MATERNAL DEHYDRATION--FETAL/AMNIOTIC FLUID HOMEOSTASIS

母体脱水--胎儿/羊水稳态

• 批准号: 6389065
• 负责人: Michael Glenn Ross
• 金额: $ 35.32万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389065
• 关键词: RNase protection assay; amniotic fluid; arginine vasopressin; blood volume; body water dehydration; drug screening /evaluation; electrolyte balance; embryo /fetus; homeostasis; hormone receptor; hormone regulation /control mechanism; hyponatremia; in situ hybridization; laboratory rat; nonhuman therapy evaluation; northern blottings; placental transfer; pregnancy; pregnancy disorder chemotherapy; prenatal stress; radioimmunoassay; scintillation counter; sheep; swallowing; ultrasound blood flow measurement; urinalysis

Amniotic fluid (AF) is an essential accompaniment of normal pregnancy, necessary for fetal movement, growth and development. Oligohydramnios, or reduced AF volume, occurs in 8 to 38 percent of all pregnancies. The majority of oligohydramnios patients have no identifiable medical or antepartum complication and only 7 percent of cases have associated fetal malformations. However, oligohydramnios is often associated with conditions of chronic fetal stress, such as intrauterine growth retardation, preeclampsia and postterm pregnancy. These conditions, together with the direct effect of reduced AF volume, results in significant perinatal morbidity and mortality. Increasing AF volume in laboring patients with oligohydramnios improves fetal outcome, though this generally requires rupture of fetal membranes. However, our studies demonstrate that modulation of AF production (fetal urine flow) and AF resorption (fetal swallowing and intramembranous flow) may be utilized to increase AF volume in patients with intact membranes. We have developed a novel model to increase AF volume utilizing maternal administration of the arginine vasopressin (AVP) antidiuretic agonist [desamino, D-Arg8]-AVP (DDAVP). Our studies in the ovine model indicate that maternal hydration and DDAVP induces maternal and fetal plasma hyponatremia, marked increases in fetal urine flow, reduced fetal swallowing and expansion of AF volume. Our human studies have supported the clinical utility of these interventions. Despite these promising results, critical issues of efficacy and safety of DDAVP therapy for both the mother and fetus must be resolved prior to clinical use. Firstly, in studies of efficacy, we will determine the minimum level of maternal hyponatremia which induces and maintains fetal fluid responses, and examine the effects of alterations in placental osmolality gradients. Long term studies will examine the effects of hyponatremia on ovine AF volume, maternal plasma volume and umbilical and uterine blood flows in both normal and oligohydramnios ovine pregnancies. Secondly, in studies of fetal safety, we will determine if fetal brain edema and/or loss of brain electrolytes are induced by hyponatremia. As AVP has important fetal fluid and cardiovascular regulatory roles, we will determine the effect of hyponatremia on fetal osmotic and non- osmotic stimulated AVP secretion. Finally, as permanent imprinting of AVP synthesis and secretion regulatory systems may occur in response chronic tonicity alterations in newborn rats, we will examine the effects of chronic tonicity alterations on fetal AVP transcription and translation. Physiologic assessments will focus on measurements of fetal fluid exchange and fetal plasma and AF volume and composition. Endocrine and molecular assessments will include determination of fluid regulatory hormones and hypothalamic AVP mRNA and pituitary AVP contents, utilizing our newly developed ovine 130 bp cDNA probe and solution and in situ hybridization techniques. The goal of this project is to determine critical efficacy and fetal safety issues central to maternal DDAVP treatment, prior to widespread clinical use in human pregnancies with oligohydramnios.

羊水（AF）是正常妊娠的重要伴随物， 胎儿运动、生长和发育所必需的。羊水过少， 或 AF 体积减少，发生在所有妊娠的 8% 至 38% 中。 这 大多数羊水过少患者没有可识别的医疗或 产前并发症，只有 7% 的病例与之相关 胎儿畸形。 然而，羊水过少通常与 慢性胎儿应激状况，例如宫内生长 发育迟缓、先兆子痫和过期妊娠。 这些条件， 加上自动对焦体积减少的直接影响，导致 显着的围产期发病率和死亡率。 增加 AF 音量 不过，羊水过少的临产患者可以改善胎儿结局 这一般需要胎膜破裂。 然而，我们的 研究表明，调节 AF 的产生（胎儿尿流量） AF 吸收（胎儿吞咽和膜内流量）可能是 用于增加膜完整患者的房颤体积。 我们 开发了一种利用母体增加 AF 体积的新模型 精氨酸加压素 (AVP) 抗利尿激动剂的给药 [去氨基，D-Arg8]-AVP (DDAVP)。 我们对绵羊模型的研究表明 母体水合作用和 DDAVP 诱导母体和胎儿血浆 低钠血症，胎儿尿流量显着增加，胎儿减少 吞咽和扩大 AF 体积。 我们的人体研究支持 这些干预措施的临床效用。 尽管有这些希望 结果、DDAVP 治疗的有效性和安全性的关键问题 临床使用前必须先解决母亲和胎儿的问题。 首先，在功效研究中，我们将确定最低水平 母亲低钠血症会诱导并维持胎儿液体反应， 并检查胎盘渗透压改变的影响 梯度。 长期研究将检查低钠血症的影响 对绵羊 AF 容量、母体血浆容量以及脐带和子宫的影响 正常和羊水过少的绵羊妊娠时的血流量。 其次，在胎儿安全性的研究中，我们将确定胎儿大脑是否 低钠血症会引起水肿和/或脑电解质丢失。 由于 AVP 具有重要的胎儿液体和心血管调节作用， 我们将确定低钠血症对胎儿渗透压和非渗透压的影响 渗透压刺激 AVP 分泌。 最后，作为永久的印记 AVP 合成和分泌调节系统可能会发生响应 新生大鼠的慢性张力改变，我们将检查 慢性张力改变对胎儿 AVP 转录的影响 翻译。 生理评估将侧重于测量 胎儿体液交换和胎儿血浆以及 AF 容量和成分。 内分泌和分子评估将包括液体测定 调节激素和下丘脑 AVP mRNA 和垂体 AVP 内容，利用我们新开发的绵羊 130 bp cDNA 探针和 溶液和原位杂交技术。 该项目的目标 是确定关键疗效和胎儿安全问题的核心 在人类临床广泛使用之前，母体 DDAVP 治疗 妊娠羊水过少。