Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic-Pituitary-Adrenal Ultradian Activity in Healthy Males
Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic-Pituitary-Adrenal Ultradian Activity in Healthy Males
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DOI：
10.1523/jneurosci.5332-09.2010
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发表时间：
2010-04-28
影响因子：
5.3
通讯作者：
Lightman, Stafford L.
中科院分区：
文献类型：
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作者：
Russell, Georgina M.;Henley, David E.;Lightman, Stafford L.
复杂的动态超昼夜节律是下丘脑-垂体-肾上腺（HPA）昼夜节律的基础。我们在正常人类男性受试者中研究了快速基础皮质类固醇反馈及其与促肾上腺皮质激素释放激素（CRH）驱动的相互作用的重要性、作用位点和受体介导的过程。在醒来期间或下午晚些时候，使用自动血液采样系统每 10 分钟测量一次健康男性的阿片黑皮质素原 (POMC)、ACTH 和皮质醇。对离散活动脉冲的数学建模表明，静脉输注合成混合糖皮质激素/盐皮质激素激动剂泼尼松龙可在早上和下午 30 分钟内快速抑制 ACTH 和皮质醇搏动。注射时开始的任何脉搏均不受影响，并且随后的脉动受到抑制。泼尼松龙还可以响应外源性 CRH 刺激而抑制 ACTH 和皮质醇的分泌，推断垂体前叶的快速反馈抑制。循环 POMC 肽浓度不受影响，表明快速皮质类固醇抑制作用专门针对垂体促肾上腺皮质激素分泌的 ACTH。泼尼松龙快速反馈仅通过糖皮质激素受体拮抗剂预处理而减少，而不是通过盐皮质激素受体拮抗作用减少，表明糖皮质激素受体介导的途径。静脉注射泼尼松龙抑制试验提供了一种强大的新工具来研究代谢和精神疾病状态下的 HPA 异常。
A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.