title: The effects of A-803467 on cardiac Nav1.5 channels.
abstract: A-803467 is a selective Nav1.8 blocker, but its mechanism of action at cardiac sodium channels is uncertain. Thus, we investigated the mechanistic effects of A-803467 on cardiac sodium channels in isolated mouse ventricular myocytes and in human embryonic kidney 293 (HEK293) cell lines that transiently expressed Nav1.5/SCN5A, the predominant cardiac sodium channel. At 0.3μM and greater, A-803467 blocked cardiac sodium currents in a dose-dependent manner in both ventricular myocytes and in SCN5A-expressing HEK293 cell lines. In both models, the drug caused significant depolarizing shifts at the conductance voltage relationship midpoint, hyperpolarizing shifts in voltage-dependent channel inactivation, and slower recovery from inactivation. Also, the drug reduced sodium current amplitude in a frequency-dependent manner, and blocked late sodium currents, accelerated inactivation, and enhanced the intermediate inactivation state. Our results provide strong evidence that A-803467 affects multiple biophysical characteristics of the canonical cardiac Nav1.5 channel and our data can be used to study potential applications of A-803467 as an antiarrhythmic drug.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China. Electronic address: njzyl165@126.com.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China. Electronic address: 328450715@qq.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China. Electronic address: xiao_ambition2012@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China. Electronic address: kjcao@njmu.edu.cn.
authors.forename: Kejiang
authors.initials: K
authors.lastname: Cao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China. Electronic address: david37212@hotmail.com.
authors.forename: Dao W
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D005663:Furans / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers
keywords: A-803467; A-803467 (PubChem CID: 16038374); Cardiac sodium current; Dimethyl sulfoxide (PubChem CID: 679); Lidocaine hydrochloride (PubChem CID: 6314); Mexiletine (PubChem CID: 4178); Mouse; Nickel chloride (PubChem CID: 24385); Nisoldipine (PubChem CID: 4499); Patch clamp; SCN5A; Sea anemone toxin II (ATX II) (PubChem CID: 56841750)