CELLULAR MECHANISMS OF OXYTOCIN ACTION

催产素作用的细胞机制

• 批准号: 3327508
• 负责人: ROBERT K RIEMER
• 金额: $ 10.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1994-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3327508
• 关键词: birth; calcium flux; diacylglycerols; eicosanoid metabolism; endometrium; enzyme inhibitors; estrogens; fluorescence microscopy; high performance liquid chromatography; hormone receptor; hormone regulation /control mechanism; indomethacin; inositol phosphates; laboratory rabbit; lipid metabolism; lipoxygenase; muscle contraction; myometrium; myosins; oxytocin; phospholipase A2; phospholipase C; phosphorylation; progesterone; prostaglandin endoperoxide synthase; prostaglandins; tissue /cell culture

The pituitary hormone oxytocin is thought to play an important role in parturition in mammals including humans. Although it has been and is extensively used to induce labor in women, little is known about its mechanism of action. Oxytocin concentration in the circulation changes little at the onset of labor, however, our previous studies in the rabbit indicate that myometrial oxytocin receptor levels increase tenfold just before the onset of labor in association with a marked increase in sensitivity to this hormone. In this project, we will utilize our recently developed dispersal and primary culture technique for rabbit uterus to characterize directly the myometrial and endometrial mechanisms of oxytocin action and also determine how they are regulated and how they interact with other uterotonic agents. We propose to characterize the post-receptor response to oxytocin by examining the production of inositol 1,4,5 triphosphate and 1,2, diacylglycerols, the elevation of intracellular calcium concentration, and myosin light chain phosphorylation. We have previously shown that the contractile sensitivity to oxytocin in rabbits increase sharply prior to term and is associated with a ten fold increase in specific receptor concentration. We will determine whether changes in receptor concentration completely explain increased sensitivity by comparing changes in receptor concentration induced by in vivo treatment with estrogen and progesterone to determine the sites at which the response cascade can be chronically regulated. We have also shown that eicosanoid production accompanies oxytocin action, that such production can enhance myometrial response to oxytocin, and that these changes can be mimicked by in nonpregnant animals by estrogen treatment. The role of diacylglycerol production via phospholipases C and arachidonate production via phospholipases A2 and C in the subcellular response to oxytocin receptor occupancy will also be examined in terms of the potential for eicosanoid production and acute regulation of response. The interaction of the endometrial and myometrial actions of oxytocin will be examined for effects on myometrial activation. To understand how this response mechanism is acutely regulated, we will determine whether the oxytocin receptors are subject to homologous or heterologous desensitization. Thee studies will provide a mechanistic basis for understanding the physiologic effects of oxytocin on myometrium. This information is necessary to ultimately determine why oxytocin is sometimes unable to cause labor or has only a brief effect to stimulate uterine contractions, despite the presence of receptors. It may also suggest methods which ensure successful induction of labor.

垂体激素催产素被认为在 包括人类在内的哺乳动物的分娩。尽管过去和现在都是 广泛用于妇女引产，但人们对其知之甚少 作用机制。 循环中催产素浓度 在分娩开始时变化不大，然而，我们之前的研究 兔子表明子宫肌层催产素受体水平增加 临产前十倍，伴有明显的 对这种激素的敏感性增加。 在这个项目中，我们将 利用我们最近开发的分散和原代培养技术 用于兔子宫直接表征子宫肌层和 子宫内膜催产素作用机制并决定它们如何 的调节以及它们如何与其他子宫收缩剂相互作用。 我们 建议通过以下方式来表征对催产素的受体后反应 检查肌醇1,4,5三磷酸和1,2的生产， 二酰甘油，细胞内钙浓度升高， 和肌球蛋白轻链磷酸化。 我们之前已经证明了 家兔收缩对催产素的敏感性急剧增加 足月前，与特定的十倍增加相关 受体浓度。我们将确定受体是否发生变化 通过比较，浓度完全解释了灵敏度的增加 体内处理引起的受体浓度变化 雌激素和孕激素以确定反应的位点 级联可以被长期调节。 我们还表明 类二十烷酸的产生伴随着催产素的作用，这种产生 可以增强子宫肌层对催产素的反应，并且这些变化可以 通过雌激素治疗可在非怀孕动物中模仿。 角色 通过磷脂酶 C 和花生四烯酸生产二酰甘油 在亚细胞反应中通过磷脂酶 A2 和 C 产生 催产素受体占用情况也将根据以下方面进行检查 类二十烷酸生产和反应急性调节的潜力。 催产素对子宫内膜和子宫肌层作用的相互作用 将检查对子宫肌层激活的影响。 要了解 如何严格调节这种反应机制，我们将确定 催产素受体是同源的还是异源的 脱敏。 这些研究将为 了解催产素对子宫肌层的生理作用。 这 需要信息来最终确定为什么催产素是 有时无法引起分娩或仅具有短暂的刺激作用 尽管存在受体，但子宫收缩。 也可能是 建议确保成功引产的方法。