Evidence that corticotropin-releasing hormone modulates myometrial contractility during human pregnancy

As human pregnancy advances, CRH increases exponentially and is hypothesized to trigger the transition from myometrial quiescence to active contractions at labor. Paradoxically, CRH stimulates cAMP production, suggesting it should cause relaxation. To evaluate CRH as a mediator of quiescence, the effect of CRH on contractions in preterm and term myometria with concurrent progesterone (P4) was determined. In late gestation, we hypothesized that high concentrations of CRH down-regulate agonist-activated-cAMP relaxatory pathways and that increased phosphodiesterase (PDE) activity induces heterologous down-regulation of agonist-activated-cAMP pathways. CRH caused dose-dependent relaxation of spontaneously contracting myometrial strips of 31 +/- 8% (mean +/- sem; n = 12) and 35 +/- 20% (n = 3) in term and preterm samples, respectively. CRH with P4 pretreatment caused a 40 +/- 13% (n = 4) reduction in contractility, whereas in matched samples, CRH alone exerted a 26 +/- 6% (n = 4) reduction, with a shift of CRH dose-response curves (P < 0.01, ANOVA). Pretreatment of strips with 10(-7) m CRH did not attenuate relaxation induced by subsequent CRH (n = 3) or salbutamol (beta(2)-agonist) treatment (n = 9). PDE inhibition by rolipram showed a 2.2- and 1.5-fold increase in maximal relaxation induced by CRH and salbutamol, respectively, with a shift of both dose-response curves (P < 0.05 and P < 0.01, ANOVA). In conclusion, CRH at physiological concentrations acts synergistically with P4 contributing to myometrial quiescence. P4 withdrawal may reduce CRH-mediated relaxation. Our functional model does not support homologous or heterologous down-regulation of agonist-stimulated-cAMP pathways by high CRH concentrations. PDE inhibition potentiates CRH and salbutamol-induced relaxation. Up-regulation of PDEs, through chronic cAMP elevation by CRH, could provide a mechanism for down-regulation of agonist-stimulated-cAMP pathways at term.