Fetal sheep defend blood pressure, blood volume, and blood gases using baro- and chemoreflexes that influence autonomic and neuroendocrine responses. The local generation of prostanoids within the fetal brain is also an important component in activating hormone responses to these stimuli, but the relationship between the reflexes and prostanoid biosynthesis is unclear. The present study was performed to test the hypothesis that the abundances of prostaglandin biosynthetic enzymes in the fetal brain are dependent upon the activity of the baro- and chemoreflex pathways. We subjected chronically catheterized fetal sheep in late gestation to a 10-minute period of brachiocephalic occlusion (BCO), a stimulus that provokes brisk cardiovascular and neuroendocrine responses. We compared the central nervous system abundance of prostaglandin endoperoxide synthases 1 and 2 (PGHS-1 and PGHS-2) after BCO to (1) fetal sheep that had been subjected to BCO after chronic sinoaortic denervation plus bilateral vagotomy and (2) fetal sheep in which the N-methyl d-aspartate (NMDA) receptor antagonist, ketamine, had been administered prior to BCO. Abundances of messenger RNA (mRNA) for PGHS-1 and of mRNA and protein for PGHS-2 in fetal hippocampus were reduced significantly by either prior denervation or ketamine administration. Prostaglandin endoperoxide synthases 1 and 2 mRNA in pituitary were decreased and increased, respectively, by ketamine pretreatment. The results of this study are consistent with the conclusion that the expression of PGHS-1 and -2 in fetal hippocampus and pituitary are influenced by the baro- and/or chemoreflex pathways within the fetal brain in late gestation.
GiussaniDAMcGarrigleHHMoorePJBennetLSpencerJAHansonMA. Carotid sinus nerve section and the increase in plasma cortisol during acute hypoxia in fetal sheep. J Physiol Lond. 1994;477(pt 1):75–80.
2.
BoddyKJonesCTMantellCRatcliffeJGRobinsonJS. Changes in plasma ACTH and corticosteroid of the maternal and fetal sheep during hypoxia. Endocrinology1974;94(2):588–591.
3.
GiussaniDAMcGarrigleHHSpencerJAMoorePJBennetLHansonMA. Effect of carotid denervation on plasma vasopressin levels during acute hypoxia in the late-gestation sheep fetus. J Physiol Lond. 1994;477(pt 1):81–87.
4.
WoodCE. Sinoaortic denervation attenuates the reflex responses to hypotension in fetal sheep. Am J Physiol. 1989;256(5 pt 2):R1103–R1110.
5.
TongHLakhdirFWoodCE. Endogenous prostanoids modulate the ACTH and AVP responses to hypotension in late-gestation fetal sheep. Am J Physiol. 1998;275(3 pt 2):R735–R741.
6.
RobillardJEWeitzmanREFisherDASmithFG. The dynamics of vasopressin release and blood volume regulation during fetal hemorrhage in the lamb fetus. Pediat Res. 1979;13(5 pt 1):606–610.
7.
RoseJCMorrisMMeisPJ. Hemorrhage in newborn lambs: effects on arterial blood pressure, ACTH, cortisol, and vasopressin. Am J Physiol. 1981;240(6):E585–E590.
8.
NortonJLAdamsonSLBockingADHanVK. Prostaglandin-H synthase-1 (PGHS-1) gene is expressed in specific neurons of the brain of the late gestation ovine fetus. Brain Res Dev Brain Res. 1996;95(1):79–96.
9.
DegiRBariFBeasleyTCRegional distribution of prostaglandin H synthase-2 and neuronal nitric oxide synthase in piglet brain. Pediat Res. 1998;43(5):683–689.
10.
WongWYRichardsJS. Induction of prostaglandin H synthase in rat preovulatory follicles by gonadotropin-releasing hormone. Endocrinology. 1992;130(6):3512–3521.
11.
KujubuDAHerschmanHR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem. 1992;267(12):7991–7994.
12.
YamagataKAndreassonKIKaufmannWEBarnesCAWorleyPF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993;11(2):371–386.
13.
SairanenTRistimakiAKaralainen-LindsbergMLPaetauAKasteMLindsbergPJ. Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol. 1998;43(6):738–747.
14.
WangLHHajibeigiAXuXMLoose-MitchellDWuK. Characterization of the promotor of human prostaglandin H synthase-1 gene. Biochem Biophys Res Commun. 1993;190(2):406–411.
15.
HoffTDeWittDKaeverVReschKGoppelt-StruebeM. Differentiation-associated expression of prostaglandin G/H synthase in monocytic cells. FEBS Lett. 1993;320(1):38–42.
16.
WoodCEGirouxD. Central nervous system prostaglandin endoperoxide synthase-1 and -2 responses to oestradiol and cerebral hypoperfusion in late-gestation fetal sheep. J Physiol. 2003;549(pt 2):573–581.
17.
AnisNABerrySCBurtonNRLodgeD. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79(2):565–575.
18.
ThomsonAMWestDCLodgeD. An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine?Nature. 1985;313(6002):479–481.
19.
VardhanAKachrooASapruHN. Excitatory amino acid receptors in commissural nucleus of the NTS mediate carotid chemoreceptor responses. Am J Physiol. 1993;264(1 pt 2):R41–R50.
20.
ViardESapruHN. Carotid baroreflex in the rat: role of glutamate receptors in the medial subnucleus of the solitary tract. Neuroscience. 2004;126(3):785–794.
21.
NardoLSoongYWuDYoungIRWalkerDSzetoHH. Site and mechanism of action of dynorphin A-(1-13) and N-methyl-d-aspartate on ACTH release in fetal sheep. Am J Physiol Endocrinol Metab. 2002;282(6):E1301–E1307.
22.
BrooksANHoweDC. Adrenocorticotrophin and luteinizing hormone responses to N-methyl-d-aspartate during fetal development in sheep. J Neuroendocrinol. 1996;8(4):315–321.
23.
BoekkooiPFBaanJTeitelDFRudolphAM. Effect of drugs on chemoreceptor responsiveness in fetal sheep. Pediatr Res. 1995;38(6):938–943.
24.
PowersMJWoodCE. Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):1542–1549.
25.
ItskovitzJRudolphAM. Denervation of arterial chemoreceptors and baroreceptors in fetal lambs in utero. Am J Physiol. 1982;242(5):H916–H920.
26.
SchaubCEKeller-WoodMWoodCE. Blockade of estrogen receptors decreases CNS and pituitary prostaglandin synthase expression in fetal sheep. Neuroendocrinology. 2008;87(2):121–128.
27.
GlaznerGWCamandolaSGeigerJDMattsonMP. Endoplasmic reticulum D-myo-inositol 1,4,5-trisphosphate-sensitive stores regulate nuclear factor-kappaB binding activity in a calcium-independent manner. J Biol Chem. 2001;276(25):22461–22467.
ChenHGWoodCE. Reflex control of fetal arterial pressure and hormonal responses to slow hemorrhage. Am J Physiol. 1992;262(1 pt 2):H225–H233.
30.
TongHDhillonHWoodCE. Induction of PGHS-2 mRNA in response to cerebral hypoperfusion in late-gestation fetal sheep. Prostaglandins Other Lipid Mediat. 2000;62(2):165–172.
31.
TongHRichardsEWoodCE. Prostaglandin endoperoxide synthase-2 abundance is increased in brain tissues of late-gestation fetal sheep in response to cerebral hypoperfusion. J Soc Gynecol Investig. 1999;6(3):127–135.
32.
TongHGridleyKEWoodCE. Induction of immunoreactive prostaglandin H synthases 1 and 2 and fos in response to cerebral hypoperfusion in late-gestation fetal sheep. J Soc Gynecol Investig. 2002;9(6):342–350.
33.
GerstingJASchaubCEWoodCE. Development of prostaglandin endoperoxide synthase expression in the ovine fetal central nervous system and pituitary. Gene Expr Patterns. 2009;9(8):603–611.
34.
KaufmannWEWorleyPFPeggJBremerMIsaksonP. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996;93(6):2317–2321.
35.
de KloetERVreugdenhilEOitzlMSJoelsM. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19(3):269–301.
36.
HermanJPFigueiredoHMuellerNKCentral mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol. 2003;24(3):151–180.
37.
McDonaldTJLiCVincentSENijlandMJ. Fetal fornix transection and gestation length in sheep. Exp Neurol. 2006;200(2):532–537.
38.
SuliburkJWHelmerKSGonzalezEARobinsonEKMercerDW. Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2. Surgery. 2005;138(2):134–140.
39.
ShibakawaYSSasakiYGoshimaYEffects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth. 2005;95(6):803–810.
40.
SchneiderNLanzSRamerRSchaeferDGoppelt-StruebeM. Up-regulation of cyclooxygenase-1 in neuroblastoma cell lines by retinoic acid and corticosteroids. J Neurochem. 2001;77(2):416–424.
41.
TaniuraSKamitaniHWatanabeTElingTE. Transcriptional regulation of cyclooxygenase-1 by histone deacetylase inhibitors in normal human astrocyte cells. J Biol Chem. 2002;277(19):16823–16830.
42.
DeLongCJSmithWL. An intronic enhancer regulates cyclooxygenase-1 gene expression. Biochem Biophys Res Commun. 2005;338(1):53–61.
43.
PurintonSCWoodCE. Oestrogen augments the fetal ovine hypothalamus-pituitary-adrenal axis in response to hypotension. J Physiol. 2002;544(pt 3):919–929.
