Mechanism of Guigan Longmu Decoction in the Treatment of Arrhythmias
Based on Network Pharmacology and Untargeted Metabolomics Assays
Authors: Deng Tuo , Guo Sheng , Yang Jie , Huang Xiao-yu , Lu Xiao-bin , Lu Jing , Liu Liang , Du Ze 
Published: June 2024

Background::

Guigan longmu decoction (GGLM), a traditional Chinese medicine
compound, has demonstrated efficacy in treating rapid arrhythmia clinically. Nevertheless, its
mechanism of action remains elusive. This study aims to elucidate the molecular mechanism underlying
the efficacy of GGLM in treating arrhythmia utilizing non-targeted metabolomics,
widely-targeted metabolomics, and network pharmacology, subsequently validated through animal
experiments.

Methods::

Initially, network pharmacology analysis and widely-targeted metabolomics were performed
on GGLM. Subsequent to that, rats were administered GGLM intervention, and nontargeted
metabolomics assays were utilized to identify metabolites in rat plasma postadministration.
The primary signaling pathways, core targets, and key active ingredients of
GGLM influencing arrhythmia were identified. Additionally, to validate the therapeutic efficacy
of GGLM on arrhythmia rat models, a rat model of rapid arrhythmia was induced via subcutaneous
injection of isoproterenol, and alterations in pertinent pathogenic pathways and proteins in
the rat model were assessed through qRT-PCR and Western blot following GGLM administration.

Results::

The results of network pharmacology showed that 99 active ingredients in GGLM acted
on 249 targets and 201 signaling pathways, which may be key to treating arrhythmia. Widelytargeted
metabolic quantification analysis detected a total of 448 active ingredients in GGLM,
while non-targeted metabolomics identified 279 different metabolites and 10 major metabolic
pathways in rats. A comprehensive analysis of the above results revealed that the core key active
ingredients of GGLM in treating arrhythmia include calycosin, licochalcone B, glabridin,
naringenin, medicarpin, formononetin, quercetin, isoliquiritigenin, and resveratrol. These active
ingredients mainly act on the relevant molecules and proteins upstream and downstream of the
MAPK pathway to delay the onset of arrhythmia. Animal experimental results showed that the
heart rate of rats in the model group increased significantly, and the mRNA and protein expression
of p38, MAPK, JNK, ERK, NF-kb, IL-1β, and IL-12 in myocardial tissue also increased
significantly. However, after intervention with GGLM, the heart rate of rats in the drug group
decreased significantly, while the mRNA and protein expression of p38 MAPK, JNK, ERK1,
NF-kb, IL-1β, and IL-12 in myocardial tissue decreased significantly.

Conclusion::

GGLM, as an adjunctive therapy in traditional Chinese medicine, exhibits favorable
therapeutic efficacy against arrhythmia. This can be attributed to the abundant presence of bioactive
compounds in the formulation, including verminin, glycyrrhizin B, glabridine, naringenin,
ononin, quercetin, isorhamnetin, and kaempferol. The metabolites derived from these active ingredients
have the potential to mitigate myocardial inflammation and decelerate heart rate by
modulating the expression of proteins associated with the MAPK signaling pathway in vivo.