NOVEL MECHANISMS OF OXYTOCIN ACTION

催产素作用的新机制

• 批准号: 8543851
• 负责人: Sarah K. England
• 金额: $ 22.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543851
• 关键词: Action Potentials; Affect; Attenuated; Binding; Birth; Cell Line; Cells; Cesarean section; Clinical; Development; Discipline of obstetrics; Dose; Exposure to; Frequencies; Generations; Genes; Guidelines; Human; Individual; Institutes; Knowledge; Labor Presentation; Laboratories; Ligand Binding; Malpractice; Measures; Methods; Modeling; Myometrial; Nature; Neurons; Oxytocin; Oxytocin Receptor; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Pregnant Women; Process; Property; Protocols documentation; Public Health; Publishing; Recommendation; Regulation; Sampling; Smooth Muscle Myocytes; Sodium; Testing; Tetrodotoxin; Therapeutic Agents; Titrations; Translating; United States; Uterine Contraction; Uterus; Variant; Woman; Women' s Group; Work; channel blockers; clinical phenotype; defined contribution; experience; fetal; improved; in vivo; myometrium; novel; public health relevance; receptor; response; voltage

DESCRIPTION (provided by applicant): Despite the fact that oxytocin is used safely to induce or augment labor in the majority of births in the United States, roughly half of all paid obstetric malpractice cases involve claims of its misuse, and the Institute for Safe Medication Practices lists oxytocin as a High-Alert medication. Clinical guidelines for safe use of low versus high doses of oxytocin have recently been published, but the authors recognize the paucity of evidence to support firm recommendations and acknowledge that individual patients may require higher doses than their proposed guidelines. Development of the most effective methods of therapy will require detailed characterization of the basic mechanisms underlying oxytocin's mode of action. Although effects of oxytocin on uterine contractile strength are well documented, multiple studies have now indicated its ability to also regulate the frequency of contraction via an increase in the generation of uterine myometrial smooth muscle cell (MSMC) action potentials; however, the mechanism by which this occurs remains unclear. Intriguingly, oxytocin can depolarize vagal neurons by generating an inward Na+ current that is Na+-dependent and insensitive to the voltage-gated Na+ channel blocker tetrodotoxin. Recently, a sodium leak channel (NALCN; Na+ leak channel, non-selective) with similar properties was identified in MSMCs. Our preliminary studies demonstrate that human MSMCs express NALCN and produce a NALCN-like current, and that inhibition of this channel alters the frequency of human uterine contractions in an ex vivo model. We have also discovered that oxytocin increases NALCN-like current in myometrial cells derived from pregnant women, but not in myometrial cells derived from non-pregnant women. Lastly, oxytocin receptor variants that have attenuated ligand binding have been identified and may affect the response of the uterus to oxytocin either directly or indirectly via NALCN. The objective of this proposal is to advance knowledge of the underlying mechanism of oxytocin action in pregnant women. Both oxytocin and its receptor are important to the process of labor, yet why oxytocin elicits an unpredictable response in women who experience labor arrest is unknown. Recently, identified variants in the oxytocin receptor that have weaker oxytocin binding have been identified, but whether this translates into a clinical presentation of labor protraction or arrest is unknown. Our central hypothesis is that oxytocin binding to the oxytocin receptor regulates the NALCN channel, which underlies the background leak current that sets the frequency of spontaneous rhythmic contractions of the uterus. We speculate that women who require higher doses of oxytocin harbor sequence variants in the oxytocin receptor and will present with altered frequency in their contraction patterns.

描述（由申请人提供）：尽管催产素在美国的大多数分娩中被安全地用于诱导或增加分娩，但大约一半的有偿产科医疗事故案件涉及其滥用的索赔，安全药物实践研究所将催产素列为高度警戒药物。安全使用低剂量和高剂量催产素的临床指南最近已经出版，但作者认识到缺乏证据支持坚定的建议，并承认个别患者可能需要比他们提出的指南更高的剂量。开发最有效的治疗方法将需要详细描述催产素作用模式的基本机制。 虽然催产素对子宫收缩强度的影响有很好的记录，但多项研究表明，催产素还能够通过增加子宫肌层平滑肌细胞（MSMC）动作电位的产生来调节收缩频率;然而，发生这种情况的机制仍不清楚。有趣的是，催产素可以通过产生内向Na+电流来使迷走神经元兴奋，该电流是Na+依赖性的，并且对电压门控Na+通道阻断剂河豚毒素不敏感。最近，钠泄漏通道（NALCN; Na+泄漏通道，非选择性）具有类似的属性被确定在MSMCs。我们的初步研究表明，人MSMCs表达NALCN并产生NALCN样电流，并且该通道的抑制改变了离体模型中人子宫收缩的频率。我们还发现，催产素增加来自孕妇的子宫肌层细胞中的NALCN样电流，但不增加来自非孕妇的子宫肌层细胞中的NALCN样电流。最后，已经鉴定了具有减弱的配体结合的催产素受体变体，并且其可以直接或经由NALCN间接地影响子宫对催产素的反应。 该提案的目的是促进对孕妇催产素作用的潜在机制的了解。催产素及其受体对分娩过程都很重要，但为什么催产素会在经历分娩停滞的妇女中产生不可预测的反应还不清楚。最近，已经鉴定了催产素受体中具有较弱催产素结合的变体，但这是否转化为分娩延长或分娩停滞的临床表现尚不清楚。我们的中心假设是催产素结合到催产素受体调节NALCN通道，其是背景漏电流的基础，该背景漏电流设定子宫自发节律性收缩的频率。我们推测，需要更高剂量催产素的女性在催产素受体中存在序列变异，并将在收缩模式中出现频率改变。