ATRIAL NATRIURETIC FACTOR--FETAL BLOOD VOLUME REGULATION

心房钠尿因子--胎儿血容量调节

• 批准号: 2194600
• 负责人: GARY MICHAEL SILBERBACH
• 金额: $ 8.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-09 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2194600
• 关键词: albumins; atrial natriuretic peptide; blood volume; congenital aplastic anemia; embryo /fetus; fluid flow; heart function; hemodynamics; intracardiac pressure; intracardiac volume; sheep; vascular endothelium permeability

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.

这项提议的广泛目标是定义心房的作用 利钠肽(ANF)对胎儿血容量的调节作用 健康和疾病中的心脏功能。这项提议是基于 心钠素直接和间接调节胎儿心功能的假说 通过对血管通透性的影响快速降低血容量 液体和蛋白质进入间质。在这个模型中， 胎儿心脏心房是监测心脏的感觉器官。 填充并详细说明ANF，这是一种化学信号 调节血管内外液体量的平衡，按顺序 保持心脏充盈之间最有利的关系 和心输出量。ANF可能在协调 每搏输出量、心脏增长、 血流动力学稳定。心钠素水平通常被发现是 死于胎儿积水的婴儿比例极高。在婴儿中 出生时患有积水的人有50%到98%无法存活。我们实验室的工作形式有 测定ANF增加胎儿体内液体和蛋白质的渗透率 纸巾。心钠素在胎儿病理生理学中的中心地位 我们的实验室已经确定了水肿症的治疗用途 ANF增加了液体和蛋白质在胎儿组织中的渗透。这个 发现ANF在胎儿积水的病理生理学中起中心作用 提示新近发现的ANF受体的治疗用途 拮抗剂HS-142-1。 本次调查的具体目的是：1)确定ANF是否 生理范围内的浓度会导致胎儿血液中的浓度下降 并调节心脏功能。2)确定胎儿心钠素是否降低 循环血药浓度和ANF受体阻断引起的增加 血容量和每搏输出量通过减少血管 水和白蛋白的渗透。3)确定长期服药是否 ANF会导致胎儿积水，如果ANF受体阻断可以防止 绵羊慢性胎儿贫血引起的积水模型中的水肿形成。 为了在长期使用器械的近月胎儿中实现这些目标 羔羊：A)注入ANF以产生循环激素的增量 在生理盐水容量加载过程中发现的范围内。B)双侧心房 将进行附件结扎，ANF受体拮抗剂HS-142- 1白蛋白的给药和血管渗透对容量的影响 将测量扩张，以及，c)血管内和间质液体 体量将在慢性运动前和五天期间进行测量。 胎儿心钠素及心钠素受体拮抗剂HS- 142-1将用于慢性等容积水的胎儿 大出血。这些具体目标将长期承诺整合到 了解ANF在胎儿和新生儿体液生理中的作用 在胎儿血流动力学和脑室方面拥有专业知识的实验室 功能。