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血管紧张素-(1-7)改善野百合碱诱导的肺动脉高压大鼠内皮依赖性血管舒张

刘宣宣¹, 陈艾东^1,2, 潘艳³, 张枫^1,2, 綦振宝⁴, 曹囡¹, 韩莹^1,2,*

¹南京医科大学康达学院生理学教研室，连云港 222000；²南京医科大学生理学系，南京 211166；³江苏医药职业学院基础医学部，盐城 224005；⁴齐鲁工业大学(山东省科学院)工程训练中心，济南 250000

摘要

本研究采用野百合碱(monocrotaline, MCT)诱导的肺动脉高压(pulmonary arterial hypertension, PAH)大鼠模型，旨在探讨血管紧张素(angiotensin, Ang)-(1-7)在调控PAH大鼠肺动脉舒张功能中的作用及机制。皮下注射MCT或生理盐水3周后用右心导管检测大鼠右心室收缩压(right ventricular systolic pressure, RVSP)和右心肥厚指数(right ventricular hypertrophy index, RVHI)来鉴定PAH模型。通过肺动脉等长张力实验评价血管舒张功能，应用乙酰胆碱(acetylcholine, ACh)诱导的血管舒张评价血管内皮依赖性舒张功能，应用硝普钠(sodium nitroprusside, SNP)诱导的血管舒张评价血管平滑肌舒张功能。Ang-(1-7)孵育人肺动脉内皮细胞(human pulmonary artery endothelial cells, HPAECs)测定一氧化氮(nitric oxide, NO)释放水平。结果显示：与对照大鼠相比，MCT-PAH大鼠RVSP和RVHI明显升高，ACh或SNP诱导的血管舒张功能均变差。采用1 × 10−9~1 × 10−4 mol/L Ang-(1-7)孵育MCT-PAH大鼠离体肺动脉血管环，引起明显的肺动脉舒张。MCT-PAH大鼠肺动脉孵育Ang-(1-7)预处理后，明显改善ACh诱导的血管内皮依赖性舒张，但对SNP诱导的血管内皮非依赖性舒张无明显作用。Ang-(1-7)孵育HPAECs明显升高其释放的NO水平。Mas受体拮抗剂A-779抑制Ang-(1-7)的改善ACh诱导的血管舒张功能、促进内皮细胞NO释放作用。上述结果表明，Ang-(1-7)通过激活Mas受体促使内皮细胞释放NO，改善PAH大鼠肺动脉血管内皮依赖性舒张功能。

关键词： 血管紧张素-(1-7)l肺动脉高压l内皮依赖性舒张功能l一氧化氮lMas受体

Angiotensin-(1-7) improves endothelium-dependent vasodilation in rats with monocrotaline-induced pulmonary arterial hypertension

LIU Xuan-Xuan¹, CHEN Ai-Dong^1,2, PAN Yan³, ZHANG Feng^1,2, QI Zhen-Bao⁴, CAO Nan¹, HAN Ying^1,2,*

¹Department of Physiology, Kangda College of Nanjing Medical University, Lianyungang 222000, China；²Department of Physiology, Nanjing Medical University, Nanjing 211166, China；³Department of Basic Medicine, Jiangsu Vocational College of Medicine, Yancheng 224005, China；⁴Engineering Training Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250000, China

Abstract

In this study, we used a rat model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) to investigate the role and mechanism of angiotensin (Ang)-(1-7) in regulating pulmonary artery diastolic function. Three weeks after subcutaneous injection of MCT or normal saline, the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) of rats were detected using a right heart catheter. Vascular endothelium-dependent relaxation was evaluated by acetylcholine (ACh)- induced vasodilation. The relaxation function of vascular smooth muscle was evaluated by sodium nitroprusside (SNP)-induced vasodilation. Human pulmonary artery endothelial cells (HPAECs) were incubated with Ang-(1-7) to measure nitric oxide (NO) release levels. The results showed that compared with control rats, RVSP and RVHI were significantly increased in the MCT-PAH rats, and both ACh or SNP-induced vasodilation were worsened. Incubation of pulmonary artery of MCT-PAH rats with Ang-(1-7) (1 × 10−9–1 × 10−4 mol/L) caused significant vaso-relaxation. Pre-incubation of Ang-(1-7) in the pulmonary artery of MCT-PAH rats significantly improved ACh-induced endothelium-dependent relaxation, but had no significant effect on SNP-induced endothelium-independent relaxation. In addition, Ang-(1-7) treatment significantly increased NO levels in HPAECs. The Mas receptor antagonist A-779 inhibited the effects of Ang-(1-7) on endothelium-dependent relaxation and NO release from endothelial cells. The above results demonstrate that Ang-(1-7) promotes the release of NO from endothelial cells by activating Mas receptor, thereby improving the endothelium-dependent relaxation function of PAH pulmonary arteries.

Key words: angiotensin-(1-7)

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通讯作者：韩莹　　E-mail: yhancn@njmu.edu.cn

引用本文：

刘宣宣, 陈艾东, 潘艳, 张枫, 綦振宝, 曹囡, 韩莹. 血管紧张素-(1-7)改善野百合碱诱导的肺动脉高压大鼠内皮依赖性血管舒张[J]. 生理学报 2023; 75 (4): 497-502.

LIU Xuan-Xuan, CHEN Ai-Dong, PAN Yan, ZHANG Feng, QI Zhen-Bao, CAO Nan, HAN Ying. Angiotensin-(1-7) improves endothelium-dependent vasodilation in rats with monocrotaline-induced pulmonary arterial hypertension. Acta Physiol Sin 2023; 75 (4): 497-502 (in Chinese with English abstract).