Aconitine blocks HERG and Kv1.5 potassium channels.
BACKGROUND
Aconitum has been widely used to treat various diseases in China for a long time. However, improper use of this drug results in severe intoxication. Aconitine (ACO), a diterpenoid alkaloid from aconitum, mainly contributes to cardio-toxic effects of aconitum and has also been commonly known to induce arrhythmias in animal models. However, its pro-arrhythmic mechanisms are not clear.


OBJECTIVE
The effects of ACO on HERG and Kv1.5 channels were investigated.


METHODS
HERG and Kv1.5 channels were expressed in Xenopus laevis oocytes, and the resulting currents were recorded using a two-microelectrode voltage clamp technique.


RESULTS
In HERG channels, ACO exhibited a blockade in a voltage- and time-dependent manner. The blockade was enhanced by further activation of currents, which were consistent with an open-channel blockade. In Kv1.5 channels, ACO produced a voltage-, time-, and frequency-dependent inhibition. The blockade was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state. In addition, ACO blocked Kv1.5 and HERG channels in a concentration-dependent manner with an IC(50) of 0.796+/-0.123 and 1.801+/-0.332 microM, respectively.


CONCLUSIONS
ACO blocks HERG and Kv1.5 potassium channels in the open state. Blockade of potassium channels, particular the HERG channel, may be one of the important mechanisms of how ACO induces arrhythmias.
Li
Yifu
Y
Ion Channelopathy Research Center, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.
Tu
Danna
D
Xiao
Hua
H
Du
Yimei
Y
Zou
Anruo
A
Liao
Yuhua
Y
Dong
Shaohong
S
D000157:Aconitine / Q000494:pharmacology*; D000818:Animals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D014982:Xenopus laevis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D000157:Aconitine