Tanshinone IIA: a new activator of human cardiac KCNQ1/KCNE1 (I(Ks)) potassium channels.
Tanshinone IIA, one of the main active components from Chinese herb Danshen, is widely used to treat cardiovascular diseases including arrhythmia in Asian countries especially in China. However, the mechanisms underlying its anti-arrythmia effects are not clear. In this study we investigate the effects of tanshinone IIA on human KCNQ1/KCNE1 potassium channels (I(Ks)), human ether-a-go-go-related gene potassium channels (hERG), Kv1.5 potassium channels, inward rectifier potassium channels (I(K1)) expressed in HEK 293 cells using patch clamp technique. Tanshinone IIA potently and reversibly enhanced the amplitude of I(Ks) in a concentration dependent manner with an EC(50) of 64.5 microM, accelerated the activation rate of I(Ks) channels, decelerated their deactivation and shifted the voltage dependence of I(Ks) activation to negative direction. Isoproteronol, a stimulator of beta-adrenergic receptor, at 1 microM and sodium nitroprusside (SNP), a NO donor, at 1 mM, had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a selective protein kinase A inhibitor, at 0.1 microM and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), a selective nitric oxide-sensitive guanylyl cyclase inhibitor, at 10 microM, also had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. Tanshinone IIA did not affect expressed hERG channels, Kv1.5 channels and I(K1) channels. These results indicate that tanshinone IIA directly and specifically activate human cardiac KCNQ1/KCNE1 potassium channels (I(Ks)) in HEK 293 cell through affecting the channels' kinetics.
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Dong-Dong
DD
Sun
Hai-Chang
HC
Wang
Xiao-Bin
XB
Wang
Ying
Y
Luo
Zhen-Xiao
ZX
Jin
Zhi-Chao
ZC
Li
Gui-Rong
GR
Li
Ming-Qing
MQ
Dong
D045784:Abietanes; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000187:drug effects*; D051666:Kv1.5 Potassium Channel / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D045784:Abietanes; D004365:Drugs, Chinese Herbal; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C496981:KCNA5 protein, human; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051666:Kv1.5 Potassium Channel; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010616:Phenanthrenes; D024642:Potassium Channels, Voltage-Gated; D011810:Quinoxalines; C021751:tanshinone; D017868:Cyclic AMP-Dependent Protein Kinases; D006162:Guanylate Cyclase