30 - Bitter taste receptor TAS2R5 agonist phenanthroline as a broad-spectrum uterine relaxant

Objective: Uterine contractions in term and preterm parturition can be caused by diverse uterotonics ranging from hormones to inflammatory mediators. Tocolytics are often used in managing preterm labor, although none of them have been approved by FDA. In light of the diverse nature of uterotonics, a desirable tocolytic should be broad spectrum. We recently found that uterine smooth muscle express bitter taste receptors (TAS2Rs), and their activation reverses depolarization- and oxytocin-induced human uterine smooth muscle contraction. However, whether TAS2Rs activation can relax human uterine contraction induced by inflammatory mediators remains unknown.

Study Design: Among 25 human TAS2Rs, phenanthroline activates only TAS2R5. We therefore selected phenanthroline, a TAS2R5 agonist, to investigate the role of TAS2R5 in bitter tastant-mediated human uterine smooth muscle relaxation. Uterine smooth muscle was acquired from pregnant women (37-40 weeks) at scheduled cesarean delivery who gave informed consent. Tissue was collected for isometric contraction bioassays. The contractile responses to inflammatory mediators with and without phenanthroline were measured and normalized to 60 mM KCl to minimize donor and strip variations. Data were analyzed with one-way ANOVAs with Dunnett’s multiple comparisons tests.

Results: : PGF2a robustly contracted human uterine smooth muscle from term pregnancy (Figure), so did oxytocin, U46619, 5-HT and endothelin-1. Phenanthroline dose-dependently inhibited the contraction evoked by PGF2a (Figure), oxytocin, U46619, 5-HT and endothelin-1, respectively.

Conclusion: TAS2R5 activation markedly inhibits uterine contraction caused by different inflammatory mediators. TAS2R5 agonists may be developed as a new class of broad-spectrum tocolytic.