INTERACTION OF NO AND ET-1 IN PULMONARY HYPERTENSION

NO 和 ET-1 在肺动脉高压中的相互作用

• 批准号: 6630915
• 负责人: IVAN F MCMURTY
• 金额: $ 12.36万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630915
• 关键词: calcium flux; endothelin; gene expression; genetic disorder; genetic strain; hormone receptor; in situ hybridization; laboratory rat; nitric oxide; nitric oxide synthase; northern blottings; pathologic process; perfusion; pulmonary hypertension; respiratory hypoxia; respiratory pharmacology; tissue /cell culture; vascular endothelium; vascular resistance; vascular smooth muscle; vasoconstriction; vasoconstrictors; vasomotion; western blottings

Human and animal studies suggest that decreased nitric oxide (NO) vasodilation and increased endothelin vasoconstriction are key components of the pathogenesis of pulmonary hypertension (PH). However, there are important areas of uncertainty and controversy regarding the roles of these two mediators, and better understanding of the regulation and interaction of NO and ET-1 in experimental models of PH would be useful in the development of more effective therapies for the diverse vascular disease. We have preliminary results that in contrast to the hypertensive lungs of chronically-hypoxic albino rats which express increased levels of eNOS MRNA and protein but little or no increase in ET-1, the spontaneously-hypertensive lungs of normoxic fawn-hooded rats express decreased levels of eNOS but high levels of ET-1 mRNA and peptide. These and other findings indicate that there are significant differences in the regulation of eNOS and ET-1 gene expression and NO1 and ET-1 vasoreactivity in these two animal models of PH. Thus, our overall hypothesis is that there are important differences in mechanisms of regulation of NO vasodilation and ET-1 vasoconstriction in different forms of PH. To test this idea, physiologic, pharmacologic, and molecular biologic techniques will be used in intact rats and isolated rat lungs to compare lung and pulmonary vascular gene expression, production, and vasoreactivity of NO and ET-1 in hypoxic versus spontaneous (fawn-hooded) PH. The specific aims are to test the hypothesis that: 1) while hypoxic PH is associated with increased expression of eNOS mRNA and protein but little increase in ET-1, spontaneous PH is accompanied by decreased expression of eNOS but high levels of ET-1, 2) hypertensive vascular tone is due to decreased No synthesis in hypoxic lungs and to high levels of ET-1 in fawn-hooded lungs and is differentially mediated by ETA and ETB receptors in the two models, 3) upregulation of eNOS in hypoxic hypertensive lungs is due to non-hemodynamic effects of hypoxia, and the increased expansion of ET-1 in spontaneously-hypertensive lungs is in response to hemodynamic signals.

人类和动物研究表明，一氧化氮 (NO) 减少 血管舒张和内皮素血管收缩增加是关键组成部分 肺动脉高压（PH）的发病机制。然而，有 关于角色的不确定性和争议的重要领域 这两个调解员，以及对监管和更好的理解 NO 和 ET-1 在 PH 实验模型中的相互作用将有助于 开发针对不同血管的更有效疗法 疾病。我们有初步结果，与高血压相比 长期缺氧的白化大鼠的肺部表达水平升高 eNOS mRNA 和蛋白质，但 ET-1 很少或没有增加， 含氧量正常的黄褐色大鼠的自发性高血压肺表达 eNOS 水平降低，但 ET-1 mRNA 和肽水平升高。这些 和其他研究结果表明，两者之间存在显着差异 eNOS 和 ET-1 基因表达以及 NO1 和 ET-1 的调节 这两种PH动物模型的血管反应性。因此，我们总体 假设是，机制之间存在重要差异 不同形式对NO血管舒张和ET-1血管收缩的调节 PH值。为了检验这个想法，生理学、药理学和分子学 生物技术将用于完整的大鼠和离体的大鼠肺 比较肺和肺血管基因的表达、产生和 缺氧与自发（黄褐色）中 NO 和 ET-1 的血管反应性 PH值。具体目的是检验以下假设：1）当缺氧 PH 时 与 eNOS mRNA 和蛋白质表达增加有关，但 ET-1 增加很少，自发 PH 伴随下降 eNOS 表达，但 ET-1、2) 高血压血管张力水平高 是由于缺氧肺中合成减少以及高水平的 ET-1 存在于黄褐色肺中，并由 ETA 和 ETB 差异介导 两种模型中的受体，3）缺氧时 eNOS 上调 肺高血压是由于缺氧的非血流动力学效应造成的， 自发性高血压肺中 ET-1 的扩张增加 对血流动力学信号的反应。