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

Abstract

The effectiveness of β2-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 ratin vitro.Rat uterine tissues from late pregnancy (days 15, 18, 20 and 22) were used.In vitroelectrical 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 β-adrenergic receptor density and mRNA level and the plasma sex hormone level, respectively. The activated G-protein level of the β-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 EC50and maximal inhibition values. A drop in plasma progesterone level was also detected. Binding studies revealed an increase in β-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 β2-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 β2-agonist stimulation. The decrease in plasma progesterone level has a crucial role in this process. The effects of β2-adrenergic receptor agonists in tocolytic therapy may possibly be potentiated with progesterone.