ABSTRACT
Se ha reportado una asociación entre CIE y distrés fetal, muerte fetal in utero y síntomas de parto prematuro/parto prematuro. Con la hipótesis que en la CIE el aumento en los ácidos biliares, en particular ácido cólico, activa la vía ocitocina-receptor de ocitocina (OT-ROT) en el miometrio, generando un inicio prematuro del trabajo de parto, evaluamos la sensibilidad miometrial a OT in vitro e in vivo, y la expresión de mRNA en pacientes CIE y controles y la capacidad de ácido cólico para regular la activación de la vía OT-ROT. Las pacientes con CIE mostraron una alta sensibilidad a OT in vivo e in vitro comparado con controles. Al incubar segmentos/células en cultivo de miometrio con ácido se observó una marcado aumento de la sensibilidad contráctil para la OT y un aumento de la expresión celular del mRNA y los niveles de la proteína del ROT. La activación de la vía OT-ROT parece ser el resultado de un aumento de la síntesis/función de RsOT mediada por el ácido cólico. Esto resultados entregan las bases celulares/moleculares que podrían explicar la asociación entre CIE y parto prematuro.
Intrahepatic cholestasis of pregnancy is associated with preterm labor and delivery. We hypothesize that in the course of this disease, bile acids activate the oxytocin receptor pathway leading to the premature onset of labor. We evaluated in vitro and in vivo myometrial sensitivity to oxytocin and the oxytocin-receptor expression in patients with cholestasis and control. Furthermore, we evaluated the ability of cholic acid to mediate the activation of the oxytocin-receptor pathway. Patients with cholestasis of pregnancy, compared to controls, required lower doses of oxytocin to elicit 3 uterine contractions in 10 minutes (1.3 ± 0.6 vs 3.6 ± 0.8 Units; p < 0.05) and had lower in vitro ED50 (1.6 x 10_10 M vs 1.0 x 10_8 M; p < 0.05), reflecting higher oxytocin sensitivity. The long-term (24 h) incubation of myometrial strips from control patients with cholic acid (20 µM) markedly increased the sensitivity to oxytocin, but not to endothelin-1 or prostaglandin F2a. The 24 h incubation of cultured myometrial cells with cholic acid increased the expression of oxytocin-receptor at mRNA (northern blot) and protein levels (western blot and immunohistochemistry). Our results demonstrate that in the setting of intrahepatic cholestasis of pregnancy, an activation of the oxytocin-receptor pathway occurs. The activation of such pathways seems to be the result of a cholic acid mediated increase in receptor expression, which in turn could explain the increase in the preterm labor and delivery rate observed in this disease.