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天然黄酮Acacetin选择性抑制人心房去极化钾电流并防止实验狗的心房纤颤
发表日期: 2008-07-03
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背景: 开发选择性作用于心房的抗心律失常药物是治疗心房纤颤(简称房颤,或AF)的主要策略。本文研究来源于传统中药雪莲花中的黄酮化合物acacetin能否成为对心房有选择性的抗房颤药物。
方法与结果:用全细胞膜片技术研究acacetin对人心房肌细胞超快速激活钾离子电流及其它心脏离子电流的影响。研究表明acacetin抑制人心房肌细胞电流IKur及瞬间外向K+电流(IC50分别为3.2和9.2微摩尔/升),延长心房肌细胞动作电位时程。此外,该化合物在抑制由乙酰胆碱激活的豚鼠心肌细胞K+电流的时,对Na+电流,L-型Ca2+电流或内向整流性K+电流没有抑制作用。尽管acacetin可引起HEK 293细胞中表达的hERG和hKCNQ1/hKCNE1通道抑制,但不会延长离体兔子心脏心电图QT间期。在麻醉犬的实验中,我们发现十二指肠给药acacetin (5mg/kg)显著延长心房不应期1到4小时而不增加QT间期,而临床抗心律不齐药甲磺胺心定(sotalol)在延长心房不应期同时,增加QT间期。在急性犬房颤模型实验中,我们发现单次给药2.5-10毫克/公斤,显著防止房颤的发生,作用比甲磺胺 心定强。
结论:本研究表明天然化合物acacetin是一个对心房有选择性的抗房颤化合物,能够显著延长心房不应期而不增加QT间期,并且在麻醉犬十二指肠给药后能有效防止房颤的发生。这些研究结果表明acacetin是天然的高选择性抗房颤先导化合物,值得进一步研究和开发。
       秦国伟课题组自2003年始与香港大学医学院的李荣贵博士合作研究此课题。Acacetin的抗房颤作用为首次发现,目前已与香港大学联合申请美国专利,同时本研究成果已发表于国际著名杂志Circulation(117 2449-2457,2008;IF12.755),随后被《自然中国》作为研究亮点予以介绍( “Atrial fibrillation: Back in the rhythm”,Published online:11 June,2008)。
 
Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs
 
Gui-Rong Li, PhD; Hong-Bing Wang, PhD; Guo-Wei Qin, PhD; Man-Wen Jin, PhD; Qiang Tang, PhD; Hai-Ying Sun, BSc; Xin-Ling Du, MD, PhD; Xiu-Ling Deng, PhD; Xiao-Hua Zhang, MSc; Jing-Bo Chen, MSc; Lei Chen, MB; Xiao-Hui Xu, BSc; Lik-Cheung Cheng, MD; Shui-Wah Chiu, MD; Hung-Fat Tse, MD; Paul M. Vanhoutte, MD, PhD; Chu-Pak Lau, MD
 
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 (IKur) 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 µmol/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. (Circulation. 2008;117:2449-2457.)
 
(供稿部门:秦国伟课题组)
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