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: 6272508
• 负责人: IVAN F MCMURTY
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272508
• 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，减少一氧化氮（NO） 血管舒张和内皮素血管收缩增加是关键成分 肺动脉高压（PH）的发病机制。但有 关于联合国作用的不确定性和争议的重要领域 这两个调解人，更好地了解规则， NO和ET-1在PH实验模型中的相互作用将有助于 为各种血管疾病开发更有效的治疗方法 疾病我们有初步的结果，与高血压相比， 慢性缺氧性白化病大鼠的肺表达增加的水平， 内皮型一氧化氮合酶mRNA和蛋白质，但很少或没有增加ET-1， 常氧小鹿冠大鼠自发性高血压肺表达 eNOS水平降低，ET-1 mRNA和肽水平升高。这些 和其他研究结果表明，有显着差异，在 eNOS和ET-1基因表达及NO-1和ET-1的调控 血管反应性在这两种动物模型的PH。因此，我们的整体 一种假说认为， 不同形式的NO血管舒张和ET-1血管收缩的调节 为了验证这个想法，生理学，药理学和分子生物学 生物技术将用于完整大鼠和离体大鼠肺， 比较肺和肺血管的基因表达，生产， 缺氧与自发（驼色）NO和ET-1的血管反应性 博士具体目的是检验以下假设：1）当缺氧PH 与eNOS mRNA和蛋白表达增加有关， ET-1轻度升高，自发PH值下降 高血压血管紧张度 是由于缺氧肺中NO合成减少和高水平的 ET-1在驼鹿肺中的表达，并由ETA和ETB差异介导 3）缺氧时eNOS表达上调， 高血压肺是由于缺氧的非血流动力学效应， 在自发性高血压肺中ET-1的增加扩张， 对血流动力学信号的反应。