Phytomedicine ( IF 6.7 ) Pub Date : 2022-06-09 , DOI: 10.1016/j.phymed.2022.154257 Jingmei Fang 1 , Ran Li 1 , Yue Zhang 1 , Patrick Kwabena Oduro 1 , Sa Li 1 , Ling Leng 2 , Zhimei Wang 1 , Yao Rao 1 , Lu Niu 1 , Hong-Hua Wu 2 , Qilong Wang 2
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Background
Nardostachys jatamansi DC. is a common medicinal herb used to treat cardiovascular diseases, particularly hypertension. Previously, our lab characterized the chemical compounds of N. jatamansi. However, the bioactive compounds of N. jatamansi and their mechanisms of action on blood pressure and blood vessels are unknown.
Purpose
The vasorelaxant effects of the methanolic extract (MeOH ext.) of the roots and rhizomes of N. jatamansi, its main compounds, and their underlying mode of action, were investigated.
Methods
The main compounds of N. jatamansi were isolated and identified using UHPLC-TOF MS. The antihypertensive effect of N. jatamansi extracts and (-)-aristolone were determined using spontaneously hypertensive rats. The extracts, fractions, and compounds were also evaluated for their vasorelaxant effects on U46619 contractile responses in isolated thoracic aortic and mesenteric arterial rings. The endothelial-dependent relaxation, as well as the regulatory pathways and targets of (-)-aristolone, were studied in-vitro and ex-vivo. Molecular docking and biophysical characterization (Surface plasmon resonance) studies were utilized to investigate the molecular interaction between (-)-aristolone and the target protein.
Results
MeOH ext. (200 mg/kg) reduces the systolic and diastolic blood pressure in spontaneously hypertensive rats. MeOH ext. and its ethyl acetate fraction (EtOAc Fr.), but not the H2O fraction, had a significant relaxing effect on the thoracic aorta. (-)-aristolone and kanshone H from EtOAc Fr. induced vasorelaxation of the thoracic aorta and mesenteric artery. In human umbilical vein endothelial cells, (-)-aristolone treatment upregulated phosphorylation of Akt (T308) and eNOS. Molecular docking and surface plasmon resonance experiments revealed an interaction between (-)-aristolone and phosphoinositide-dependent protein kinase 1 (PDK1), an upstream protein kinase that phosphorylates Akt at T308. Treatment with PDK1 inhibitor PHT-427 and eNOS inhibitor L-NAME consistently inhibited (-)-aristolone-induced vasorelaxation. In addition, KATP channel inhibitor glibenclamide dramatically inhibited the vasorelaxant effects of (-)-aristolone and kanshone H in the endothelium-denuded thoracic aorta. Finally, (-)-aristolone lowers hypertensive rats' systolic and diastolic blood pressure.
Conclusions
The extracts of N. jatamansi promote vasorelaxation and alleviate hypertension. The essential chemicals responsible for producing vasorelaxation effects are (-)-aristolone and kanshone H, which activate the PDK1-Akt-eNOS-NO relaxing pathway and stimulate the opening of the KATP channel. These findings point to N. jatamansi and aristolone as possible antihypertensive agents.
中文翻译：
Nardostachys jatamansi DC 中的亚里士多龙。通过激活 KATP 通道和 PDK1-Akt-eNOS 通路诱导肠系膜血管舒张和改善高血压
背景
Nardostachys jatamansi DC. 是一种常用的药草，用于治疗心血管疾病，尤其是高血压。以前，我们的实验室对N. jatamansi的化合物进行了表征。然而，N. jatamansi的生物活性化合物及其对血压和血管的作用机制尚不清楚。
目的
研究了N. jatamansi根和根茎的甲醇提取物 (MeOH ext.) 的血管舒张作用、其主要化合物及其潜在的作用方式。
方法
使用 UHPLC-TOF MS 分离和鉴定N. jatamansi的主要化合物。使用自发性高血压大鼠测定N. jatamansi提取物和 (-)- 马里士酮的抗高血压作用。还评估了提取物、级分和化合物对孤立胸主动脉和肠系膜动脉环中 U46619 收缩反应的血管舒张作用。在体外和离体研究了内皮依赖性舒张以及 (-)-马里士酮的调节途径和靶点。分子对接和生物物理表征（表面等离子体共振）研究用于研究 (-)-马里士酮与靶蛋白之间的分子相互作用。
结果
甲醇分机。(200 mg/kg) 降低自发性高血压大鼠的收缩压和舒张压。甲醇分机。及其乙酸乙酯部分 (EtOAc Fr.)，但不是 H 2O分数，对胸主动脉有显着的放松作用。(-)-亚里士酮和 kanshone H 来自 EtOAc Fr。引起胸主动脉和肠系膜动脉的血管舒张。在人脐静脉内皮细胞中，(-)-aristolone 处理上调 Akt (T308) 和 eNOS 的磷酸化。分子对接和表面等离子共振实验揭示了 (-)-马里士酮和磷酸肌醇依赖性蛋白激酶 1 (PDK1) 之间的相互作用，PDK1 是一种上游蛋白激酶，可在 T308 处磷酸化 Akt。用 PDK1 抑制剂 PHT-427 和 eNOS 抑制剂 L-NAME 治疗持续抑制 (-)- 马里士龙诱导的血管舒张。此外，K ATP通道抑制剂格列本脲显着抑制内皮剥脱的胸主动脉中 (-)-马里士酮和 kanshone H 的血管舒张作用。最后，(-)-aristolone 降低高血压大鼠的收缩压和舒张压。
结论
N. jatamansi的提取物促进血管舒张和缓解高血压。负责产生血管舒张作用的基本化学物质是 (-)-aristolone 和 kanshone H，它们激活 PDK1-Akt-eNOS-NO 松弛途径并刺激 K ATP通道的打开。这些发现表明N. jatamansi和 aristolone 作为可能的抗高血压药物。
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