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Pregnancy-induced decrease in the relaxant effect of terbutaline in the late-pregnant rat myometrium: role of G-protein activation and progesterone

¹ Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary, ² Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, Hungary and ³ Department of Obstetrics and Gynecology, Faculty of Medicine, University of Szeged, WHO Collaborating Research Center in Human Reproduction, H-6725 Szeged, Semmelweis u. 1, Hungary

Correspondence should be addressed to George Falkay; Email: falkay{at}pharma.szote.u-szeged.hu

The effectiveness of ß₂-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 ß-adrenergic receptor density and mRNA level and the plasma sex hormone level, respectively. The activated G-protein level of the ß-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 ß-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 ß₂-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 ß₂-agonist stimulation. The decrease in plasma progesterone level has a crucial role in this process. The effects of ß₂-adrenergic receptor agonists in tocolytic therapy may possibly be potentiated with progesterone.

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