Synergistic Improvement of L-NAME Induced Hypertension Through the Combination of Chuanxiong Rhizoma Hort. and Ganoderma lucidum Karst.

Background: This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of the combining of Chuanxiong Rhizoma Hort. (CX) and Ganoderma lucidum Karst. (GL) in treating hypertension (HTN) induced by chronic oxidative stress (OS). This research provides novel insights into the development of anti-hypertensive agents within the scope of medicine and food homologues, using network pharmacology and in vivo experimental validation. Methods: Active constituents and corresponding targets of CX and GL were respectively retrieved on the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform. Molecular docking was utilized to assess the binding efficacy between the constituents and core targets. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology Biological Process (GOBP) enrichment analyses were performed against the core targets. The anti-hypertensive effects of the combination were validated in the N-Nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rat model; meanwhile, the potential mechanism of action was investigated through indices assay and pathological examination. Results: A total of 6 and 14 core active constituents of CX and GL, respectively, were identified, along with 30 and 39 potential corresponding targets. The molecular docking established prostaglandin-endoperoxide synthase 2 (PTGS2) as the target with the highest binding affinity for treating both HTN and OS. The KEGG pathway analysis revealed the presence of the “estrogen signaling” and “vascular endothelial growth factor (VEGF) signaling” pathways. Additionally, the GOBP analysis showed significant enrichment in the terms “positive regulation of nitric oxide (NO) biosynthetic process” and “negative regulation of smooth muscle contraction”. These findings highlight the shared pathways between CX and GL in relation to HTN and OS. Moreover, the in vivo experiments validated that the combined CX and GL treatment contributed to significantly decreasing systolic blood pressure (SBP) and serum Ang-Ⅱ levels, increasing aortic prostaglandin I2 (PGI2) and total antioxidant capacity (T-AOC), reducing aortic vascular cell adhesion molecule-1 (VCAM-1), reactive nitrogen species (RNS), and heart index, and improving the aortic damage in a synergistic pattern in the L-NAME-induced hypertensive rat model. Conclusion: Administering the combination of CX and GL synergistically treated OS-induced HTN by improving vascular endothelial NO transduction, vasodilation, and anti-oxidative capacity, via co-regulation of the estrogen and VEGF signaling pathways. This finding provides a perspective for the development of novel therapeutic strategies in the treatment of HTN based on the dietary-medicinal properties of Chinese medicine in treatment of HTN.