Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs
Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs
复制标题
DOI：
10.1161/circulationaha.108.769554
复制
发表时间：
2008-05-13
期刊：
影响因子：
37.8
通讯作者：
Lau, Chu-Pak
中科院分区：
文献类型：
--
作者：
Li, Gui-Rong;Wang, Hong-Bing;Lau, Chu-Pak
心房选择性抗心律失常药物的开发是目前抑制心房颤动（AF）的策略。本研究探讨中药雪莲花中的天然黄酮金合欢素是否会成为一种心房选择性抗房颤药物。方法和结果-采用全细胞贴片技术研究金合欢素对人心房超速延迟整流K+电流（I-Kur）和其他心脏离子电流的影响。金合欢素抑制IKur和瞬时外向钾电流（IC_（50）分别为3.2和9.2 μ mol/L），延长人心房肌细胞动作电位时程。该化合物阻断乙酰胆碱激活的K+电流;然而，它对豚鼠心肌细胞的Na+电流、L型Ca 2+电流或内向整流K+电流没有影响。虽然金合欢素引起HEK 293细胞中稳定表达的hERG和hKCNQ 1/hKCNE 1通道的微弱减少，但它并不延长兔心脏的校正QT间期。在麻醉犬中，阿卡西丁（5 mg/kg）在十二指肠内给药后1 - 4小时延长了右心房和左心房的心房有效不应期，而未延长校正的QT间期，而索他洛尔5 mg/kg延长了心房有效不应期和校正的QT间期。在2.5 mg/kg（50%）、5 mg/kg（85.7%）和10 mg/ kg（85.7%）剂量下，金合欢素可预防AF诱导。索他洛尔5 mg/ kg也可预防AF诱导（60%）。结论-本研究表明，天然化合物金合欢素是一种心房选择性药物，在十二指肠内给药后，可延长心房有效不应期而不延长校正QT间期，并有效预防麻醉犬的AF。这些结果表明，口服金合欢素是一种很有前途的心房选择性药物，用于治疗AF。
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.Methods and 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 IKur and the transient outward K+ current (IC50 3.2 and 9.2 mu mol/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 Ca2+ 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.