BACKGROUND Shenxian-Shengmai (SXSM) Oral Liquid is a CFDA-approved patent Chinese Herbal medicine, which has been clinically used for the treatment of bradycardia. However, its active components and action mechanism remain to be established. The present study aimed to evaluate the efficacy of SXSM on bradycardia and to identify the possible active components and their pharmacological targets for this action. METHODS A literature-based meta-analysis was performed to evaluate the clinical efficacy of SXSM on bradycardia, which was confirmed by a rat ex vivo cardiac model. Network pharmacology analysis was then conducted to reveal the potential targets of SXSM active components and their anti-arrhythmia mechanisms. Finally, the identified drug-target interaction was confirmed by immunofluorescence assay in cardiomyocyte. RESULTS Meta-analysis of the available clinical study data shows that Shenxian-Shengmai Oral Liquid has a favorable effect for bradycardia. In an ex vivo bradycardia model of rat heart, SXSM restored heart rate by affecting Heart rate variability (HRV) which is associated with autonomic nervous system activity. A drug-target-pathway network analysis connecting SXSM components with arrhythmia suggested that a prominent anti-arrhythmia mechanisms of SXSM was via β1-adrenergic signaling pathway, which was subsequently validated by immunofluorescence assay showing that SXSM indeed increased the expression of ADRB1 in cultured cardiomyocytes. CONCLUSION By combining approaches of clinical evidence mining, experimental model confirmation, network pharmacology analyses and molecular mechanistic validation, we show that SXSM is an effective treatment for bradycardia and it involves multiple component interacting via multiple pathways, among which is the critical β1-adrenergic receptor upregulation. Our integrative approach could be applied to other multi-component traditional Chinese medicine investigation where ample clinical data are accumulated but advanced mechanistic studies are lacking.

中文翻译：

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临床证据引导的网络药理学分析揭示了β1-肾上腺素受体上调对神仙生脉缓解心动过缓的关键贡献。


背景技术神仙生脉口服液是国家食品药品监督管理总局批准的中成药，临床上用于治疗心动过缓。但其活性成分和作用机制仍有待确定。本研究旨在评估 SXSM 对心动过缓的功效，并确定该作用可能的活性成分及其药理学靶点。方法基于文献的荟萃分析评价SXSM治疗心动过缓的临床疗效，并通过大鼠离体心脏模型得到证实。然后进行网络药理学分析，揭示SXSM活性成分的潜在靶点及其抗心律失常机制。最后，通过心肌细胞中的免疫荧光测定证实了所确定的药物-靶标相互作用。结果现有临床研究数据的Meta分析表明神仙生脉口服液对心动过缓有良好的疗效。在离体大鼠心脏心动过缓模型中，SXSM 通过影响与自主神经系统活动相关的心率变异性 (HRV) 来恢复心率。将 SXSM 成分与心律失常联系起来的药物-靶标-通路网络分析表明，SXSM 的一个显着的抗心律失常机制是通过 β1 肾上腺素能信号通路，随后通过免疫荧光分析验证，表明 SXSM 确实增加了培养的心肌细胞中 ADRB1 的表达。 结论通过结合临床证据挖掘、实验模型验证、网络药理学分析和分子机制验证的方法，我们表明SXSM是治疗心动过缓的有效方法，它涉及多个成分通过多种途径相互作用，其中关键的β1-肾上腺素能受体上调。我们的综合方法可以应用于其他多成分的中药研究，这些研究积累了丰富的临床数据，但缺乏先进的机制研究。