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CELLULAR MECHANISMS OF OXYTOCIN ACTION

催产素作用的细胞机制

基本信息

批准号：
2199845
负责人：
ROBERT K RIEMER
金额：
$ 15.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-09-01 至 1995-05-31
项目状态：
已结题

项目摘要

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.

脑下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。尽管它过去是，现在也是广泛用于妇女引产，对其知之甚少作用机制。循环中的催产素浓度然而，在分娩开始时，变化很小，然而，我们之前在兔子宫肌层催产素受体水平升高在分娩开始前的十倍，与显著的对这种荷尔蒙的敏感性增加。在这个项目中，我们将利用我们最新开发的扩散和原代培养技术用兔子宫直接测定子宫肌层和肌层催产素作用的子宫内膜机制以及它们是如何以及它们如何与其他子宫紧张剂相互作用。我们建议通过以下方法来表征催产素的受体后反应考察了1，4，5-三磷酸肌醇和1，2-三磷酸肌醇的生产情况。二酰甘油，细胞内钙浓度的升高，肌球蛋白轻链磷酸化。我们之前已经表明，兔对催产素的收缩敏感性急剧增加在学期之前，这与特定的受体浓度。我们将确定受体的变化浓度完全解释了敏感度的提高黄曲霉毒素体内处理后受体浓度的变化雌激素和黄体酮来确定反应的部位级联可以被长期调节。我们还表明，二十烷类化合物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，这些变化可以在未怀孕的动物身上通过雌激素治疗而被模仿。角色磷脂酶C和花生四烯酸生产甘油二酯的研究在亚细胞反应中通过磷脂酶A2和C产生催产素受体占有率也将从以下方面进行检查二十烷类化合物的生产潜力和对反应的急性调节。催产素对子宫内膜和肌层作用的相互作用将检查对子宫肌层激活的影响。要理解这种反应机制是如何受到严格调控的，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。这为了最终确定催产素为什么有时无法引起分娩或仅有短暂的刺激作用子宫收缩，尽管有受体的存在。它还可能建议确保成功引产的方法。