ATRIAL NATRIURETIC PEPTIDE IN PULMONARY HYPERTENSION

当前提案的目标是阐明心房肌的作用 心钠素在缺氧性肺动脉高压中的作用及意义 正常受试者的肺动脉压控制。我们的实验 模型为雄性SD大鼠常压低氧(10% O2，1 atm)×4周或更短时间。我们的工作假设是心钠素基因 缺氧可增强心钠素的表达，并由此产生心钠素 对缺氧性肺损伤的发生有保护作用 高血压。对特定目标1和2的研究将阐明这些影响 急、慢性常压低氧对心钠素基因表达的影响 大鼠和Will的释放、受体机制和代谢清除 这与低氧引起的肺动脉压升高有关。 具体目标3和4的研究将通过以下方式验证我们的工作假设 被动与主动清除内源性心钠素效果的比较 抗ANP免疫和提高内源性ANP水平的研究 给予选择性心钠素清除(C)受体阻断剂 在这个模型中，缺氧性肺动脉高压的自然历史。一个 在特定目标5中的最后一组实验将检验以下假设 低氧刺激大鼠心脏ANP基因表达和ANP释放 培养中的肌细胞。这将允许我们将缺氧与 增加压力和伸展，尽可能减少心肌肥厚 低氧适应对心钠素基因表达和心钠素释放的刺激 心。这些研究将增加我们对心钠素在 低氧性肺动脉高压的发病机制 为治疗缺氧症提供有趣的新方法的基础工作 人的肺动脉高压。

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.