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The transient receptor potential melastatin 4 channel inhibitor 9-phenanthrol modulates cardiac sodium channel.

Authors
  • Hou, Jian-Wen1
  • Fei, Yu-Dong1
  • Li, Wei1
  • Chen, Yi-He1
  • Wang, Qian1
  • Xiao, Ying1
  • Wang, Yue-Peng1
  • Li, Yi-Gang1
  • 1 Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. , (China)
Type
Published Article
Journal
British Journal of Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Dec 01, 2018
Volume
175
Issue
23
Pages
4325–4337
Identifiers
DOI: 10.1111/bph.14490
PMID: 30153324
Source
Medline
Language
English
License
Unknown

Abstract

9-Phenanthrol, known as a specific inhibitor of the transient receptor potential melastatin 4 (TRMP4) channel, has been shown to modulate cardiac electrical activity and exert antiarrhythmic effects. However, its pharmacological effects remain to be fully explored. Here, we tested the hypothesis that cardiac sodium current inhibition contributes to the cardioprotective effect of 9-phenanthrol. Single ventricular myocytes (VMs) and Purkinje cells (PCs) were enzymatically isolated from rabbits. Arterially perfused rabbit wedge preparations were also used, and transmural electrocardiogram and endocardial action potentials (APs) were simultaneously recorded. Wild-type and mutated human recombinant SCN5A were expressed in HEK293 cells. Anemonia toxin II (ATX-II) was used to amplify the late sodium current (INaL ) and induce arrhythmias. Whole-cell patch clamp technique was used to record APs and ionic currents. 9-Phenanthrol (10-50 μM) stabilized ventricular repolarization and abolished arrhythmias induced by ATX-II in both isolated VMs, PCs and wedge preparations. Further study revealed that 9-phenanthrol modulated the gating properties of cardiac sodium channels and dose-dependently inhibited INaL and peak sodium current (INaP ) in VMs with an IC50 of 18 and 71.5 μM respectively. Its ability to inhibit INaL was further confirmed in PCs and HEK293 cells expressing SCN5A mutations. Our results indicate that 9-phenanthrol modulates the gating properties of cardiac sodium channels and inhibits INaL and INaP , which may contribute to its antiarrhythmic and cardioprotective effects. © 2018 The British Pharmacological Society.

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