Clinical evidence-guided network pharmacology analysis reveals a critical contribution of [beta]1-adrenoreceptor upregulation to bradycardia alleviation by Shenxian-Shengmai

• Published in: BMC complementary and alternative medicine 2019-12, Vol.19 (1)
• Main Authors: Gao, Jiaming, Wang, Taiyi, Yao, Xi, Xie, Weiwei, Shi, Xianru, He, Shuang, Zhao, Tao, Wang, Chunhua, Zhu, Yan
• Format: Article
• Language: English
• Subjects: Antiarrhythmia agents; Asian medicine; Bradycardia; Drug interactions; Fluorescent antibody technique; Heart cells; Heart rate; Herbal medicine; Mining industry; Oral drugs; Pharmacology; Traditional Chinese medicine
• ISSN: 1472-6882; 1472-6882
• DOI: 10.1186/s12906-019-2769-0

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 [beta]1-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 [beta]1-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. Keywords: Traditional Chinese medicine, Shenxian-Shengmai oral liquid, Bradycardia, [beta]1-adrenergic signaling, Network pharmacology, Meta-analysis