西拉普利对低氧大鼠肺动脉和心肌细胞增殖的抑制作用

目的：探索cilazapril 对低氧大鼠肺血管和心肌细胞增殖的抑制机理。 方法： 采用生化、放射免疫、免疫组织化学、细胞凋亡标记和血流动力学技术研究低氧肺血管及心肌细胞增殖和结构重建。 结果： （1）低氧大鼠mPAP显著增高，伴有肺动脉血管管腔狭窄、管壁增厚，心肌肥大，R/L+S增高。（2）B组、C组大鼠肺动脉和右心肌细胞增殖指数（PI）均分别明显高于A组，而C组明显低于B组。ET-1免疫组化染色阳性细胞主要分布在肺动脉血管壁和心肌细胞上，染色程度由强到弱依次为B组>C组>A组。（3）B组大鼠ET-1水平和ACE活性明显高于A组，而C组显著低于B组。（4）直线相关分析显示ET-1、ACE分别与R/(L+S)、mPAP、肺动脉PI、心肌PI呈正相关；多元回归分析显示ET-1和ACE可能是影响PI的主要因素。 结论： 低氧大鼠存在细胞过度增殖状态，继发肺血管、右心结构重建是低氧性肺动脉高压发病机理之一。Cilazapril通过抑制ACE和ET-1的促增殖作用，阻止肺血管及心肌重建，对低氧性肺动脉高压的防治有一定作用。

Chronic inhibition of cilazapril on pulmonary vascular and myocardial cell proliferation in hypoxic rats

AIM: To explore the mechanism of cilazapril inhibiting proliferation of pulmonary vascular and myocardial cells in hypoxic rats. METHODS: 30 male Wistar rats were used and divided into three groups: normal control (group A)， intermittent hypoxia for 4 weeks (group B) and intermittent hypoxia for 4 weeks plus cilazapril treatment (group C). The cell proliferation and structural remodeling in pulmonary vasculature and myocardium during hypoxia were studied by biochemical analysis, radioimmunoassay, immunohistochemistry, terminal deoxyuridine tripnosphate nick end labeling and correlated with hemodynamic. RESULTS: (1) The mean pulmonary artery pressure (mPAP) and the right ventricle to left ventricle plus ventricular septum ratio (R/L±S) were significantly higher in the hypoxic rat than that in control animals, while increased thickness of the pulmonary vascular wall and vascular lumen with decrease in the caliber as well as myocardial hypertrophy were observed in hypoxic rats. (2) The proliferative index (PI) of pulmonary arteria and myocardium was significantly higher in group B and C than that in group A. The distribution of ET-1 positive cells was seen in pulmonary arterial wall and cardiomyocytes. The ET-1 immunoreactivity was group B>group C>group A by turns. (3) The concentrations of plasma endothelin-1 (ET-1) and angiotensin converting enzyme (ACE) were significantly higher in group B than that in group A. However, the ET-1 and ACE were significantly lower in group C than those in group B. (4) The ET-1 and ACE had a significant positive correlation with R/L+S, mPAP and PI, respectively. The multivariate linear regression analysis revealed that ET-1 and ACE were major factor affecting PI. CONCLUSION: The pulmonary vascular and myocardial structural remodeling are one of the pathogenesis accompanied with excessive cell proliferation in hypoxic pulmonary hypertension (PH). Cilazapril effectively prevents and treats the hypoxic PH by inhibiting cell proliferation and structural remodeling of pulmonary circulation, as induced by ET-1 and ACE.