ATRIAL NATRIURETIC PEPTIDE IN PULMONARY HYPERTENSION

当前提案的目标是阐明心房肌的作用， 利钠肽（ANP）在缺氧性肺动脉高压中的作用及意义 控制正常人的肺动脉压。 我们的实验 模型是经受常压缺氧（10%）的雄性Sprague-Dawley大鼠 我们的工作假设是，ANP基因可能是一个重要的基因， 表达通过暴露于缺氧而增强， 对缺氧性肺动脉高压的发展有保护作用 高血压 具体目标1和2中的研究将阐明 急性和慢性常压缺氧对心钠素基因表达的影响 释放，受体机制和代谢清除率在大鼠和将 将这些与缺氧诱导的肺动脉压增加相关。 具体目标3和4中的研究将通过以下方式检验我们的工作假设： 测定被动或主动清除内源性ANP的效果， 免疫抗ANP和增加内源性ANP水平， 在所述细胞上施用用于ANP的清除（C）受体的选择性阻断剂， 在该模型中缺氧诱导的肺动脉高压的自然史。 一 具体目标5中的最后一组实验将检验以下假设： 缺氧刺激大鼠心肌心钠素基因表达和心钠素释放 培养的心肌细胞。 这将使我们能够将缺氧与 增加的压力和伸展和心脏肥大， 缺氧适应中ANP基因表达和ANP释放的刺激 心 这些研究将增加我们对ANP在 缺氧性肺动脉高压的发病机制，并将奠定 一种有趣的新方法来治疗缺氧 男性肺动脉高压

The goal of the current proposal is to elucidate the role of atrial natriuretic peptide (ANP) in hypoxia-induced pulmonary hypertension and the control of pulmonary artery pressure in normal subjects. Our experimental model is the male Sprague-Dawley rat subjected to normobaric hypoxia (10% O2, 1 atm) X 4 weeks or less. Our working hypothesis is that ANP gene expression is enhanced by exposure to hypoxia and that the ANP so generated has a protective effect against the development of hypoxic pulmonary hypertension. Studies in Specific Aims 1 and 2 will elucidate the effects of acute and chronic normobaric hypoxia on ANP gene expression, ANP release, receptor mechanisms and metabolic clearance in the rat and will relate these to the hypoxia induced increase in pulmonary artery pressure. Studies in Specific Aims 3 and 4 will test our working hypothesis by determining the effects of removing endogenous ANP by passive or active immunization against ANP and of augmenting endogenous ANP levels by administering a selective blocker of clearance (C) receptors for ANP on the natural history of hypoxia induced pulmonary hypertension in this model. A final set of experiments in Specific Aim 5 will test the hypothesis that hypoxia stimulates ANP gene expression and ANP release in rat cardiac myocytes in culture. This will permit us to dissociate hypoxia from increased pressure and stretch and from cardiac hypertrophy as possible stimuli for ANP gene expression and ANP release in the hypoxia adapted heart. These studies will increase our understanding of the role of ANP in the pathogenesis of hypoxia induced pulmonary hypertension and will lay the ground work for an interesting new approach to the treatment of hypoxic pulmonary hypertension in man.