Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium

Abstract

This version is available at https://strathprints.strath.ac.uk/59989/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. ABSTRACTIn recent times, additional pathways involved in myometrial regulation and also in the action of oxytocin and -adrenergic agonists on the myometrium, other than what has been known previously has been suggested. Knowledge of other pathways will prove useful in designing better therapies for myometrial pathologies. This study was therefore aimed at investigating the possibility of other pathways involved in the activity of either oxytocin or a -adrenergic agonists (ritodrine was used in this study) in myometrial activity with the aid of metabolomics and bioinformatics. High resolution Fourier transform mass spectrometry (HRFTMS), and nuclear magnetic resonance (NMR) spectroscopy coupled with functional uterine assays were combined for an innovative assessment. In vitro pharmacological assay of oxytocin (1 nM) and ritodrine (0.1 nM) on isolated mice uteri mounted in 3 ml organ baths were performed. Mice uteri, treated with oxytocin (OT) or ritodrine (RIT), as well as the physiological buffer in which the uterine tissues were immersed, were rapidly collected and analysed using HRFTMS, 1 HNMR and bioinformatics. Resulting data were analyzed via pair-wise chemometric comparison models with p ≤ 0.05 considered statistically significant. In addition to previously known metabolites, anandamide, nicotinamide adenine dinucleotide, gamma aminobutyric acid and sphingosine were significantly associated with OT's activity while a downstream involvement of prostaglandin F1 and phosphatidylinositol signalling was observed with RIT's activity. These findings adds evidence to the reports on additional regulation of myometrial activity by these drugs and also offers newer pathways for therapeutic manipulation.

Green Tea Inhibits Uterine Contractility in Ex Vivo (Non-Pregnant) Mice Models

“…67 Quinic acid has been reported to inhibit Nuclear Factor-kappa B (NF-κB) by increasing the production of nicotinamide and tryptophan. 68 However, an increase in nicotinamide has been shown to be positively correlated to the activity of OT in stimulating uterine contractions 69 suggesting a contraction stimulatory role for quinic acid and may not contribute to the inhibitory effect of green tea at higher concentrations in this study. Sedoheptulose is a seven-carbon ketose sugar originally found in Sedum spectabile and can also be found as part of the human diet.…”

Metabolomic Pathways Predicting Labor Dystocia by Maternal Body Mass Index

“…88 Metabolomics has also been used to identify biomarkers produced in mice uterine tissue following pharmacologic stimulation versus inhibition of contractions, revealing new detail on the mechanisms of uterine contractility in rodents. 89 Our study has several strengths. First, potential differences in labor duration that could potentially be caused by differences in labor management were offset in this study by our focus on participants who were managed by the same team of physicians and midwives following the same protocols across two hospitals.…”

Lost OTR Expression and HIF-1α Self-protection in Myometrium of Intractable Postpartum Hemorrhage

“…Quickly and effectively compressing myometrium to stop bleeding is very important in IPPH rescue time [9]. The effective speed of uterotonic to form myometrium contractile force, as the rst step in the classical route of postpartum hemorrhage treatment , is always of great concern in hemostasis in which OTR is an important target for regulating myometrium contractility [10]. However, the reactivity of myometrium to uterotonic show declined sharply in IPPH mostly just as in prolonged labor [11] but studies on the regulation of myometrium contractility are still lacking.…”