Improving the relaxing effect of terbutaline with phosphodiesterase inhibitors: studies on pregnant rat uteri in vitro.
OBJECTIVE
Previous results by our group showed that the in vitro uterus-relaxing potency of β(2)-adrenergic receptor (β(2)-AR) agonists and uterine cAMP accumulation are enhanced in case of visceral inflammation. Our aim was to study the effects of the non-selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on the uteri of intact late-pregnant female rats (on days 20 and 22 of pregnancy) and of pregnant rats treated with lipopolysaccharide (LPS) to evoke preterm labor (on day 20).


METHODS
The effects of theophylline and rolipram alone and of rolipram with terbutaline were investigated in isolated organ system. Contractions were evoked with KCl. The forskolin- and terbutaline-stimulated cAMP accumulations were determined by enzyme immunoassay, with or without rolipram.


RESULTS
The maximum uterus-relaxing effects of theophylline and rolipram decreased significantly (p<0.05) with the progression of pregnancy in intact rats. The most pronounced effect of rolipram was detected in rats challenged with LPS on day 20. Rolipram increased the in vitro effect of terbutaline both in intact and in LPS-treated rats. In the presence of rolipram, the forskolin- and terbutaline-stimulated cAMP accumulations were higher in LPS-treated than in intact rats.


CONCLUSIONS
The previous findings led us to conclude that the combined administration of PDE4 inhibitors with β(2)-agonists is of therapeutic value for the inhibition for uterine contractions, especially in the case of genital inflammation, which often triggers preterm birth. Combination therapy in general is associated with lesser side-effects, as a consequence of lower effective doses of each drug.
Klukovits
Anna
A
Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary.
Verli
Judit
J
Falkay
George
G
Gáspár
Róbert
R
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D047928:Premature Birth; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*; D013726:Terbutaline / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D000242:Cyclic AMP; D020889:Rolipram; D013726:Terbutaline