ATRIAL NATRIURETIC PEPTIDE AND THE LUNG

本提案的总体目标是阐明生理学 心房钠尿肽（ANP）和肺之间的相互作用。 我们 第一个假设是ANP调节肺动脉高压反应， 无论是急性还是慢性。 为了探索这一点，我们将测量血浆ANP 静脉、肺动脉（PA）和全身动脉中的RIA水平 急性暴露于缺氧、血管紧张素-II或苯肾上腺素期间的血液 清醒的，长期使用仪器的大鼠。 然后我们将尝试抑制 使用ANP抗体增强ANP的作用， ANP代谢的抑制剂，试图改变生理 反应 我们将在患有慢性肺结核的大鼠中进行类似的研究。 慢性缺氧和野百合碱注射引起的高血压， 一种自发性肺动脉高压的老鼠。 我们将 测定血浆心钠素水平在静脉和PA血液中的发展过程中， 肺动脉高压，右心房和左心房的组织ANP水平， 心室和肺中的肺动脉高压的发展。 我们 还将检测这些组织中ANP的mRNA水平，并确定 慢性心钠素输注对肺动脉高压严重程度的影响 高血压 基于在细胞培养系统中的初步观察， ANP对弹性蛋白产生的刺激作用和对 平滑肌细胞增殖，我们还假设ANP调节 肺动脉高压时血管重构的程度。 我们将 确定ANP对结缔组织作用的剂量反应关系 以及大鼠PA中弹性和胶原的DNA合成和mRNA水平， 胸主动脉血管外植体。 我们还将尝试在体内获得 通过评估这些观察结果的mRNA水平变化， 弹性蛋白和胶原蛋白以及组织中弹性蛋白和胶原蛋白水平 肺和主动脉血管以及无氧和慢性肺组织中 缺氧大鼠静脉注射外源性ANP。 第三个假设是肺在肺的病理过程中起着重要作用。 循环ANP的清除和代谢。 我们将确定特异性 离体大鼠肺摄取ANP的百分比和结合位点的比例 它们是使用特定C受体配体的清除（或C）受体。 我们 还将检查注射ANP后的肺流出液和匀浆 使用反相HPLC测定代谢物，并将确定是否急性 或慢性缺氧影响摄取。 最后，我们将确定位置 使用电子显微镜观察肺中特定的ANP结合位点， 放射自显影 通过探索ANP和肺的上述相互作用，我们的目的是获得 深入了解这种最近发现的肽激素如何参与 肺动脉高压反应的生理调节。 等 新的见解可能会导致新的方法来药物治疗肺 高血压

The overall objective of this proposal is to clarify physiological interactions between atrial natriuretic peptide (ANP) and the lung. Our first hypothesis is that ANP modulates pulmonary hypertensive responses, both acute and chronically. To explore this, we will measure plasma ANP levels by RIA in venous, pulmonary arterial (PA), and systemic arterial blood during acute exposures to hypoxia, angiotensin-II or phenylephrine in awake, chronically instrumented rats. We will then attempt to inhibit the action of ANP using ANP antibodies and to augment the action of ANP using inhibitors of ANP metabolism in an attempt to modify the physiologic response. We will perform similar studies in rats with chronic pulmonary hypertension induced by chronic hypoxia and monocrotaline injection, and in a strain of rat that develops spontaneous pulmonary hypertension. We will assay plasma ANP levels in venous and PA blood during the development of pulmonary hypertension, and tissue ANP levels in right and left atria and ventricles and in lung following development of pulmonary hypertension. We will also assay mRNA levels for ANP in these tissues and will determine the effects of a chronic infusion of ANP on the severity of pulmonary hypertension. Based upon preliminary observations in cell culture systems demonstrating stimulatory effects of ANP on elastin production and inhibitory effects on smooth muscle cell proliferation, we also hypothesize that ANP modulates the degree of vascular remodeling in pulmonary hypertension. We will determine dose response relationships of ANP effects on connective tissue and DNA synthesis and mRNA levels for elastic and collagen in rat PA and thoracic aortic vessel explants. We will also attempt to obtain in vivo correlations for these observations by assessing changes in mRNA levels for elastin and collagen and tissue levels for elastin and collagen in pulmonary and aortic vessels and in lung tissue of nonmoxic and chronically hypoxic rats following intravenous infusions of exogenous ANP. A third hypothesis is that the lung plays an important role in the clearance and metabolism of circulating ANP. We will determine specificity of uptake of ANP in isolated rat lungs and the proportion of binding sites that are clearance (or C) receptors using a specific C-receptor ligand. We will also examine lung effluent and homogenates following injection of ANP for metabolites using reverse phase HPLC, and will determine whether acute or chronic hypoxia affects uptake. Finally, we will determine the location of specific ANP binding sites in the lung using electron microscopy and autoradiography. By exploring the above interactions of ANP and the lung, we aim to gain insight into how this recently discovered peptide hormone participates in the physiologic regulation of pulmonary hypertensive responses. Such insights may lead to new approaches to pharmacotherapy of pulmonary hypertension.