NITRIC OXIDE CONTROL OF UTERINE CONTRACTILITY

一氧化氮控制子宫收缩

• 批准号: 2202583
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 13.31万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2202583
• 关键词: amine oxidoreductase; arginine; birth; cyclic GMP; enzyme activity; hormone regulation /control mechanism; human subject; immunocytochemistry; laboratory rat; muscle contraction; nitric oxide; northern blottings; nucleic acid probes; phosphodiesterases; polymerase chain reaction; pregnancy; protein isoforms; uterus

Uterine quiescence during pregnancy, until term, is required for successful completion of gestation by providing a tranquil environment for the growing fetus. Failure to maintain uterine relaxation until term results in preterm delivery, which is the leading cause of infant mortality and morbidity. Recent evidence suggests that nitric oxide (NO) is a potent mediator of smooth muscle relaxation. We initiated studies to examine if an L-arginine-NO-cGMP-relaxation system is present in the rat uterus and if it inhibits contractility. Our preliminary studies provide strong evidence for the presence of a NO-relaxation pathway in the rat uterus and suggest that this system might play a role in maintaining uterine quiescence during pregnancy. To extend these studies we propose to test the following hypotheses: a. A L-arginine NO-cGMP-pathway is present in the uterus and that it specifically inhibits uterine contractility. b. The NO-cGMP-relaxation pathway is upregulated during pregnancy. c. The generation of NO-cGMP and relaxation effects of NO-cGMP are hormonally regulated. The specific aims of this study are: 1. To further establish the existence of a NO-cGMP-relaxation system in the uterus and determine if NO is produced in the uterus. For this we will use various agents to modulate the pathway and measure uterine contractility in vitro. 2. To localize nitric oxide synthase (NOS) activity in the uterine tissues and to ascertain which isoform(s) of NOS are present in this tissue. 3. To investigate whether the NO-cGMP-relaxation system is upregulated during pregnancy and if it is hormone regulated. 4. To examine the mechanisms involved in the NO-cGMP regulation of uterine contractility. 5. To ascertain whether manipulation of the NO-cGMP cascade during pregnancy will affect the pregnancy outcome. 6. To investigate the existence of NO-cGMP system in the human uterus and determine if the uterus reacts to this system differently in pregnant delivering, nondelivering and nonpregnant women. To accomplish these studies, we will use pharmacological studies of in vitro contractility measurement, biochemical assays for NO and cGMP production, arginine to citrulline conversion, histochemical localization and determine the isoform(s) of the NOS in the uterus. These studies will provide important information on the mechanisms through which uterine contractility is regulated during gestation and initiation of labor. Knowledge from these studies may provide the basis for designing appropriate therapeutic strategies to reduce preterm labor.

怀孕期间的子宫静止，直到足月，需要 通过提供宁静的环境，成功完成妊娠 成长中的胎儿。未能在足月前保持子宫松弛 导致早产，这是婴儿的主要原因 死亡率和发病率。最近的证据表明，一氧化氮(NO) 是一种强有力的肌肉松弛的中介物。我们发起了研究，以 检查大鼠体内是否存在L-精氨酸-一氧化氮-环鸟苷-松弛系统 如果它抑制了子宫的收缩。我们的初步研究提供了 大鼠体内存在非松弛通路的有力证据 子宫，提示这个系统可能在维持 怀孕期间子宫静止。为了扩展这些研究，我们建议 测试以下假设： A.子宫中存在L-精氨酸NO-cGMP途径，它 特别抑制子宫收缩能力。 B.NO-cGMP-松弛途径在妊娠期间上调。 C.NO-cGMP的生成及其松弛效应 荷尔蒙调节的。 这项研究的具体目的是： 1.进一步证明了无cGMP-松弛系统的存在性 并确定是否在子宫中产生NO。为此，我们将 使用各种药物调节通路和测量子宫 体外收缩能力。 2.定位子宫组织中一氧化氮合酶(NOS)活性 并确定该组织中存在哪种亚型(S)的一氧化氮合酶。 3.探讨NO-cGMP-松弛系统是否上调 在怀孕期间，如果是激素调节的话。 4.探讨NO-cGMP对子宫的调控机制 伸缩性。 5.确定NO-cGMP的操纵是否在 怀孕会影响妊娠结局。 6.探讨NO-cGMP系统在人子宫中的存在及 确定怀孕期间子宫对这一系统的反应是否不同 分娩、未分娩和未怀孕的妇女。 为了完成这些研究，我们将使用In的药理学研究 NO和cGMP的体外收缩测定和生化测定 生产、精氨酸转化为瓜氨酸、组织化学定位 并测定子宫中一氧化氮合酶的异构体(S)。这些研究将 提供了有关子宫通过哪些机制 收缩能力在妊娠和分娩开始时受到调节。 来自这些研究的知识可能会为设计提供基础 采取适当的治疗策略，减少早产。