Inhibition of brain prostaglandin endoperoxide synthase-2 prevents the preparturient increase in fetal adrenocorticotropin secretion in the sheep fetus.
Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (i.c.v) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E(2) concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.
Gersting
Jason
J
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610-0274, USA.
Schaub
Christine E
CE
Keller-Wood
Maureen
M
Wood
Charles E
CE
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005865:Gestational Age; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007276:Injections, Intraventricular; D036801:Parturition / Q000187:drug effects / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D011272:Pregnancy, Multiple / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012756:Sheep; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014427:Twins
D052246:Cyclooxygenase 2 Inhibitors; D013449:Sulfonamides; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D051546:Cyclooxygenase 2; C012655:nimesulide