Regulation by progesterone of the high-affinity state of myometrial β-adrenergic receptor and of adenylate cyclase activity in the pregnant rat

Cohen‐Tannoudji, Joëlle; Vivat, Valérie; Heilmann, Joerg; Legrand, Chantal; Maltier, J. P.

doi:10.1677/jme.0.0060137

Cited by 45 publications

(34 citation statements)

References 18 publications

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“…Activation of rat -ARs, which are selectively localized in this muscle layer , significantly decreases myometrial InsP production through both cAMP-dependent and -independent mechanisms (Khac et al 1996, Dodge et al 1999, Mhaouty-Kodja et al 2004. At the end of pregnancy, progesterone withdrawal and the subsequent -AR desensitization (Cohen-Tannoudji et al 1991) probably relieve the PLC system from inhibitory constraints in the longitudinal muscle. Concomitantly, the increase in oestradiol concentrations enhances transcription of the transduction entities involved in the PLC signalling pathway (OTR, PLC 1 and PLC 3) in the circular muscle.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of rat myometrial phospholipases Cβ1 and Cβ3 correlates with increased term sensitivity to carbachol and oxytocin

Houdeau

Levy²,

Mhaouty-Kodja³

2005

Journal of Endocrinology

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In the present study, we compared rat uterine contractility and myometrial inositol phosphate (InsP) production in response to activation of muscarinic and oxytocin receptors during pregnancy and at term. The level of myometrial phospholipase (PL) C was also determined by Western blotting at different stages of pregnancy and following administration of oestradiol, progesterone or vehicle. The results showed an increased potency of carbachol (CCh), a cholinergic muscarinic agonist, and oxytocin (OT) to enhance myometrial InsP production at term. This correlated with an increased potency of both agonists to induce contraction of the circular but not the longitudinal muscle. For both InsP production and contractile activity, the maximal response of CCh was unaltered, while that of OT was significantly increased. Interestingly, the increased responsiveness to CCh and OT was associated with an up-regulation of PLC 1 and PLC 3 enzymes. Such regulation is under the control of oestradiol since administration of this steroid to pregnant rats increased the amount of both enzymes by 200-260%. In contrast, progesterone administration was without effect. The present study presents the first evidence that the expression of rat myometrial PLC 1 and PLC 3 is under the positive control of oestradiol. This could participate in the enhancement of myometrial InsP accumulation and uterine contraction at term in response to CCh and OT. Based on contraction studies, we also propose that the longitudinal and circular uterine muscles differ in the regulation of the PLC pathway during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Up-regulation of rat myometrial phospholipases Cβ1 and Cβ3 correlates with increased term sensitivity to carbachol and oxytocin

Houdeau

Levy²,

Mhaouty-Kodja³

2005

Journal of Endocrinology

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“…During pregnancy, this subtype is selectively up-regulated by progesterone at the level of gene transcription (Vivat et al 1992). In addition, progesterone has been shown to stabilize the high affinity state of the receptor, thus increasing the coupling of the 2 -ARs to adenylyl cyclase (Cohen-Tannoudji et al 1991) and facilitating uterine quiescence. In contrast, the 1 -ARs play an important role in the mechanism of parturition, as supported by several lines of evidence (Legrand & Maltier 1986, Pennefather et al 1993.…”

Section: Introductionmentioning

confidence: 99%

“…Potentiation of cAMP production by the 2 /G i pathway at midpregnancy is related to the -AR activation of G s , high levels of G i3 and G i2 proteins and the presence of type II and IV adenylyl cyclases in the rat myometrium . At the end of pregnancy, the stimulabilities of the cAMP generating system by isoproterenol (Litime et al 1989, Cohen-Tannoudji et al 1991) and 2 agonists decline. Concomitantly, a reduction in the myometrial levels of ADP-ribosylated G s and G i3 as well as in the 2A -AR subtype expression is observed (Elwardy-Mérézak et al 1994.…”

Section: Introductionmentioning

confidence: 99%

In vivo stimulation of the beta(2)-adrenergic pathway increases expression of the Gi proteins and the alpha(2)A-adrenergic receptor genes in the pregnant rat myometrium

Lecrivain

Mhaouty-Kodja²,

Cohen‐Tannoudji³

et al. 1998

Journal of Endocrinology

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Cross-regulations between G s and G i mediated pathways controlling the adenylyl cyclase activity have been clearly demonstrated in vitro. To elucidate whether activation of the -adrenergic pathway in the pregnant myometrium might affect G i proteins and 2 -adrenergic receptors (ARs), we treated late pregnant rats from day 18 to day 21 with twice-daily administration of isoproterenol (8 mg/ kg). This treatment increased myometrial cAMP levels and led after 76 h to a significant and maximal rise in the immunoreactive amount of myometrial G i 2 and G i 3 proteins (1·4-and 1·7-fold respectively) associated with a parallel increase of the steady-state levels of both G i 2 and G i 3 mRNA (1·6-and 1·9-fold respectively). Propranolol antagonized this response indicating the implication of the -adrenergic pathway. Nuclear run-on assays demonstrated that isoproterenol enhanced respectively by 1·3-and 1·2-fold the transcription rate of the G i 2 and G i 3 genes. Quantification of myometrial 2 -ARs by [3 H]rauwolscine binding revealed that the total number of receptors was also increased at 76 h by 1·7-fold when compared with controls, with no change in the affinity of the 2 -ARs for the ligand. This effect was antagonized by propranolol. Quantification of both 2A -and 2B -subtypes by Northern blotting analysis demonstrated that this elevation was due to a selective increase of the 2A -subtype mRNAs. The present results indicate that in vivo stimulation of the -adrenergic pathway by isoproterenol increases both G i 2 /G i 3 and 2A -AR expression in the pregnant rat myometrium. The possible contribution of such a mechanism in pregnancy-related changes of both entities is discussed.

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“…The number of b-ARs also dropped during the last 7 h before term in rats, which may contribute to the weakening effect of b-AR agonists (Maltier & Legrand 1988). Cohen-Tannoudji et al (1991) demonstrated a pregnancy-dependent uncoupling of b-ARs and a decreased responsiveness of rat myometrial adenyl cyclase to isoproterenol. These changes were pronounced in the last few hours before delivery in the rat and controlled by progesterone.…”

Section: Introductionmentioning

confidence: 96%

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

et al. 2005

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The effectiveness of b 2 -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 b-adrenergic receptor density and mRNA level and the plasma sex hormone level, respectively. The activated G-protein level of the b-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 EC 50 and maximal inhibition values. A drop in plasma progesterone level was also detected. Binding studies revealed an increase in b-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 b 2 -adrenergic receptors and their mRNA level and increased the G-proteinactivating property of terbutaline. These data provide evidence of a pregnancy-induced decrease in activated G-protein level after b 2 -agonist stimulation. The decrease in plasma progesterone level has a crucial role in this process. The effects of b 2 -adrenergic receptor agonists in tocolytic therapy may possibly be potentiated with progesterone.

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Regulation by progesterone of the high-affinity state of myometrial β-adrenergic receptor and of adenylate cyclase activity in the pregnant rat

Cited by 45 publications

References 18 publications

Up-regulation of rat myometrial phospholipases Cβ1 and Cβ3 correlates with increased term sensitivity to carbachol and oxytocin

Up-regulation of rat myometrial phospholipases Cβ1 and Cβ3 correlates with increased term sensitivity to carbachol and oxytocin

In vivo stimulation of the beta(2)-adrenergic pathway increases expression of the Gi proteins and the alpha(2)A-adrenergic receptor genes in the pregnant rat myometrium

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

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