title: Allitridi inhibits multiple cardiac potassium channels expressed in HEK 293 cells.
abstract: Allitridi (diallyl trisulfide) is an active compound (volatile oil) from garlic. The previous studies reported that allitridi had anti-arrhythmic effect. The potential ionic mechanisms are, however, not understood. The present study was designed to determine the effects of allitridi on cardiac potassium channels expressed in HEK 293 cells using a whole-cell patch voltage-clamp technique and mutagenesis. It was found that allitridi inhibited hKv4.3 channels (IC(50) = 11.4 µM) by binding to the open channel, shifting availability potential to hyperpolarization, and accelerating closed-state inactivation of the channel. The hKv4.3 mutants T366A, T367A, V392A, and I395A showed a reduced response to allitridi with IC(50)s of 35.5 µM, 44.7 µM, 23.7 µM, and 42.4 µM. In addition, allitridi decreased hKv1.5, hERG, hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells with IC(50)s of 40.2 µM, 19.6 µM and 17.7 µM. However, it slightly inhibited hKir2.1 current (100 µM, inhibited by 9.8% at -120 mV). Our results demonstrate for the first time that allitridi preferably blocks hKv4.3 current by binding to the open channel at T366 and T367 of P-loop helix, and at V392 and I395 of S6 domain. It has a weak inhibition of hKv1.5, hERG, and hKCNQ1/hKCNE1 currents. These effects may account for its anti-arrhythmic effect observed in experimental animal models.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Xu
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Sun
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Kui-Hao
authors.initials: KH
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Deng
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Man-Wen
authors.initials: MW
authors.lastname: Jin
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D018929:Cell Culture Techniques; D004594:Electrophysiology / Q000379:methods; D005737:Garlic / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D015233:Models, Statistical; D009822:Oils, Volatile; D010936:Plant Extracts / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051672:Shal Potassium Channels / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D000975:Antioxidants; C489461:Kir2.1 channel; D051666:Kv1.5 Potassium Channel; D009822:Oils, Volatile; D010936:Plant Extracts; D024661:Potassium Channels, Inwardly Rectifying; D051672:Shal Potassium Channels; D013440:Sulfides; C042577:diallyl trisulfide