Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?

The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the β3-adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour

Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium-1

<p><b>Copyright information:</b></p><p>Taken from "Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium"</p><p>http://www.biomedcentral.com/1471-2393/7/S1/S4</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S4-S4.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892061.</p><p></p>a two fold or more factor. White boxes denote insufficiently documented links in context. Comparison between Preterm not in labor and Term not in labor or Term in labor. Pathways are shown with their known links to cytokine, growth factors (GF) and G-protein coupled membrane receptors (GPCR). CAMs, cell adhesion molecules. ECM, extra-cellular matrix)

Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium-0

<p><b>Copyright information:</b></p><p>Taken from "Functional genomics of the pregnant uterus: from expectations to reality, a compilation of studies in the myometrium"</p><p>http://www.biomedcentral.com/1471-2393/7/S1/S4</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S4-S4.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892061.</p><p></p>s OR microarray) AND uterus (closed grey circles); (functional genomics OR microarray) AND uterus AND pregnant (open white circles); (functional genomics OR microarray) AND uterus AND myometrium (open white diamonds). On the graph, the number of papers is divided by 100 for the total papers on functional genomics OR microarray (black squares)

Beta3-adrenoceptor is the predominant beta-adrenoceptor subtype in human myometrium and its expression is up-regulated in pregnancy.

International audienceTo assess whether pregnancy might influence the functionality and expression of human myometrial beta(2)- and beta(3)-adrenoceptors (beta(2)- and beta(3)-AR), we performed functional, binding, Western blot, and molecular biology experiments in human nonpregnant and near-term pregnant myometrium. Inhibition of spontaneous contractions induced by a beta(3)-AR agonist, SR 59119A, was significantly greater in pregnant, compared with nonpregnant, myometrial strips (E'(max) = 61 +/- 5% vs. 44 +/- 5% for pregnant and nonpregnant myometrium, respectively), whereas salbutamol, a beta(2)-AR agonist, was significantly less efficient in pregnant, compared with nonpregnant, myometrium (E(max) = 29 +/- 4 vs. 54 +/- 8%). Although two populations of binding sites corresponding to beta(2)- and beta(3)-AR were identified in both nonpregnant and pregnant myometrium, we found a clear predominance of the beta(3)-AR subtype. Moreover, beta(3)-AR binding sites were up-regulated 2-fold in myometrium at the end of pregnancy. Both beta(2)- and beta(3)-AR mRNA were expressed in human nonpregnant and pregnant myometrium. Contrary to beta(2)-AR, the expression of the beta(3)-AR transcripts and immunoreactive proteins was increased in pregnant, compared with nonpregnant, myometrium. Such compelling data suggest a predominant role for beta(3)-AR in the regulation of human myometrium contractility, especially at the end of pregnancy, which might have important consequences for the clinical management of preterm labor

Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?-2

<p><b>Copyright information:</b></p><p>Taken from "Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?"</p><p>http://www.biomedcentral.com/1471-2393/7/S1/S14</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S14-S14.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892055.</p><p></p>ts, and beta2 microglobulin expression was used as a standard reference

Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?-3

<p><b>Copyright information:</b></p><p>Taken from "Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?"</p><p>http://www.biomedcentral.com/1471-2393/7/S1/S14</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S14-S14.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892055.</p><p></p>membranes from myometrium of non-pregnant and pregnant women. Expected sizes are 67 kDa for ADRB2 and 68 kDa for ADRB3. These experiments were performed on myometrium from five non-pregnant and five pregnant women. Homogenate of Chinese Hamster Ovary cells transfected with the human ADRB3 (ADRB3-CHO) was used as positive control. Analysis of the expression of ADRB2 and ADRB3 immunoreactive proteins in myometrium of non-pregnant and pregnant women. A.D.U. represents the intensity of the bands evaluated by densitometry. Each bar represents the mean ± s.e.m. from five different non-pregnant and five different pregnant women. Figure reproduced from the paper by Rouget [29]

Concentration-response curve for SR59119 and Salbutamol (ADRB3 and ADRB2 agonists respectively) in human near term myometrium

<p><b>Copyright information:</b></p><p>Taken from "Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?"</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S14-S14.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892055.</p><p></p

Representative recording of the effect of SR 59119A on spontaneous contractions of human non-pregnant (upper trace) and near-term (lower trace) myometrial strips

<p><b>Copyright information:</b></p><p>Taken from "Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?"</p><p>http://www.biomedcentral.com/1471-2393/7/S1/S14</p><p>BMC Pregnancy and Childbirth 2007;7(Suppl 1):S14-S14.</p><p>Published online 1 Jun 2007</p><p>PMCID:PMC1892055.</p><p></p