Effect of antalarmin, a novel corticotropin-releasing hormone antagonist, on the dynamic function of the preterm ovine fetal hypothalamo-pituitary-adrenal axis.
This study describes the effect of antalarmin on basal and stimulated activity of the hypothalamo-pituitary-adrenal (HPA) axis function in the late gestation ovine fetus. Fetuses received antalarmin (15 mg/h i.v.) or vehicle (cremophor El 50% in ethanol) from day 130 gestational age. Antalarmin infusion did not significantly affect immunoreactive corticotropin (ir-ACTH) concentrations, although there was a tendency for ir-ACTH to be lower and cortisol concentrations were lower in the antalarmin-treated fetuses (p < 0.01). The ir-ACTH response to corticotropin-releasing hormone (CRH) challenge was attenuated (p < 0.05) in the antalarmin-treated fetuses, but neither antalarmin- nor vehicle-treated fetuses had significant cortisol responses to CRH. The ir-ACTH response to hypoxia was diminished (p < 0.05) in the antalarmin-treated fetuses while the cortisol responses of antalarmin- and vehicle-treated fetuses were indistinguishable. Deconvolution analysis revealed no effect of antalarmin treatment on ir-ACTH secretory dynamics. In contrast, antalarmin decreased (p < 0.05) basal, mean and integrated cortisol. The plasma cortisol responses of antalarmin- and vehicle-treated fetuses to exogenous ACTH(1-24) were indistinguishable. These data indicate that, while antalarmin inhibits CRH- and stress-induced ir-ACTH secretion, basal ir-ACTH secretion may be less affected by antalarmin treatment. Paradoxically, cortisol secretion is impaired by antalarmin infusion, although adrenal responsiveness to ACTH is not impaired. These results confirm a role for CRH in stress-induced ACTH secretion in the ovine fetus, though its role in the regulation of basal ACTH and cortisol secretion is unclear.
Young
I Ross
IR
Department of Physiology, Monash University, Clayton, Vic., Australia. young @med.monash.edu.au
Chan
E Cheng
EC
Smith
Roger
R
Chrousos
George P
GP
Veldhuis
Johannes D
JD
Canny
Benedict J
BJ
D000311:Adrenal Glands / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D003366:Cosyntropin / Q000494:pharmacology; D005260:Female; D005311:Fetal Hypoxia / Q000503:physiopathology; D005865:Gestational Age; D006854:Hydrocortisone / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D007700:Kinetics; D010100:Oxygen / Q000097:blood; D010902:Pituitary Gland / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012756:Sheep
D011743:Pyrimidines; D011758:Pyrroles; C103016:antalarmin; D003366:Cosyntropin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D010100:Oxygen; D006854:Hydrocortisone