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

BACKGROUND: The 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 α(2)-adrenergic receptor (AR) subtypes after progesterone pretreatment in late pregnancy. METHODS: Sprague Dawley rats from pregnancy day 15 were treated with progesterone for 7 days. The myometrial expressions of the α(2)-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 (α(2A)), ARC 239 (α(2B/C)) and spiroxatrine (α(2A)). The accumulation of myometrial cAMP was also measured. The activated G-protein level was investigated via GTPγS binding assays. RESULTS: Progesterone pretreatment decreased the contractile effect of (−)-noradrenaline through the α(2)-ARs. The most significant reduction was found through the α(2B)-ARs. The mRNA of all of the α(2)-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. CONCLUSIONS: The expression of the α(2)-AR subtypes is progesterone-sensitive. It decreases the contractile response of (−)-noradrenaline through the α(2B)-AR subtype, blocks the function of α(2A)-AR subtype and alters the G protein coupling of these receptors, promoting a G(s)-dependent pathway. A combination of α(2C)-AR agonists and α(2B)-AR antagonists with progesterone could be considered for the treatment or prevention of preterm birth.