title: Peimine inhibits hERG potassium channels through the channel inactivation states.
abstract: OBJECTIVE
  Fritillaria is a Chinese traditional herb. It has a long history and many medicinal usages including antitussive, anti-inflammatory and pain relieving actions. It is also used as food. However, its cardiac safety has not been tested. Peimine is one of the main active compounds of Fritillaria. To be listed as an herb in the Chinese Pharmacopoeia, a special minimal percentage of Peimine in the dry sample of Fritillaria is required. The main concern for cardiac safety determination is the possible inhibition of hERG ion channels. Thus, Peimine was chosen to investigate its inhibitory effects on hERG channels.
  
  
  METHODS
  Whole cell patch clamp technique was used.
  
  
  CONCLUSIONS
  We found that Peimine inhibited the hERG peak tail currents in a concentration dependent manner with an IC50value of 43.7μM (n=4) by whole cell patch clamp techniques. Multiple results suggest that the inhibition was related to the channel inactivation. First, Peimine inhibition was significantly increased when the prepulse voltage was increased from -30mV to +10mV. Second, increasing prepulse length also significantly increased blockade by Peimine. Third, our finding that the inhibition by Peimine was use-dependent is related to changes in the inactivated state of the channel. Finally, the result that Peimine significantly decreased inactivation constant also suggested that Peimine affect the channel inactivation state. Mutation of Y652 to Alanine reduced sensitivity to Peimine, suggesting that Y652 is an important hERG binding sites for Peimine.
authors.affiliation: Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, PR China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Kan
authors.affiliation: Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China; The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China; The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China.
authors.forename: Lanying
authors.initials: L
authors.lastname: Pan
authors.affiliation: Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China; The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Xu
authors.affiliation: Safety Pharmacology Division, Olivepharmasolutions Ltd, 333 Changhong Road, Wukang 313200, PR China.
authors.forename: Qingmao
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Safety Pharmacology Division, Olivepharmasolutions Ltd, 333 Changhong Road, Wukang 313200, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
authors.affiliation: Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China; The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China; The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin'an 311300, PR China. Electronic address: ychen@zafu.edu.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D002595:Cevanes / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D018408:Patch-Clamp Techniques
chemical_list: D002595:Cevanes; D051638:Ether-A-Go-Go Potassium Channels; C014242:verticine
keywords: Cardiac safety; Fritillaria; Inactivation; Peimine; hERG