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 α2-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 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.


RESULTS
Progesterone 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.


CONCLUSIONS
The 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.
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, H-6701, P.O. Box 121, Hungary.
Judit
J
Hajagos-Tóth
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, H-6701, P.O. Box 121, Hungary.
Judit
J
Bóta
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, H-6701, P.O. Box 121, Hungary.
Eszter
E
Ducza
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, Szeged, H-6726, Hungary.
Reza
R
Samavati
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, Szeged, H-6726, Hungary.
Anna
A
Borsodi
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt 62, Szeged, H-6726, Hungary.
Sándor
S
Benyhe
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, H-6701, P.O. Box 121, Hungary. gaspar@pharm.u-szeged.hu.
Róbert
R
Gáspár
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D014590:Uterine Contraction / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D054833:Isoindoles; D018341:Receptors, Adrenergic, alpha-2; D011374:Progesterone; D000242:Cyclic AMP; D009638:Norepinephrine; C072125:BRL 44408
Gestation; Myometrium; Progesterone; Rat; α2-adrenergic receptor subtypes