NOVEL MECHANISMS OF OXYTOCIN ACTION

催产素作用的新机制

• 批准号: 8697084
• 负责人: Sarah K. England
• 金额: $ 18.47万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697084
• 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）：尽管催产素被安全地用于诱导或增加美国大多数出生的劳动，但大约所有有付费的产科弊端案件中，大约一半涉及其滥用的索赔，而安全药物实践研究所则将催产素列为高级药物。最近发布了有关安全使用低剂量和高剂量的催产素的临床指南，但作者认识到证据很少来支持公司的建议，并承认单个患者可能需要比他们建议的准则更高的剂量。开发最有效的治疗方法将需要详细描述催产素作用方式的基本机制。 尽管催产素对子宫收缩强度的影响已得到充分的文献证明，但现在多项研究表明它也能够通过增加子宫肌层平滑肌细胞（MSMC）动作电位来调节收缩频率；但是，发生这种情况的机制尚不清楚。有趣的是，催产素可以通过产生对Na+依赖性且对电压门控的Na+通道阻滞剂四毒素不敏感的内向Na+电流去极化迷走神经元。最近，在MSMC中鉴定出具有相似特性的钠泄漏通道（NALCN; Na+泄漏通道，非选择性）。我们的初步研究表明，人MSMC表达纳尔克并产生类似NALCN的电流，并且对该通道的抑制会改变离体模型中人子宫收缩的频率。我们还发现，催产素会增加源自孕妇的肌层细胞中的NALCN样电流，而不是源自非孕妇的肌层细胞中。最后，已经鉴定出了减弱配体结合的催产素受体变体，并可能直接或通过NALCN直接或间接影响子宫对催产素的反应。 该提案的目的是提高人们对孕妇催产素作用的潜在机制的了解。催产素及其受体对劳动过程都很重要，但是为什么催产素会引起经历劳动逮捕的妇女的不可预测的反应。最近，已经鉴定出了催产素受体较弱的催产素受体中鉴定的变异，但是尚不清楚这是否转化为劳动力突起或抑制的临床表现。我们的中心假设是，与催产素受体结合的催产素结合调节NALCN通道，该通道是背景泄漏电流的基础，该泄漏电流设置了子宫自发节律收缩的频率。我们推测，需要更高剂量的催产素怀氧受体的女性，并将在收缩模式中发生变化的频率。