Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs.
BACKGROUND
The development of atrium-selective antiarrhythmic agents is a current strategy for inhibiting atrial fibrillation (AF). The present study investigated whether the natural flavone acacetin from the traditional Chinese medicine Xuelianhua would be an atrium-selective anti-AF agent.


RESULTS
The effects of acacetin on human atrial ultrarapid delayed rectifier K(+) current (I(Kur)) and other cardiac ionic currents were studied with a whole-cell patch technique. Acacetin suppressed I(Kur) and the transient outward K(+) current (IC(50) 3.2 and 9.2 mumol/L, respectively) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K(+) current; however, it had no effect on the Na(+) current, L-type Ca(2+) current, or inward-rectifier K(+) current in guinea pig cardiac myocytes. Although acacetin caused a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin (5 mg/kg) prolonged the atrial effective refractory period in both the right and left atria 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol at 5 mg/kg prolonged both the atrial effective refractory period and the corrected QT interval. Acacetin prevented AF induction at doses of 2.5 mg/kg (50%), 5 mg/kg (85.7%), and 10 mg/kg (85.7%). Sotalol 5 mg/kg also prevented AF induction (60%).


CONCLUSIONS
The present study demonstrates that the natural compound acacetin is an atrium-selective agent that prolongs the atrial effective refractory period without prolonging the corrected QT interval and effectively prevents AF in anesthetized dogs after intraduodenal administration. These results indicate that oral acacetin is a promising atrium-selective agent for the treatment of AF.
Li
Gui-Rong
GR
Department of Medicine, Li Ka Shing Faculty of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Rd, Pokfulam, Hong Kong SAR, China. grli@hkucc.hku.hk
Wang
Hong-Bing
HB
Qin
Guo-Wei
GW
Jin
Man-Wen
MW
Tang
Qiang
Q
Sun
Hai-Ying
HY
Du
Xin-Ling
XL
Deng
Xiu-Ling
XL
Zhang
Xiao-Hua
XH
Chen
Jing-Bo
JB
Chen
Lei
L
Xu
Xiao-Hui
XH
Cheng
Lik-Cheung
LC
Chiu
Shui-Wah
SW
Tse
Hung-Fat
HF
Vanhoutte
Paul M
PM
Lau
Chu-Pak
CP
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000517:prevention & control*; D016275:Atrial Function / Q000187:drug effects; D002478:Cells, Cultured; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006801:Humans; D008516:Medicine, Chinese Traditional; D032383:Myocytes, Cardiac; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D047309:Flavones; C023717:acacetin; D011188:Potassium