NITRIC OXIDE CONTROL OF UTERINE CONTRACTILITY

一氧化氮控制子宫收缩

基本信息

批准号：
2403297
负责人：
CHANDRASEKHAR YALLAMPALLI
金额：
$ 14.4万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 1999-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2403297
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

项目摘要

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为止，直到任期为止通过提供宁静的环境来成功完成妊娠增长的胎儿。无法维持子宫放松直到学期结果是早产，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）是平滑肌松弛的有效介体。我们开始研究检查大鼠中是否存在L-精氨酸-NO-CGMP - 释放系统子宫及如果抑制收缩力。我们的初步研究提供大鼠中存在无释放途径的有力证据子宫并建议该系统可能在维持怀孕期间的子宫静止。为了扩展这些研究，我们建议测试以下假设：一个。子宫中存在L-精氨酸NO-CGMP-Pathway，特别抑制子宫收缩性。 b。在怀孕期间，NO-CGMP - 释放途径被上调。 c。无CGMP的产生和无CGMP的放松效应是荷尔蒙调节。这项研究的具体目的是： 1。进一步建立在子宫并确定是否在子宫中产生无。为此，我们将使用各种药物调节途径并测量子宫体外收缩性。 2。在子宫组织中定位一氧化氮合酶（NOS）活性并确定该组织中存在哪些非NOS的同工型。 3。调查无CGMP - 放松系统是否上调在怀孕期间，如果受到激素的调节。 4。检查子宫无CGMP调节涉及的机制收缩力。 5。确定是否操纵无CGMP级联怀孕会影响怀孕。 6。调查人子宫中无CGMP系统的存在确定子宫对该系统的反应是否有所不同交付，非保释和未怀孕的妇女。为了完成这些研究，我们将使用体外收缩度测量，NO和CGMP的生化测定生产，精氨酸到瓜氨酸转化，组织化学定位并确定子宫中NOS的同工型。这些研究会提供有关子宫的机制的重要信息收缩性在妊娠和劳动力开始期间受到监管。这些研究的知识可能为设计提供了基础适当的治疗策略来减少早产劳动。