title: Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis.
abstract: Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5-7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E(2) (PGE(2)) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE(2), which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE(2). We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation.
authors.affiliation: Departments of Pediatrics and Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610-0274, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Knutson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism* / Q000494:pharmacology; D026603:D-Aspartic Acid / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000378:metabolism; D006854:Hydrocortisone / Q000097:blood; D007031:Hypothalamus / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009490:Neurosecretory Systems / Q000378:metabolism; D036801:Parturition; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism* / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D000077185:Resveratrol; D012756:Sheep; D013267:Stilbenes; D013449:Sulfonamides
chemical_list: D007527:Isoenzymes; D011453:Prostaglandins; D013267:Stilbenes; D013449:Sulfonamides; D026603:D-Aspartic Acid; D016202:N-Methylaspartate; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077185:Resveratrol; C012655:nimesulide; D006854:Hydrocortisone
references.citation: Am J Physiol. 1999 Dec;277(6):R1541-52
references.pmid: 10600898
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1542-9
references.pmid: 17158270
references.citation: Am J Physiol. 1981 Jun;240(6):E585-90
references.pmid: 6264789
references.citation: Neurochem Res. 2009 Aug;34(8):1451-63
references.pmid: 19337831
references.citation: Endocrinology. 1995 Mar;136(3):1233-40
references.pmid: 7867577
references.citation: Endocrinology. 1974 Feb;94(2):588-91
references.pmid: 4359133
references.citation: Biol Reprod. 2004 Aug;71(2):676-83
references.pmid: 15115726
references.citation: Endocrinology. 1967 Nov;81(5):1140-6
references.pmid: 6052942
references.citation: Biol Neonate. 1973;22(3):177-88
references.pmid: 4147780
references.citation: J Physiol. 1994 May 15;477(Pt 1):81-7
references.pmid: 8071890
references.citation: Neuroendocrinology. 2006;83(1):4-11
references.pmid: 16682807
references.citation: Reprod Fertil Dev. 1995;7(3):479-89
references.pmid: 8606959
references.citation: Eur J Pharmacol. 2009 Aug 15;616(1-3):64-7
references.pmid: 19445926
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2317-21
references.pmid: 8637870
references.citation: Am J Physiol. 1989 May;256(5 Pt 2):R1103-10
references.pmid: 2719152
references.citation: Am J Physiol. 1998 Sep;275(3):R735-41
references.pmid: 9728070
references.citation: Am J Physiol. 1984 Sep;247(3 Pt 2):R412-7
references.pmid: 6089593
references.citation: Pediatr Res. 1995 Dec;38(6):938-43
references.pmid: 8618797
references.citation: Neuron. 1993 Aug;11(2):371-86
references.pmid: 8352945
references.citation: Anesthesiology. 1967 Sep-Oct;28(5):823-33
references.pmid: 6035012
references.citation: Circ Res. 1972 Nov;31(5):710-8
references.pmid: 5084884
references.citation: Am J Physiol. 1992 Oct;263(4 Pt 2):R880-4
references.pmid: 1415801
references.citation: Am J Physiol. 1992 Jul;263(1 Pt 2):R136-40
references.pmid: 1322065
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Jun;296(6):R1813-9
references.pmid: 19297537
references.citation: J Dev Physiol. 1991 Feb;15(2):71-9
references.pmid: 1865094
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1294-9
references.pmid: 11158633
references.citation: Endocrinology. 2008 Aug;149(8):4128-36
references.pmid: 18450957
references.citation: J Neurotrauma. 2002 May;19(5):627-38
references.pmid: 12042097
references.citation: J Comp Neurol. 1995 May 1;355(2):296-315
references.pmid: 7608344
references.citation: J Soc Gynecol Investig. 2005 May;12(4):e13-9
references.pmid: 15866108
references.citation: Annu Rev Med. 1975;26:137-41
references.pmid: 1096753
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):450-5
references.pmid: 19439250
references.citation: Gene Expr Patterns. 2009 Dec;9(8):603-11
references.pmid: 19706338
references.citation: Endocrine. 2005 Dec;28(3):287-94
references.pmid: 16388118
references.citation: Pediatr Res. 1979 May;13(5 Pt 1):606-10
references.pmid: 471593
references.citation: J Soc Gynecol Investig. 2002 Nov-Dec;9(6):342-50
references.pmid: 12445598