ATRIAL NATRIURETIC FACTOR: FETAL BLOOD VOLUME REGULATION

该提案的主要目标是定义心房肌的作用， 利钠肽（ANF）在调节胎儿血容量和 健康和疾病中的心脏功能。 所涉提议主要是 心钠素通过直接和间接调节胎儿心功能假说 通过对血管渗透的影响迅速减少血容量 大量的液体和蛋白质进入组织间室。 在这个模型中， 胎儿心房作为监测心脏感觉器官 填充并响应ANF的精心制作，一种化学信号， 调节血管内外液体量的平衡， 为了维持心脏充盈和心脏收缩之间的最有利关系， 和心输出量 胜利阵线可以在协调 心室每搏输出量，心脏生长， 和血液动力学稳定性。 ANF水平通常被发现是 婴儿死于胎儿水肿的几率极高 产下 出生时有积水的人有50 - 98%不能存活 我们实验室的工作形式 确定ANF增加胎儿的液体和蛋白质渗透， 组织中 心钠素在胎儿生长发育的病理生理学中起着重要作用， 我们的实验室已经确定 ANF增加胎儿组织中的液体和蛋白质渗透。 的 发现ANF在胎儿水肿的病理生理学中起中心作用， 建议最近发现的ANF受体的治疗用途 拮抗剂HS-142-1。 本研究的具体目的是：1）确定ANF是否 生理范围内的浓度导致胎儿血液中 调节心脏功能。2)确定胎儿ANF是否降低 循环浓度和ANF受体阻断导致增加 血容量和心室每搏输出量， 水和白蛋白的渗透。3)确定长期给药是否 的ANF产生胎儿水肿，如果ANF受体阻断剂阻止 在慢性胎儿贫血诱导水肿的绵羊模型中的水肿形成。 为了实现这些目标，在长期仪器近足月胎儿 羔羊：a）将输注ANF以产生循环激素的增量 在生理盐水体积加载期间发现的范围内。 B）双侧心房 将进行附件结扎，ANF受体拮抗剂HS-142- 1次给药和白蛋白的血管渗透对体积的反应 将测量扩张，以及，c）血管内和间质液 将在5天慢性给药前和给药期间测量体积 给予胎儿ANF和ANF受体拮抗剂HS- 将142-1给予通过慢性等容给药使胎儿水肿的胎儿。 出血 这些具体目标包括长期承诺， 了解心钠素在胎儿和新生儿体液生理学中的作用， 一个拥有胎儿血流动力学和心室动力学专业知识的实验室， 功能

The broad objective of this proposal is to define the role of atrial natriuretic peptide (ANF) in the regulation of fetal blood volume and cardiac function in health and disease. The proposal is based on the hypothesis that ANF modulates fetal cardiac function by directly and rapidly decreasing blood volume through its effect on vascular permeation of fluid and protein into the interstitial compartment. In this model, the fetal cardiac atria operate as a sense organ that monitors cardiac filling and responds with elaboration of ANF, a chemical signal that regulates the balance of intra-and extra-vascular fluid volume, in order to maintain the most advantageous relationship between cardiac filling and cardiac output. ANF may play a fundamental role in orchestrating the critical relationship between ventricular stroke volume, cardiac growth, and hemodynamic stability. ANF levels are routinely found to be extremely high in infants dying from fetal hydrops. Among the infants born with hydrops 50 to 98% do not survive. Work form our laboratory has determined that ANF increases fluid and protein permeation in fetal tissues. The finding that ANF is central in the pathophysiology of fetal hydrops would suggest a therapeutic use for our laboratory has determined that ANF increases fluid and protein permeation in fetal tissues. The finding that ANF is central in the pathophysiology of fetal hydrops would suggest a therapeutic use for the recently discovered ANF receptor antagonists HS-142-1. The specific aims of this investigation are to: 1) Determine if ANF concentrations in the physiologic range cause decreases in fetal blood volume and modulate cardiac function. 2) Determine if decreased fetal ANF circulating concentrations and ANF receptor blockage cause increased blood volume, and ventricular stroke volume by decreasing vascular permeation of water and albumin. 3) Determine if chronic administration of ANF produces hydrops fetalis and if ANF receptor blockade prevents edema formation in a sheep model of chronic fetal anemia induced hydrops. To accomplish these aims in the chronically instrumented near term fetal lamb: a) ANF will be infused to produce increments of circulating hormone within the range found during saline volume loading. b) Bilateral atrial appendage ligation will be performed, the ANF receptor antagonist HS-142- 1 administered and vascular permeation of albumin in response to volume expansion will be measured and, c) Intravascular and interstitial fluid volume will be measured before and during a five day chronic administration of ANF to the fetus and the ANF receptor antagonist HS- 142-1 will be administered to fetuses made hydropic by chronic isovolumic hemorrhage. These specific aims integrate the long term commitment to understanding the role of ANF in fetal and newborn fluid physiology with a laboratory possessing expertise in fetal hemodynamics and ventricular function.