arrhythmia; Na(v)1.5; Norquetiapine; Quetiapine; Voltage-gated sodium channel.

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