INTERACTION OF NO AND ET-1 IN PULMONARY HYPERTENSION

人类和动物研究表明，一氧化氮(NO)减少 血管扩张和内皮素性血管收缩是关键成分 对肺动脉高压(PH)的发病机制进行研究。然而，有一些 关于非政府组织的作用的不确定和争议的重要领域 这两个调解人，并更好地了解监管和 在PH的实验模型中，NO和ET-1的相互作用将有助于 针对不同血管的更有效治疗方法的发展 疾病。我们有了初步的结果，与高血压形成对比 慢性缺氧性白化大鼠的肺组织表达水平升高 内皮型一氧化氮合酶(ENOS)的mRNA和蛋白表达增加，而ET-1的表达几乎或不增加。 常氧条件下自发性高血压大鼠肺组织表达 内皮型一氧化氮合酶(ENOS)水平降低，内皮型一氧化氮合酶(ET-1)mRNA和多肽水平升高。这些 而其他研究结果表明，在 ENOS、ET-1基因表达与NO1、ET-1的调控 这两种PH动物模型的血管反应性。因此，我们的整体 假说是在机制上有重要的差异 NO、ET-1不同形式对血管舒缩作用的调节 PH值。为了测试这个想法，生理学、药理学和分子学 将在完整的大鼠和分离的大鼠肺中使用生物技术 比较肺和肺血管基因的表达、产生和 低氧与自发性(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)当低氧PH 与enos mRNA和蛋白表达增加有关，但 ET-1轻度升高，自发性PH伴降低 ENOS表达但ET-1高水平，2)高血压血管紧张性 是由于低氧肺中NO合成减少和高水平的 ET-1在金丝鹿肺中的表达及其与ETA和ETB的差异调节 两种模型中的受体，3)低氧时eNOS的上调 肺高血压是由于低氧的非血流动力学影响，而 ET-1在自发性高血压肺中的扩张增加 对血流动力学信号的反应。

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.