title: Uterus-relaxing effect of β2-agonists in combination with phosphodiesterase inhibitors: studies on pregnant rat in vivo and on pregnant human myometrium in vitro.
abstract: OBJECTIVE
  Our aims were to examine the effects of a simultaneous stimulation of β(2) -adrenergic receptors and inhibition of uterine phosphodiesterases (PDE), in the pregnant rat uterus in vivo and on human uterine tissue in vitro. We also set out to measure cAMP levels and detect the expressions of the isoenzymes PDE4B and PDE4D in human uterine tissue samples.
  
  
  METHODS
  Preterm birth was induced in Sprague-Dawley rats with bacterial lipopolysaccharide. The uterine effects of terbutaline alone or in combination with rolipram were tested in vivo. Human myometrial strips from cesarean sections at full-term pregnancy and at preterm labor were stimulated with oxytocin, and the inhibitory effects of theophylline, rolipram and terbutaline were studied. The myometrial accumulation of cAMP in the presence of rolipram and terbutaline was determined by enzyme immunoassay. The expressions of PDE4B and PDE4D proteins were detected by Western blotting.
  
  
  RESULTS
  The selective PDE4 inhibitor rolipram was more effective than the non-selective PDE inhibitor theophylline in inhibiting the oxytocin-induced contractions in the human uterus. The uterus-relaxing effects of low doses of terbutaline were markedly potentiated by rolipram, both in rats and in human tissues. The changes in uterine cAMP levels correlated with these results. At preterm labor, PDE4B was the predominant form of PDE4 expressed; at full term, PDE4D was expressed more strongly.
  
  
  CONCLUSIONS
  A combination of selective PDE4 inhibitors and β(2) -agonists should be considered for the treatment of preterm contractions.
authors: Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy Department of Obstetrics and Gynecology, Albert Szent-Györgyi Clinical Center, Faculty of General Medicine, University of Szeged, Szeged, Hungary.
authors: Judit
authors: J
authors: Verli
authors: Anna
authors: A
authors: Klukovits
authors: Zsolt
authors: Z
authors: Kormányos
authors: Judit
authors: J
authors: Hajagos-Tóth
authors: Eszter
authors: E
authors: Ducza
authors: Adrienn B
authors: AB
authors: Seres
authors: George
authors: G
authors: Falkay
authors: Róbert
authors: R
authors: Gáspár
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D005260:Female; D006801:Humans; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011247:Pregnancy; D047928:Premature Birth / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology; D013726:Terbutaline / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C517376:PDE4D protein, human; D020889:Rolipram; D013726:Terbutaline