title: Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis.
abstract: Liensinine and neferine, a kind of isoquinoline alkaloid, can antagonize the ventricular arrhythmias. The human ether-a-go-go-related gene (hERG) is involved in repolarization of cardiac action potential. We investigated the effects of liensinine and neferine on the biophysical properties of hERG channel and the underlying structure-activity relationships. The effects of liensinine and neferine were examined on the hERG channels in the stable transfected HEK293 cells using a whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. The pharmacokinetics and tissue distribution determination of liensinine and neferine in rats were determined by a validated RP-HPLC method. Liensinine and neferine induced decrease of current amplitude in dose-dependent. Liensinine reduced hERG tail current from 70.3±6.3 pA/pF in control group to 56.7±2.8 pA/pF in the 1 μM group, 53.0±2.3 pA/pF (3 μM) and 17.8±0.7 pA/pF (30 μM); the corresponding current densities of neferine-treated cells were 41.9±3.1 pA/pF, 32.3±3.1 pA/pF and 16.2±0.6 pA/pF, respectively. Neferine had binding affinity for the open and inactivated state of hERG channel, liensinine only bound to the open state. The inhibitory effects of liensinine and neferine on hERG current were attenuated in the F656V or Y652A mutant channels. Neferine distributed more quickly than liensinine in rats, which was found to be in higher concentration than liensinine. Both liensinine and neferine had no effect on the generation and expression of hERG channels. In conclusion, neferine is a more potent blocker of hERG channels than liensinine at low concentration (<10 μM), which may be due to higher hydrophobic nature of neferine compared with liensinine. Neferine may be safety even for long-term treatment as an antiarrhythmic drug.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin.
authors.forename: Zeng-Xiang
authors.initials: ZX
authors.lastname: Dong
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Dong-Fang
authors.initials: DF
authors.lastname: Gu
authors.forename: Yuan-Qi
authors.initials: YQ
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Xing-Xia
authors.initials: XX
authors.lastname: Hu
authors.forename: Mei-Qin
authors.initials: MQ
authors.lastname: Hu
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Yang
authors.forename: Bao-Xin
authors.initials: BX
authors.lastname: Li
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D051638:Ether-A-Go-Go Potassium Channels; D007546:Isoquinolines; D010636:Phenols; D026902:Potassium Channel Blockers; C057222:neferine; C080095:liensinine