PO2 MODULATION OF NO AND ET1 IN PULMONARY HYPERTENSION

原发性和继发性的肺动脉高压(PHT)会导致 发病率和死亡率很高，几乎没有可接受的治疗方法 选择。虽然众所周知的相关疾病状态与 原发性PHT(胶原性血管疾病，厌食暴露， 特发性)和继发性PHT(COPD、先天性心脏病) 最初的损伤导致血管收缩、血管重塑和 肺血管阻力增加是未知的。乱七八糟的 内源性血管扩张剂和血管收缩药(分别为NO和ET-1) 与高血压的肺循环有牵连 PHT的实验模型以及在人类疾病中的应用。我们的 实验室对内源性一氧化氮的作用感兴趣 内皮源性一氧化氮合酶(ENOS)产生的氧化物(NO)， 内皮素-1(ET-1)，以及低氧对血管生成的影响 PHT。具体地说，使用eNOS先天缺陷的小鼠， ET-1活性的变化及生理水平的影响 低氧对PHT发育的影响正在积极研究中。 我们假设eNOS缺乏症增加了对 轻度、生理性低氧导致PHT的发生 在丹佛，CO和许多疾病状态中看到的低氧与 PHT。此外，我们假设存在显著的相互作用， 或体内NO和ET-1之间的串扰，使得NO部分地， 下调ET-1的表达和活性。我们将向大家介绍 用离体鼠肺灌流制备的初步数据 内皮型一氧化氮合酶肺血管对低氧的反应性增强 有缺陷的小鼠。我们还将在eNOS中报告PHT的发展 在轻度缺氧(丹佛海拔)下的基因敲除小鼠与对照组相比， 它被相当于海平面的条件所衰减。初步 内皮型一氧化氮合酶缺陷型与内皮型一氧化氮合酶缺陷型相比，ET-1的表达增加。 对照小鼠也将亮相。具体地说，我们将解决 问题：1)PO2中的肺血管张力是否没有调节- 从属的态度和2)没有行动，部分地反对表达 和ET-1的活性。我们将利用体外和体内测量 常氧(海平面)、轻度、 生理性低氧(如在科罗拉多州丹佛)和严重低氧 确定eNOS缺乏后果的条件。通过使用 转基因小鼠，我们将避免使用药理学固有的问题 一氧化氮合酶异构体的拮抗剂。此外，我们将使用成熟的 我们实验室的技术来研究NO和 ET-1在体内的表达和活性。更好地理解 这些内源性血管调节物质，它们与一种 另一个主要目标是体内适度低氧的影响 并可能带来新的治疗选择。

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.