PO2 MODULATION OF NO AND ET1 IN PULMONARY HYPERTENSION

原发性和继发性肺动脉高压（PHT）导致 显著的发病率和死亡率，几乎没有可接受的治疗 选项. 虽然有众所周知的相关疾病状态， 原发性PHT（胶原血管疾病，暴露于羟乙基纤维素， 特发性）和继发性PHT（COPD，先天性心脏病）， 初始损伤导致血管收缩、血管重塑，以及 肺血管阻力增加是未知的。 混乱， 内源性血管舒张剂和血管收缩剂（分别为NO和ET-1） 与高血压肺循环有关， PHT的实验模型以及人类疾病。 我们 实验室对内源性氮的作用感兴趣 来自eNOS（内皮衍生的一氧化氮合酶）的一氧化氮（NO）， 内皮素-1（ET-1），以及缺氧对肺发育的影响。 PHT。 具体来说，使用先天性eNOS缺陷的小鼠， ET-1活性的改变和生理水平的 缺氧对PHT发展的影响正在积极研究中。 我们假设eNOS缺乏会增加对 缺氧导致PHT的发展，在温和的，生理性的， 在科罗拉多州丹佛市和许多疾病状态中所见的缺氧与 PHT。 此外，我们假设存在显著的相互作用， 或在体内NO和ET-1之间的相互作用，使得NO部分地， 下调ET-1的表达和活性。 我们将介绍 使用离体灌注小鼠肺制备物的初步数据 表明eNOS对缺氧的肺血管反应性增加 缺陷小鼠 我们还将报告PHT在eNOS中的发展 与对照组相比， 其在相当于海平面的条件下衰减。 初步 数据提示eNOS缺陷组与对照组相比ET-1表达增加。 还将提供对照小鼠。 具体而言，我们将解决 问题：1）NO是否调节PO 2-中的肺血管张力 依赖的方式和2）没有行动，部分，以反对表达 ET-1活性。 我们将利用离体和体内测量 肺血管反应性和PHT在常氧（海平面），轻度， 生理性缺氧（如科罗拉多州丹佛市所见）和严重缺氧 条件，以确定eNOS缺乏的后果。 通过使用 转基因小鼠，我们将避免使用药理学固有的问题， NOS同工型的拮抗剂。 此外，我们将使用完善的 技术在我们的实验室研究的相互作用NO和 ET-1的表达和活性。 更好地了解 这些内源性血管调节物质，它们与一种 另一个，以及体内适度缺氧的效果是主要目标 这可能会带来新的治疗选择。

Pulmonary hypertension (PHT), both primary and secondary, leads to significant morbidity and mortality with few acceptable therapeutic options. While there are well known associated disease states with primary PHT (collagen vascular diseases, anorexigen exposure, idiopathic) and secondary PHT (COPD, congenital heart disease) the initial injury leading to vasoconstriction, vascular remodeling, and increased pulmonary vascular resistance is unknown. Derangements in endogenous vasodilators and vasoconstrictors (NO and ET-1 respectively) have been implicated in the hypertensive pulmonary circulation in experimental models of PHT as well as in the human disease. Our laboratory is interested in the role of endogenously derived nitric oxide (NO) from eNOS (endothelial derived nitric oxide synthase), endothelin-1 (ET-1), and the effect of hypoxia on the development of PHT. Specifically, using mice congenitally deficient in eNOS, alterations in activity of ET-1 and the effect of physiologic levels of hypoxia on the development of PHT are actively being studied. We hypothesize that eNOS deficiency imparts an increased sensitivity to hypoxia leading to the development of PHT under mild, physiologic hypoxia as seen in Denver, CO and in many disease states associates with PHT. Further, we hypothesize that there is significant interactions, or cross-talk, between NO and ET-1 in vivo such that NO acts, in part, to downregulate the expression and activity of ET-1. We will present preliminary data using isolated perfused mouse lung preparations demonstrating increased pulmonary vasoreactivity to hypoxia in eNOS deficient mice. We will also report the development of PHT in eNOS knock-out mice at mild hypoxia (Denver's altitude) compared to controls, which is attenuated by conditions equivalent to sea level. Preliminary data suggesting an increase in expression of ET-1 in eNOS deficient vs. control mice will also be presented. Specifically, we will address the questions: 1) does NO modulate pulmonary vascular tone in a PO2- dependent manner and 2) does NO act, in part, to oppose the expression and activity of ET-1. We will utilize ex vivo and in vivo measurements of pulmonary vasoreactivity and PHT under normoxic (sea level), mild, physiologic hypoxic (as seen in Denver, CO), and severe hypoxic conditions to determine the consequences of eNOS deficiency. By using transgenic mice, we will avoid the problems inherent using pharmacologic antagonists of NOS isoforms. Additionally, we will use well established techniques in our laboratory to study the interaction of NO and the expression and activity of ET-1 in vivo. Improved understanding of these endogenous vasoregulatory substances, their interactions with one another, and the effect of modest hypoxia in vivo are the major goals of this proposal and may lead to new therapeutic options.