A CORTICOTROPIN-RELEASING HORMONE TYPE-I RECEPTOR ANTAGONIST DELAYS PARTURITION IN SHEEP

In sheep, corticotropin-releasing hormone (CRH) can stimulate the feta l release of ACTH to produce a cortisol surge which leads to the onset of parturition. We tested the hypothesis that fetal CRH is a primary factor in the onset of parturition in sheep by using a Type I CRH rece ptor antagonist, antalarmin, to block the endogenous action of CRH. Pr egnant ewes were cannulated at 130-135 days of gestation. Five cathete rs were placed into the amniotic sac, fetal femoral artery, fetal tars al vein, maternal jugular vein and carotid artery. After 5 days' recov ery, blood samples from maternal and fetal vessels were collected at t he following times: a day before the start of infusion, at {-1, 0, 1, 2, 4, 8 and 24} h, on the first day of infusion, and thereafter daily throughout a 10-day infusion. Animals (n = 6 per group) received infus ions into a fetal vein of either a vehicle comprising 1:1 mixture of e thanol and polyethoxylated castor oil (Cremophor EL) or antalarmin (50 g/L) in the vehicle at a rate of 0.3 mL/h. The plasma samples were as sayed for ACTH and cortisol using commercial RIA kits. Fetuses infused with vehicle delivered at a mean gestational age of 141.8 +/- 0.9 day s compared with antalarmin-infused sheep at 148.8 +/- 1.6 days (P = 0. 0036, unpaired Student's t-test). Fetal ACTH and cortisol did not chan ge in the antalarmin-infused sheep after 3 days' infusion compared to significant increases in vehicle-infused sheep (P = 0.004 and P = 0.01 6 respectively, ANOVA). These data show that CRH receptor antagonism i n the fetus can delay the onset of parturition. It supports the hypoth esis that hypothalamic CRH drives fetal production of ACTH and is esse ntial for the onset of parturition triggered by a surge in fetal corti sol.