Pregnancy-induced decrease in the relaxant effect of terbutaline in the late-pregnant rat myometrium: role of G-protein activation and progesterone.
The effectiveness of beta2-agonists in preterm delivery is reduced by several factors. The aim of this study was to determine the influence of late pregnancy in the uterus-relaxing effect of terbutaline in the rat in vitro. Rat uterine tissues from late pregnancy (days 15, 18, 20 and 22) were used. In vitro electrical field-stimulation (EFS) was used to evoke contractions. The radioligand-binding technique, reverse transcription-polymerase chain reaction and radioimmunoassay technique were used to determine the beta-adrenergic receptor density and mRNA level and the plasma sex hormone level, respectively. The activated G-protein level of the beta-adrenergic receptors was investigated by a radiolabelled GTP binding assay.EFS-induced contractions were inhibited by terbutaline. This effect decreased towards term with respect to both the EC50 and maximal inhibition values. A drop in plasma progesterone level was also detected. Binding studies revealed an increase in beta-adrenergic receptor number on the last day of pregnancy, which correlated with the change in receptor mRNA level. The G-protein-activating effect of terbutaline decreased continuously between days 15 and 20. Surprisingly, terbutaline decreased the G-protein activation to below the basal level on day 22. However, progesterone pretreatment set back the uterine action of terbutaline, increased the density of the beta2-adrenergic receptors and their mRNA level and increased the G-protein-activating property of terbutaline. These data provide evidence of a pregnancy-induced decrease in activated G-protein level after beta2-agonist stimulation. The decrease in plasma progesterone level has a crucial role in this process. The effects of beta2-adrenergic receptor agonists in tocolytic therapy may possibly be potentiated with progesterone.
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary.
Róbert
R
Gáspár
Eszter
E
Ducza
Attila
A
Mihályi
Arpád
A
Márki
Zoltán
Z
Kolarovszki-Sipiczki
Eszter
E
Páldy
Sándor
S
Benyhe
Anna
A
Borsodi
Imre
I
Földesi
George
G
Falkay
D000818:Animals; D004558:Electric Stimulation; D004958:Estradiol / Q000097:blood; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013726:Terbutaline / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology*; D014590:Uterine Contraction
D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D015149:Tocolytic Agents; D011374:Progesterone; D004958:Estradiol; D019204:GTP-Binding Proteins; D013726:Terbutaline