title: 18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels.
abstract: OBJECTIVE
  To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na(+) current, HERG and Kv1.5 channel currents.
  
  
  METHODS
  Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ΔKPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents.
  
  
  RESULTS
  Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1-100 μmol/L) blocked both the peak current (I(Na,P)) and late current (I(Na,L)) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked I(Na,L) (IC(50)=37.2 ± 14.4 μmol/L) to I(Na,P) (IC(50)=100.4 ± 11.2 μmol/L) generated by ΔKPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of I(Na,P) and 87% of I(Na,L) induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents.
  
  
  CONCLUSIONS
  18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels.
authors.affiliation: Ion Channelopathy Research Center, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yi-mei
authors.initials: YM
authors.lastname: Du
authors.forename: Cheng-kun
authors.initials: CK
authors.lastname: Xia
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Jia-hong
authors.initials: JH
authors.lastname: Xia
mesh_terms: D000818:Animals; D000075224:Cardiac Conduction System Disease; D002478:Cells, Cultured; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013237:Stereoisomerism; D014981:Xenopus
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496981:KCNA5 protein, human; C000606913:KCNH2 protein, human; D051666:Kv1.5 Potassium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; C119129:18alpha-glycyrrhetinic acid; D012964:Sodium; D006034:Glycyrrhetinic Acid