Departments of Pediatrics and Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610-0274, USA.
Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R365-70. doi: 10.1152/ajpregu.00163.2010. Epub 2010 May 5.
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.
前列腺素是胎儿大脑中产生的物质，是控制胎儿下丘脑-垂体-肾上腺（HPA）轴的机制的组成部分。本实验室的先前研究表明，前列腺素 G/H 合酶同工酶 2（PGHS-2）抑制可降低胎儿 HPA 轴对脑低灌注的反应，阻断分娩前胎儿血浆 ACTH 浓度的升高，并延迟分娩。我们还发现，阻断 N-甲基-D-天冬氨酸（NMDA）受体可减少胎儿对脑低灌注的 ACTH 反应。本研究旨在检验以下假设：PGHS-2 作用及其对 HPA 轴刺激的下游效应是由 NMDA 介导的谷氨酸能神经传递刺激的。对接受过慢性导管插入术的妊娠晚期胎儿羊（n=8）进行 NMDA（1mgiv）注射。所有胎儿均表现出血浆 ACTH 和皮质醇浓度增加。预先用白藜芦醇（100mgiv，n=5）预处理，一种 PGHS-1 的特异性抑制剂，不会改变 NMDA 对 HPA 轴反应的幅度。预先用尼美舒利（10mgiv，n=6）预处理，一种 PGHS-2 的特异性抑制剂，可显著降低 NMDA 对 HPA 轴的反应。为了进一步探索这种相互作用，我们在六只接受过慢性导管插入术的胎儿羊中注射了 NMDA，这些羊在五天至七天内接受了尼美舒利（n=6）的慢性侧脑室输注（1mg/天）。在这一组中，NMDA 对 ACTH 没有明显的反应。最后，我们测试了前列腺素 E2（PGE2）对 HPA 轴的反应是否由 NMDA 受体介导。对七只接受过慢性导管插入术的妊娠晚期胎儿羊进行了 100ngPGE2 注射，这显著增加了胎儿血浆 ACTH 和皮质醇浓度。预先用氯胺酮（10mgiv）预处理，一种 NMDA 拮抗剂，并没有改变 ACTH 或皮质醇对 PGE2 的反应。我们的结论是，胎儿大脑中 PGHS-2 的作用产生的前列腺素通过增强 NMDA 介导的谷氨酸能刺激对胎儿 HPA 轴的反应来增强胎儿 HPA 轴对 NMDA 的反应。
