CELLULAR MECHANISMS OF OXYTOCIN ACTION

催产素作用的细胞机制

• 批准号: 3327509
• 负责人: ROBERT K RIEMER
• 金额: $ 13.79万
• 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/3327509
• 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 广泛用于诱导妇女劳动，很少有人知道它的 作用机制。 循环中的催产素浓度 然而，我们之前的研究表明，在分娩开始时， 兔子表明子宫肌层催产素受体水平增加 在分娩开始前十倍， 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扩散和初级培养技术 对于兔子宫，直接表征子宫肌层， 子宫内膜机制催产素的行动，也决定了他们如何 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： 检测肌醇1，4，5三磷酸和1，2， 甘油二酯，细胞内钙离子浓度升高， 和肌球蛋白轻链磷酸化。 我们之前已经证明， 家兔对催产素收缩敏感性急剧增加 在足月之前，与特定的 受体浓度。我们将确定是否受体的变化 浓度完全解释了灵敏度的增加， 体内处理诱导的受体浓度变化 雌激素和孕激素，以确定反应的部位， 级联可以长期调节。 我们还表明， 类花生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，这些变化可以 通过雌激素治疗在非妊娠动物中被模仿。 的作用 通过磷脂酶C和花生四烯酸生产二酰基甘油 通过磷脂酶A2和C在亚细胞反应中产生 催产素受体的占有率也将根据 类二十烷酸产生的潜力和反应的急性调节。 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。 了解 这种反应机制是如何被剧烈调节的，我们将确定 催产素受体是否受到同源或异源的 脱敏 这些研究将为 了解催产素对子宫肌层的生理作用。 这 信息是必要的，以最终确定为什么催产素， 有时不能引起分娩或只有短暂的刺激作用 子宫收缩，尽管存在受体。 它也可以 建议确保成功引产方法。