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

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

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。

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.