Searching for synergistic calcium antagonists and novel therapeutic regimens for coronary heart disease therapy from a Traditional Chinese Medicine, Suxiao Jiuxin Pill
Searching for synergistic calcium antagonists and novel therapeutic regimens for coronary heart disease therapy from a Traditional Chinese Medicine, Suxiao Jiuxin Pill
复制标题
从中药速效救心丸中寻找协同钙拮抗剂和治疗冠心病的新疗法
DOI：
10.1016/j.jchromb.2018.06.015
复制
发表时间：
2018-08-15
影响因子：
3
通讯作者：
Bai, Gang
中科院分区：
文献类型：
--
作者：
Lei, Wei;Ni, Jianan;Bai, Gang
冠心病是世界范围内发病率和死亡率的重要原因，钙通道阻滞剂(CCB)是治疗心血管疾病的重要药物。速消救心丸(SX)是一种传统中药，广泛用于冠心病的急诊治疗。然而，了解其在细胞内钙离子浓度([Ca~(2+)](I))调节中的潜在机制仍然是一个挑战。为了鉴定有效的药理成分(APIs)，揭示一种改善心血管疾病的新的联合治疗方法，采用超高效液相色谱/四极杆飞行时间质谱仪(UPLC/Q-TOF MS)结合双荧光素酶报告[Ca~(2+)](I)检测系统。川芎嗪、阿魏酸、番泻内酯I、番泻内酯A和川芎内酯是SX中潜在的钙拮抗剂，川芎嗪与番泻内酯A配伍具有协同的钙拮抗活性。此外，通过监测荧光变化，用钙离子指示剂Fluo-4/AM进行实时成像分析，进一步探讨了协同作用的机理。结果表明，川芎嗪能有效阻断电压依赖性钙通道(VDCCs)，番泻内酯A对RYRs抑制作用最强，对VDCCs有部分抑制作用。最后，动脉环实验表明，川芎嗪和番泻叶内酯A合用比单独使用任何成分都有更好的血管扩张作用。在这项研究中，我们首次揭示了一对天然API联合作用于VDCC和RYRs，通过调节[Ca~(2+)](I)来更有效地扩张血管。
Coronary heart disease is a vital cause of morbidity and mortality worldwide, and calcium channel blockers (CCBs) are important drugs that can be used to treat cardiovascular diseases. Suxiao Jiuxin Pill (SX), a traditional Chinese medicine, is widely used as an emergency drug for coronary heart disease therapy. However, understanding its potential mechanism in intracellular calcium concentration ([Ca2+](i)) modulation remains a challenge. To identify the active pharmacological ingredients (APIs) and reveal a novel combination therapy for ameliorating cardiovascular diseases, the ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) combined with a dual-luciferase reporter [Ca2+](i) assay system was applied. Ligustrazine, ferulic acid, senkyunolide I, senkyunolide A and ligustilide were identified as potential calcium antagonists in SX, and the combination of ligustrazine and senkyunolide A showed synergetic calcium antagonistic activity. Additionally, the synergetic mechanism was further investigated by live-imaging analysis with the Ca2+ indicator fluo-4/AM by monitoring fluorescence changes. Our results indicated that ligustrazine can block voltage-operated Ca2+ channels (VDCCs) effectively and senkyunolide A can exert an inhibition effect mostly on ryanodine receptors (RYRs) and partly on VDCCs. Finally, an arterial ring assay showed that the combination of ligustrazine and senkyunolide A exerted a better vasodilatation function than using any components alone. In this study, we first revealed that a pair of natural APIs in combination acting on VDCCs and RYRs was more effective on vasodilatation by regulating [Ca2+](i).