State key Laboratory of Antiviral Drugs, Engineering Center of Henan Province of Eucommia ulmoides Cultivation and Utilization, School of Pharmacy, Henan University, Kaifeng 475004, China.
State key Laboratory of Antiviral Drugs, Engineering Center of Henan Province of Eucommia ulmoides Cultivation and Utilization, School of Pharmacy, Henan University, Kaifeng 475004, China; The First Medical Center of the Chinese People's Liberation Army General Hospital, Beijing 100141, China.
Phytomedicine. 2023 Nov;120:155033. doi: 10.1016/j.phymed.2023.155033. Epub 2023 Aug 16.
Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it is imperative to develop new treatments for hypertension. Veratrum alkaloids were once used for the clinical treatment of hypertension, the mechanism of which is still unclear. It was gradually phased out due to adverse reactions.
This study aimed to investigate the short-term and long-term hypotensive profiles of different components of Veratrum alkaloids in spontaneously hypertensive rats (SHRs) to unveil their mechanisms of action.
Total Veratrum alkaloid (V), component A (A), and veratramine (M) quickly decreased BP within 30 min of treatment, reduced renal and cardiovascular damage, and improved relevant biochemical indicators (nitric oxide [NO], endothelin-1 [ET-1], angiotensin II [Ang II)], noradrenaline [NE], etc) in SHRs to delay stroke occurrence. Thereinto, A exhibited excellent protective effects in cardiovascular disease. The metabolomic profiles of SHRs treated with V, A, and M were significantly different from those of SHRs treated with vehicle. Thirteen metabolites were identified as potential pharmacodynamic biomarkers. Through Kyoto Encyclopedia of Genes and Genomes analysis, V, A, and M-induced hypotension was mainly related to alterations in nicotinate and nicotinamide metabolism, GABAergic synapses, linoleic acid metabolism, ketone body synthesis and degradation, arginine and proline metabolism, and urea cycle, of which nicotinate and nicotinamide metabolism was the key metabolic pathway to relieve hypertension.
This work shows that A is an effective and promising antihypertensive agent for hypertension treatment to reduce BP and hypertensive target organ damage, which is mainly mediated through modulating nicotinate and nicotinamide metabolism, RAS, and NO-ET homeostasis.
高血压是一个严重的全球公共卫生问题。大约 20-30%的高血压患者血压仍未得到有效控制。因此，开发新的高血压治疗方法迫在眉睫。藜芦生物碱曾用于高血压的临床治疗，但其作用机制尚不清楚。由于不良反应，藜芦生物碱逐渐被淘汰。
本研究旨在探讨藜芦生物碱不同成分在自发性高血压大鼠（SHR）中的短期和长期降压特征，揭示其作用机制。
总藜芦生物碱（V）、成分 A（A）和藜芦定（M）在治疗后 30 分钟内迅速降低血压，减轻肾脏和心血管损伤，改善相关生化指标（一氧化氮[NO]、内皮素-1 [ET-1]、血管紧张素 II [Ang II]），减少 SHR 中风的发生。其中，A 在心血管疾病方面表现出优异的保护作用。用 V、A 和 M 治疗的 SHR 的代谢组学图谱与用载体治疗的 SHR 的图谱明显不同。鉴定出 13 种潜在的药效生物标志物。通过京都基因与基因组百科全书分析，V、A 和 M 引起的低血压主要与烟酸和烟酰胺代谢、GABA 能突触、亚油酸代谢、酮体合成和降解、精氨酸和脯氨酸代谢以及尿素循环的改变有关，其中烟酸和烟酰胺代谢是缓解高血压的关键代谢途径。
本研究表明，A 是一种有效的、有前途的抗高血压药物，可用于治疗高血压，降低血压和高血压靶器官损伤，其主要机制是通过调节烟酸和烟酰胺代谢、RAS 和 NO-ET 平衡。
