NOVEL MECHANISMS OF OXYTOCIN ACTION

描述（由申请人提供）：尽管事实上在美国大多数分娩中，催产素被安全地用于诱导或促进分娩，但大约一半的付费产科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惕的药物。关于低剂量与高剂量催产素安全使用的临床指南最近已经发表，但作者认识到缺乏证据来支持坚定的建议，并承认个别患者可能需要比建议的指南更高的剂量。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。虽然催产素对子宫收缩强度的影响已被充分证明，但多项研究表明，它还能通过增加子宫肌平滑肌细胞（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尚不清楚。有趣的是，催产素可以通过产生Na+依赖且对电压门控Na+通道阻滞剂河豚毒素不敏感的内向Na+电流使迷走神经细胞去极化。最近，在MSMCs中发现了具有类似性质的钠泄漏通道（NALCN； Na+泄漏通道，非选择性）。我们的初步研究表明，人类MSMCs表达NALCN并产生NALCN样电流，并且在离体模型中抑制该通道改变了人类子宫收缩的频率。我们还发现，催产素增加了孕妇子宫肌瘤细胞中nalcn样电流，但在非孕妇子宫肌瘤细胞中没有。最后，已经确定了减配体结合的催产素受体变异，并可能通过NALCN直接或间接影响子宫对催产素的反应。这项建议的目的是促进对催产素在孕妇中作用的潜在机制的了解。催产素和它的受体对分娩过程都很重要，但为什么催产素在经历分娩骤停的妇女中引起不可预测的反应尚不清楚。最近，已经确定的催产素受体变异具有较弱的催产素结合，但这是否转化为分娩延长或停搏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，调节NALCN通道，这是背景泄漏电流的基础，设置子宫自发节律性收缩的频率。我们推测，需要高剂量催产素的女性在催产素受体中存在序列变异，并将出现收缩模式频率的改变。

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.