NOVEL MECHANISMS OF OXYTOCIN ACTION

Washington University, Saint Louis MO

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Abstract

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.