药学学报, 2021, 56(1): 208-216
引用本文:
陈迪, 袁天翊, 陈俞材, 张惠芳, 牛子冉, 方莲花, 杜冠华. DL0805-2防治野百合碱诱导的大鼠肺动脉高压的药效评价[J]. 药学学报, 2021, 56(1): 208-216.
CHEN Di, YUAN Tian-yi, CHEN Yu-cai, ZHANG Hui-fang, NIU Zi-ran, FANG Lian-hua, DU Guan-hua. Evaluation of the preventive effect of DL0805-2 against monocrotaline induced rat pulmonary arterial hypertension[J]. Acta Pharmaceutica Sinica, 2021, 56(1): 208-216.

DL0805-2防治野百合碱诱导的大鼠肺动脉高压的药效评价
陈迪, 袁天翊, 陈俞材, 张惠芳, 牛子冉, 方莲花, 杜冠华
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 药物靶点研究与新药筛选北京市重点实验室, 北京 100050
摘要:
新型Rho激酶抑制剂DL0805-2在高血压危象的治疗中不仅能快速降低系统血压,也可降低肺动脉压力,并对肺部损伤具有明显保护作用。本实验拟探究DL0805-2防治肺动脉高压的药效并初步探究其分子机制。动物福利和实验过程均遵循中国医学科学院药物研究所动物伦理委员会规定。将SD(Sprague Dawley)大鼠随机分为DL0805-2低、中和高剂量组(1、3和10 mg·kg-1)、波生坦阳性对照组、模型组及空白对照组,在野百合碱造模后的第7天开始给药,实验终点第25天检测各项指标,观察DL0805-2对肺动脉高压的防治作用。DL0805-2对野百合碱导致的与肺动脉高压相关的生理指标的异常改变具有明显改善作用,包括降低右心室收缩压,减轻压力负荷导致的心脏损伤,降低肺部疾病标志物内皮素-1及炎症因子的水平,改善肺动脉重构情况,初步的机制研究发现DL0805-2通过Rho激酶通路发挥对肺动脉高压的防治作用。DL0805-2对野百合碱诱导的大鼠肺动脉高压具有良好的药效,其在疾病发生早期进行干预可有效缓解疾病的发展进程,降低模型动物死亡率,其机制与Rho激酶通路相关。
关键词:    DL0805-2      肺动脉高压      右心室压      肺动脉重构      Rho激酶通路     
Evaluation of the preventive effect of DL0805-2 against monocrotaline induced rat pulmonary arterial hypertension
CHEN Di, YUAN Tian-yi, CHEN Yu-cai, ZHANG Hui-fang, NIU Zi-ran, FANG Lian-hua, DU Guan-hua
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
In the treatment of hypertensive crisis, the novel Rho kinase inhibitor DL0805-2 can rapidly lower systematic blood pressure, reduce pulmonary artery pressure, and has a significant protective effect on lung injury. This experiment intends to evaluate the efficacy of DL0805-2 against pulmonary arterial hypertension (PAH) and preliminarily reveals its underlying mechanism. Animal welfare and experimental procedures are in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. Sprague Dawley (SD) rats were randomly divided into DL0805-2 low, medium, and high dose groups (1, 3, and 10 mg·kg-1), bosentan positive control group, model group, and blank control group. The drug was administered daily on the 7th day after model establishment by monocrotaline injection. On the 25th day of the experiment, relevant indicators were examined to observe the therapeutic effect of DL0805-2 on pulmonary hypertension. DL0805-2 significantly relieved the abnormal changes in the physiological parameters related to PAH induced by monocrotaline, including reducing right ventricular systolic pressure, alleviating cardiac damage caused by pressure overload, and reducing the levels of endothelin-1 and inflammatory factors in lung tissues. DL0805-2 also attenuated pulmonary arteries remodeling. It was preliminarily discovered that DL0805-2 exerts preventive and therapeutic effect on PAH through Rho-kinase pathway. Our results suggested that DL0805-2 had good therapeutic effects on monocrotaline-induced PAH rat model. It intervened early in the disease process, effectively prevented the development of the disease, and reduced the mortality of the diseased animals. The mechanism is related to Rho-kinase pathway.
Key words:    DL0805-2    pulmonary hypertension    right ventricular systolic pressure    pulmonary artery remodeling    Rho-kinase pathway   
收稿日期: 2020-06-15
DOI: 10.16438/j.0513-4870.2020-0981
基金项目: 国家科技重大专项(2018ZX09711001-001-014,2017ZX09101001);国家自然科学基金资助项目(81773935);中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-010,2017-I2M-1-010).
通讯作者: 方莲花,Tel:86-10-63165313,E-mail:fanglh@imm.ac.cn;杜冠华,Tel:86-10-63165184,E-mail:dugh@imm.ac.cn
Email: fanglh@imm.ac.cn;dugh@imm.ac.cn
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