Abstract
Currently available tocolytics are ineffective at significantly delaying preterm birth. This is due in part to our failure to better understand the mechanisms that drive spontaneous preterm labor (sPTL). Cyclic nucleotides are not the primary contributors to myometrial quiescence, but instead nitric oxide (NO)-mediated protein S-nitrosation (SNO) is integral to the relaxation of the tissue. Connexin-43 (Cx43), a myometrial 'contractile associated protein' (CAP) that functions as either a gap junction channel (GJC) or an hemichannel (HC), was the focus of this study. Protein analysis determined that Cx43 is downregulated in sPTL myometrium. Further, Cx43 is S-nitrosated by NO, which correlates to an increase of Cx43-pS368 (gap junction inhibition), as well as an increase in the hemichannel (HC) open-state probability (quiescence). Pharmacologic inhibition of Cx43 with 18β-Glycyrrhetinic acid (18β-GA) exhibits a negative inotropic effect on the myometrium in a dose-dependent manner, as does administration of nebivolol, a nitric oxide synthase (NOS) activator that increases total protein SNOs. When 18β-GA and nebivolol were co-administered at their IC50 values, the effect on contractile dynamics was additive, all but eliminating contractions. The development of new tocolytics demands a better understanding of the underlying mechanisms of sPTL. Here it has been shown that 18β-GA and nebivolol leverage dysregulated pathways in the myometrium, resulting in a novel approach for the treatment of sPTL.
Significance Statement While there are many known causes of preterm labor (PTL), the mechanisms of ‘spontaneous’ preterm labor (sPTL) remain obfuscated, which is why treating this condition is so challenging. Here we have identified that Cx43, an important contractile-associated protein, is dysregulated in sPTL myometrium, and that the pharmacologic inhibition of Cx43, and its S-nitrosation, with 18β-GA and nebivolol, respectively, significantly blunts contraction in human myometrial tissue, presenting a novel approach to tocolysis that leverages maladjusted pathways in women who experience sPTL.
- drug development/discovery
- Ion channel regulation
- nitric oxide
- nitric oxide synthase/NOS
- smooth muscle
- uterine pharmacology
- © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.