The effects of progesterone on the alpha2-adrenergic receptor subtypes in late-pregnant uterine contractions in vitro.

Judit Hajagos-Tóth,Anna Borsodi,Eszter Ducza,Reza Samavati,Judit Bóta,Sándor Benyhe,Róbert Gáspár

doi:10.1186/s12958-016-0166-9

Abstract

BackgroundThe adrenergic system and progesterone play major roles in the control of the uterine function. Our aims were to clarify the changes in function and expression of the α2-adrenergic receptor (AR) subtypes after progesterone pretreatment in late pregnancy.MethodsSprague Dawley rats from pregnancy day 15 were treated with progesterone for 7 days. The myometrial expressions of the α2-AR subtypes were determined by RT-PCR and Western blot analysis. In vitro contractions were stimulated with (−)-noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (α2A), ARC 239 (α2B/C) and spiroxatrine (α2A). The accumulation of myometrial cAMP was also measured. The activated G-protein level was investigated via GTPγS binding assays.ResultsProgesterone pretreatment decreased the contractile effect of (−)-noradrenaline through the α2-ARs. The most significant reduction was found through the α2B-ARs. The mRNA of all of the α2-AR subtypes was increased. Progesterone pretreatment increased the myometrial cAMP level in the presence of BRL 44408 (p < 0.001), spiroxatrine (p < 0.001) or the spiroxatrine + BRL 44408 combination (p < 0.05). Progesterone pretreatment increased the G-protein-activating effect of (−)-noradrenaline in the presence of the spiroxatrine + BRL 44408 combination.ConclusionsThe expression of the α2-AR subtypes is progesterone-sensitive. It decreases the contractile response of (−)-noradrenaline through the α2B-AR subtype, blocks the function of α2A-AR subtype and alters the G protein coupling of these receptors, promoting a Gs-dependent pathway. A combination of α2C-AR agonists and α2B-AR antagonists with progesterone could be considered for the treatment or prevention of preterm birth.

Highlights

The adrenergic system and progesterone play major roles in the control of the uterine function
We conclude that progesterone increases the expression of each α2-adrenergic receptor (AR) subtype, and reduces the (−)-noradrenalineinduced myometrial contractions via the totality of these receptors
In the case of the α2CARs, we presume that progesterone treatment mainly induces the activation of the βγ subunit of the Gi protein, eliciting an increase in the smooth muscle Cyclic adenosine monophosphate (cAMP) level [19]

Summary

Introduction

The adrenergic system and progesterone play major roles in the control of the uterine function. Myometrial contraction is regulated by a number of factors, such as female sexual hormones, the adrenergic receptor (AR) system, ion channels and transmitters. Dysregulation of the myometrial contractility can lead to either preterm or slow-toprogress labor. It is well known that the female sexual hormone progesterone is responsible for uterine quiescence [5, 6], while estrogens have major role in myometrial contractions [1, 7]. Progesterone and estrogen play an important role in the regulation of the adrenergic system [10]. Estrogen decreases the expressions of the α2-AR subtypes and alters the myometrial contracting effect of (−)-noradrenaline by reduced coupling of the α2B-ARs to Gi protein [11].

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