EDRF REGULATION OF UTERINE AND UMBILICAL BLOOD FLOW

EDRF 对子宫和脐血流量的调节

• 批准号: 3368924
• 负责人: KENNETH E CLARK
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3368924
• 关键词: blood pressure; cardiac output; catheterization; cyclic GMP; embryo /fetus hypoxia; estrogens; high performance liquid chromatography; hormone regulation /control mechanism; mathematical model; pregnancy circulation; prenatal stress; respiratory gas analyzer; sheep; ultrasound blood flow measurement; umbilical cord; uterus; vascular endothelium; vascular resistance; vascular smooth muscle; vasoconstrictors; vasodilators

Adequate uterine blood is required for normal growth and development of the fetus. Blood flowing to the uterus provides the blastocyst, embryo and fetus with all the necessary nutrients and oxygen which are required for growth and development. Since arterial blood pressure remains relatively constant during pregnancy, changes in uteroplacental blood flow are directly related to decreases in uterine vascular resistance. A significant portion of this change is due to the development of a new parallel circuit, the placenta. However, it is also thought that locally produced vasodilator agents are responsible for a significant portion of the increase in blood flow especially in late gestation. Recently, many cardiovascular scientists have turned their interest to the role of the endothelial cells in regulating blood flow in organs throughout the body. Endothelial cells produce several very potent vasodilators including endothelial derived relaxing factor (EDRF) and PGI(2). EDRF is thought to be the vasodilator nitric oxide, released during the conversion of L-arginine to L-citrulline, a reaction catalyzed by the calcium calmodulin dependent nitric oxide synthetase. This enzyme can be blocked by analogues of L-arginine (i.e., L-nitro arginine, L-mono-methyl arginine, etc.) an effect which is reversible by large doses of L-arginine but not D-arginine. The present application is based on exciting preliminary data (page 40) which demonstrates that estrogen induced increases in uterine blood flow are mediated by EDRF (NO) and that blockade of EDRF (NO) synthesis results in a 30% reduction in uteroplacental blood flow in late term sheep. Studies are outlined which will evaluate the role of EDRF in regulating systemic arterial blood pressure as well as uterine vascular resistance in normal pregnant and nonpregnant sheep and umbilical vascular resistance in the fetus. We will determine if nitric oxide synthetase (NOS) activity is increased in systemic and uterine vascular smooth muscle during pregnancy and determine if estrogen can induce NOS activity in the nonpregnant systemic and uterine vasculature. Studies are also planned which will determine if the nitric oxide breakdown product, nitrate, is elevated in the uterine and umbilical circulation in pregnancy and increases during gestation. We will also determine if estrogen administration increases systemic and uterine venous levels of plasma nitrate and cGMP. Finally, the ability of EDRF to modulate organ blood flow distribution as well as systemic and uterine vascular responses to endogenously occurring vasoconstrictors (norepinephrine, angiotensin II, serotonin and endothelin-1) in pregnant and nonpregnant sheep will be determined. These experiments should further clarify the role of endothelial derived relaxing factors in the regulation of systemic and uterine blood flow throughout pregnancy. Investigating their interactions with endogenous vasoconstrictors will increase our understanding of the physiological basis of vascular regulation and its pathologic deviation.

正常的生长发育需要充足的子宫血 胎儿 流向子宫的血液提供了胚泡， 为胚胎和胎儿提供所有必需的营养和氧气， 生长和发展所需的。 由于动脉血压 在怀孕期间保持相对恒定，子宫胎盘的变化 血流量与子宫血管减少直接相关 阻力 这一变化的很大一部分是由于 一种新的平行回路胎盘的发展 但据 我也认为，当地生产的血管扩张剂是负责， 对于血流量增加的显著部分，特别是在 妊娠晚期。 最近，许多心血管科学家 他们对内皮细胞在调节血液中的作用的兴趣 流经全身的器官 内皮细胞产生几种 非常有效的血管扩张剂，包括内皮衍生松弛因子 （EDRF）和PGI（2）。 EDRF被认为是血管扩张剂一氧化氮， 在L-精氨酸转化为L-瓜氨酸的过程中释放， 钙/钙调素依赖性一氧化氮催化反应 合成酶 这种酶可被L-精氨酸类似物阻断 (i.e., L-硝基精氨酸、L-单甲基精氨酸等）的效应 大剂量L-精氨酸可逆转，但D-精氨酸不可逆转。 的 本申请基于令人兴奋的初步数据（第40页） 这表明雌激素导致子宫血流量增加 血流由EDRF（NO）介导，阻断EDRF（NO）合成 导致晚期子宫胎盘血流减少30% 羊 研究概述将评估的作用，EDRF在 调节全身动脉血压以及子宫血管 正常妊娠和非妊娠绵羊和脐带中的阻力 胎儿的血管阻力。 我们将确定一氧化氮 全身和子宫血管中NOS活性增加 平滑肌在怀孕期间，并确定雌激素是否可以诱导NOS 在非妊娠系统和子宫血管中的活性。 研究 也将决定一氧化氮的分解 硝酸盐在子宫和脐循环中升高 在怀孕期间和怀孕期间增加。 我们还将确定 如果雌激素给药增加全身和子宫静脉水平 血浆硝酸盐和环鸟苷酸 最后，EDRF的调制能力 器官血流分布以及全身和子宫血管 对内源性血管收缩剂（去甲肾上腺素， 血管紧张素II、5-羟色胺和内皮素-1 羊的决定。 这些实验应进一步阐明 内皮源性舒张因子在调节血管内皮细胞凋亡中的作用 全身和子宫血流。 调查 它们与内源性血管收缩剂的相互作用会增加我们的 了解血管调节的生理基础及其 病理性偏差