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）：尽管在美国，大多数分娩都安全地使用催产素来引产或促进分娩，但大约一半的付费产科医疗事故案件涉及其滥用索赔，安全用药实践研究所将催产素列为高度警惕药物。最近发布了安全使用低剂量与高剂量催产素的临床指南，但作者认识到缺乏证据来支持明确的建议，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需要详细描述催产素作用模式的基本机制。 尽管催产素对子宫收缩强度的影响已有充分记录，但多项研究现已表明，它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，这种情况发生的机制仍不清楚。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去极化，该电流是 Na+ 依赖性的，并且对电压门控 Na+ 通道阻滞剂河豚毒素不敏感。最近，在 MSMC 中发现了具有类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，人类 MSMC 表达 NALCN 并产生类似 NALCN 的电流，并且抑制该通道会改变离体模型中人类子宫收缩的频率。我们还发现，催产素会增加孕妇子宫肌细胞中的 NALCN 样电流，但不会增加非孕妇子宫肌细胞中的 NALCN 样电流。最后，已鉴定出减弱配体结合的催产素受体变体，并可能直接或通过 NALCN 间接影响子宫对催产素的反应。 该提案的目的是增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产程停滞的女性中引起不可预测的反应尚不清楚。最近，已鉴定出催产素受体中具有较弱催产素结合力的变体，但这是否会转化为产程延长或停滞的临床表现尚不清楚。我们的中心假设是，催产素与催产素受体结合可调节 NALCN 通道，该通道是背景漏电流的基础，而背景漏电流设定子宫自发节律性收缩的频率。我们推测，需要较高剂量催产素的女性在催产素受体中存在序列变异，并且收缩模式的频率会发生改变。