Tao Xia, Zhang Ya-Jun, Shen Fu-Ming, Guan Yun-Feng, Su Ding-Feng
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
J Cardiovasc Pharmacol. 2008 Jan;51(1):24-31. doi: 10.1097/FJC.0b013e318159e097.
To study the effects of fosinopril on sinoaortic denervation (SAD)-induced pulmonary vascular remodeling and on phosphodiesterases (PDE) 1 in rats.
SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. The experiment included sham-operated (Sham), SAD, and fosinopril-treated SAD groups. Fosinopril (15 mg/kg/d) was given in rat chow. After 16 weeks of treatment, the pulmonary arteries were taken for investigations, including pharmacological study, measurement of cGMP, light microscopy, immunohistochemistry, Western blotting, and quantitative real-time RT-PCR.
Compared with Sham rats, blood pressure variability (BPV) was significantly increased in the SAD group. However, the mean pulmonary artery pressure (mPAP) was not significant change among 3 groups. After SAD, maximal contraction of pulmonary artery rings to phenylephrine was markedly decreased; the most prominent morphological change in the lung included thickening vascular walls, increasing number of smooth muscle cells, and greater wall-to-lumen ratio; the tissue concentrations of cGMP was reduced significantly; PDE1A or PDE1C expression was upregulated significantly, and endothelial nitric oxide synthase (eNOS) expression was downregulated significantly. Fosinopril treatment prevented these changes induced by SAD.
Pulmonary artery remodeling (structural and functional abnormalities) was induced by SAD. Fosinopril, an angiotensin-converting enzyme inhibitor, mainly via potentiating eNOS pathway and inhibiting AngII formation, effectively prevented increased blood pressure variability and vascular remodeling of the pulmonary artery after SAD by regulating the activity levels or expression of eNOS, cGMP, and PDE1s.
研究福辛普利对大鼠去窦弓神经（SAD）诱导的肺血管重塑及磷酸二酯酶（PDE）1的影响。
对10周龄雄性Sprague-Dawley大鼠进行去窦弓神经手术。实验包括假手术（Sham）组、SAD组和福辛普利治疗的SAD组。将福辛普利（15毫克/千克/天）混入大鼠饲料中。治疗16周后，取肺动脉进行研究，包括药理学研究、cGMP测定、光学显微镜检查、免疫组织化学、蛋白质印迹法和定量实时逆转录聚合酶链反应。
与假手术大鼠相比，SAD组血压变异性（BPV）显著增加。然而，三组间平均肺动脉压（mPAP）无显著变化。SAD后，肺动脉环对去氧肾上腺素的最大收缩明显降低；肺最显著的形态学变化包括血管壁增厚、平滑肌细胞数量增加和壁腔比增大；组织cGMP浓度显著降低；PDE1A或PDE1C表达显著上调，内皮型一氧化氮合酶（eNOS）表达显著下调。福辛普利治疗可预防SAD诱导的这些变化。
SAD可诱导肺动脉重塑（结构和功能异常）。血管紧张素转换酶抑制剂福辛普利主要通过增强eNOS途径和抑制血管紧张素II形成，通过调节eNOS、cGMP和PDE1s的活性水平或表达，有效预防SAD后血压变异性增加和肺动脉血管重塑。
