ENDOCRINE CONTROL OF FETAL CARDIOVASCULAR DYNAMICS

拟议研究的目的是：（1）制定一项全面的 了解心脏激素ANF在长期 正常和应激状态下胎儿心血管功能的维持 条件，2）检查内分泌和旁分泌因素， 调节ANF在正常和应激条件下的释放， 在细胞和分子水平上的作用位点，以及3）探索 心钠素基因在胎儿心房发育中表达规律 心室，以及压力在改变这种模式的影响， 表情 待研究的应激条件是长时间缺氧 和体积膨胀。 采取的方法是首先利用整个 动物模型，以确定长期心血管和肾脏影响 胜利阵线。 其次，将使用整体动物和细胞培养实验 结合描述介导ANF释放的因子， 表情 第三，应用分子生物学技术检测ANF 基因表达。 这些研究将在绵羊胎仔中进行， 妊娠105 - 115天和130 - 140天（足月= 145天） 以确定这些调节机制的发展变化。 要测量的心血管变量是动脉和静脉 血压、心率、心输出量、血气和pH、血细胞比容和 血浆蛋白浓度、尿流速和尿排泄 电解质 在第一个系列的实验中，长期的影响- 将确定足月输注ANF对胎儿心血管变量的影响 长期插管的胎儿。 胜利阵线参与回返 动脉压、血容量和尿流量恢复正常 缺氧和容量负荷将通过使用特定的 ANF拮抗剂。 第二个系列的实验将在 在长期插管的胎儿中， 内皮素、去甲肾上腺素和肾上腺素介导ANF释放， 在培养的胎儿心房心肌细胞中， 这些因子在刺激ANF分泌和表达ANF中的作用 信使RNA。 第三个系列的实验将在 胎儿心脏组织，以确定ANF的表达模式 心房和心室中的信使RNA，以及长时间 缺氧或体积膨胀改变这种表达。 我们将测试 以下假设在胎儿：1）ANF是一种重要的激素， 长期维持正常心血管功能 条件和缺氧或体积扩张应激期间，2） 内皮素和儿茶酚胺是心钠素释放的介质， 直接作用于胎儿心房心肌细胞，增强ANF分泌， 诱导心钠素信使RNA的表达; 3）心钠素基因水平 表达在心房和心室的胎儿在后者 长期的缺氧或容积应激可导致妊娠中期 扩张. 这些研究很重要，因为它们将扩大我们的 了解控制子宫内胎儿异常和压力的知识 在出生时。

The purposes of the proposed studies are 1) to generate a comprehensive understanding of the role of the cardiac hormone ANF in the long-term maintenance of fetal cardiovascular function under normal and stress conditions, 2) to examine the endocrine and paracrine factors which regulate the release of ANF under normal and stress conditions, and their site of action at the cellular and molecular levels, and 3) to explore the developmental pattern of ANF gene expression in fetal atria and ventricles, and the effects of stress in altering this pattern of expression. The stress conditions to be studied are prolonged hypoxia and volume expansion. The approach taken is to first utilize the whole animal model to define the long-term cardiovascular and renal effects of ANF. Secondly, whole animal and cell culture experiments will be used in combination to delineate the factors which mediate ANF release and expression. Thirdly, molecular techniques will be used to determine ANF gene expression. These studies will be carried out in ovine fetuses at 105 to 115 days and 130 to 140 days gestation (term = 145 days) in order to determine the developmental changes in these regulatory mechanisms. The cardiovascular variables to be measured are arterial and venous pressures, heart rate, cardiac output, blood gases and pH, hematocrit and plasma protein concentration, urine flow rate and urinary excretion of electrolytes. In the first series of experiments, the effects of a long- term infusion of ANF on fetal cardiovascular variables will be determined in chronically catheterized fetuses. The involvement of ANF in returning arterial pressure, blood volume and urine flow to normal during prolonged hypoxia and volume loading will be investigated by the use of a specific antagonist for ANF. The second series of experiments will be carried out in chronically catheterized fetuses to delineate the effects of endothelin, norepinephrine and epinephrine in mediating ANF release, and in cultured fetal atrial cardiocytes to examine the direct effects of these factors in stimulating ANF secretion and expression of ANF messenger RNA. The third series of experiments will be carried out in fetal heart tissues to determine the pattern of expression of ANF messenger RNA in the atria and ventricles, and the effects of prolonged hypoxia or volume expansion in altering this expression. We will test the following hypotheses in the fetus: 1) ANF is an important hormone in the longterm maintenance of cardiovascular function under normal conditions and during the stress of hypoxia or volume expansion, 2) endothelin and the catecholamines are mediators for ANF release, and they act directly on fetal atrial cardiocytes to enhance ANF secretion and induce the expression of ANF messenger RNA, and 3) the level of ANF gene expression in the atria and ventricles of the fetus during the latter half of gestation can be induced by prolonged stress of hypoxia or volume expansion. These studies are important because they will expand our knowledge of the control of the fetal abnormalities in utero and stress at birth.