NITRIC OXIDE CONTROL OF UTERINE CONTRACTILITY

一氧化氮控制子宫收缩

• 批准号: 2202582
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 11.81万
• 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/2202582
• 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.

怀孕期间子宫静止，直到足月，是必需的， 通过提供一个宁静的环境， 成长中的胎儿未能维持子宫松弛直至足月 导致早产，这是婴儿死亡的主要原因。 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质。我们开始研究， 检查大鼠中是否存在L-精氨酸-NO-cGMP-松弛系统 子宫，如果它抑制收缩。我们的初步研究提供了 强有力的证据表明，在大鼠中存在NO-松弛途径 子宫，并表明该系统可能在维持 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. L-精氨酸NO-cGMP-通路存在于子宫中， 特异性抑制子宫收缩 B. NO-cGMP-松弛途径在怀孕期间上调。 C. NO-cGMP的产生及其舒张作用是通过调节NO的浓度来实现的。 严格监管。 这项研究的具体目标是： 1.为了进一步确定NO-cGMP-松弛系统的存在， 检查子宫并确定子宫内是否产生NO。为此，我们将 使用各种试剂调节通路并测量子宫 体外收缩性。 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NOS同工型。 3.研究NO-cGMP-松弛系统是否被上调 在怀孕期间，如果它是激素调节。 4.探讨NO-cGMP调节子宫内膜异位症的机制。 收缩性 5.为了确定是否操纵NO-cGMP级联过程中， 怀孕会影响怀孕的结果。 6.探讨人子宫组织中NO-cGMP系统的存在， 确定在怀孕期间子宫对该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，我们将使用药理学研究， 体外收缩力测量，NO和cGMP的生化测定 生产，精氨酸转化为瓜氨酸，组织化学定位 并确定子宫中NOS的亚型。这些研究将 提供了重要的信息，通过机制，子宫 在妊娠和分娩开始期间调节收缩性。 从这些研究中获得的知识可以为设计 适当的治疗策略，以减少早产。