Uterus-relaxing effect of β2-agonists in combination with phosphodiesterase inhibitors: studies on pregnant rat in vivo and on pregnant human myometrium in vitro. 2013

Judit Verli, and Anna Klukovits, and Zsolt Kormányos, and Judit Hajagos-Tóth, and Eszter Ducza, and Adrienn B Seres, and George Falkay, and Róbert Gáspár
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.

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.

UI MeSH Term Description Entries
D007752 Obstetric Labor, Premature Onset of OBSTETRIC LABOR before term (TERM BIRTH) but usually after the FETUS has become viable. In humans, it occurs sometime during the 29th through 38th week of PREGNANCY. TOCOLYSIS inhibits premature labor and can prevent the BIRTH of premature infants (INFANT, PREMATURE). Preterm Labor,Labor, Premature,Premature Labor,Premature Obstetric Labor,Labor, Premature Obstetric,Labor, Preterm
D009215 Myometrium The smooth muscle coat of the uterus, which forms the main mass of the organ. Uterine Muscle,Muscle, Uterine,Muscles, Uterine,Uterine Muscles
D010726 Phosphodiesterase Inhibitors Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. Phosphodiesterase Antagonists,Phosphodiesterase Inhibitor,Phosphoric Diester Hydrolase Inhibitors,Antiphosphodiesterases,Inhibitor, Phosphodiesterase
D011247 Pregnancy The status during which female mammals carry their developing young (EMBRYOS or FETUSES) in utero before birth, beginning from FERTILIZATION to BIRTH. Gestation,Pregnancies
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242 Cyclic AMP An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH. Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013726 Terbutaline A selective beta-2 adrenergic agonist used as a bronchodilator and tocolytic. Arubendol,Asthmoprotect,Brethaire,Brethine,Bricanyl,Bricanyl SA,Butaliret,Butalitab,Contimit,KWD-2019,Monovent,Taziken,Tedipulmo,Terbasmin,Terbul,Terbutalin AL,Terbutalin Stada,Terbutalin-ratiopharm,Terbutaline Sulfate,Terbuturmant,terbutalin von ct,KWD 2019,KWD2019,Terbutalin ratiopharm
D013806 Theophylline A methyl xanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities. Theophylline inhibits the 3',5'-CYCLIC NUCLEOTIDE PHOSPHODIESTERASE that degrades CYCLIC AMP thus potentiates the actions of agents that act through ADENYLYL CYCLASES and cyclic AMP. 1,3-Dimethylxanthine,3,7-Dihydro-1,3-dimethyl-1H-purine-2,6-dione,Accurbron,Aerobin,Aerolate,Afonilum Retard,Aquaphyllin,Armophylline,Bronchoparat,Bronkodyl,Constant-T,Elixophyllin,Euphylong,Glycine Theophyllinate,Lodrane,Monospan,Nuelin,Nuelin S.A.,Quibron T-SR,Slo-Phyllin,Somophyllin-T,Sustaire,Synophylate,Theo Von Ct,Theo-24,Theo-Dur,Theobid,Theocin,Theoconfin Continuous,Theodur,Theolair,Theolix,Theon,Theonite,Theopek,Theophylline Anhydrous,Theophylline Sodium Glycinate,Theospan,Theostat,Theovent,Uniphyl,Uniphyllin,Uniphylline,1,3 Dimethylxanthine,Anhydrous, Theophylline,Constant T,ConstantT,Ct, Theo Von,Glycinate, Theophylline Sodium,Quibron T SR,Quibron TSR,Slo Phyllin,SloPhyllin,Sodium Glycinate, Theophylline,Somophyllin T,SomophyllinT,Theo 24,Theo Dur,Theo24,Theophyllinate, Glycine,Von Ct, Theo

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