The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans
The stimulatory effect of canrenoate, a mineralocorticoid antagonist, on the activity of the hypothalamus-pituitary-adrenal axis is abolished by alprazolam, a benzodiazepine, in humans
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DOI：
10.1210/jc.2002-020331
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发表时间：
2002-10-01
影响因子：
5.8
通讯作者：
Arvat, E
中科院分区：
文献类型：
--
作者：
Grottoli, S;Giordano, R;Arvat, E
海马中的盐皮质激素受体（MR）在控制下丘脑-垂体-肾上腺（HPA）轴中起主要作用，介导糖皮质激素在维持基础活性中的主动反馈。脑室内和海马内MR阻滞刺激HPA轴的动物;盐皮质激素拮抗剂的全身给药增强自发和CRH刺激的ACTH和皮质醇分泌在人类。苯二氮卓类药物，即阿普唑仑，激活中枢γ-氨基丁酸（GABA）能受体，其主要分布在海马中。阿普唑仑对HPA轴有抑制作用，无论是在基础条件下还是在中枢神经系统介导的刺激后。在人类中，阿普唑仑强烈降低促肾上腺皮质激素细胞对甲吡酮清除糖皮质激素反馈的反应性。我们研究了阿普唑仑（0.02 mg/kg，口服）对坎利酸（CAN）、MR拮抗剂（200 mg静脉推注，随后200 mg注入250 ml生理盐水）或安慰剂对6名正常年轻女性（年龄25-32岁;体重指数19-23 kg/m2）ACTH、皮质醇和脱氢表雄酮（DHEA）分泌的影响。在安慰剂治疗期间，ACTH、皮质醇和脱氢表雄酮的分泌呈进行性下降（基线与最低点，平均值+/- SEM，1830-2400 h，2.6 +/- 0.3 vs. 1.4 +/- 0.3 pmol/L，133.2 +/- 16.4 vs. 46.9 +/- 5.2 nmol/L，和22.6 +/- 2.3对18.6 +/- 2.3 nmol/L），尽管仅ACTH和皮质醇具有统计学意义（P < 0.05）。在CAN治疗期间，ACTH、皮质醇和DHEA分泌显示出进行性升高，其在大约2100 h开始，并在2300和2400 h之间达到峰值（分别为2.9 +/- 0.3 pmol/L、172.6 +/- 27.9 nmol/L和45.3 +/- 10.7 nmol/L; P < 0.05）。阿普唑仑消除了CAN诱导的ACTH、皮质醇和DHEA水平的升高（1.8 +/- 0.1 pmol/L，59.7 +/- 8.6 nmol/L和19.8 +/- 6.7 nmol/L; P < 0.05），诱导激素峰值与安慰剂组在没有任何治疗的情况下记录的峰值重叠。总之，我们的研究表明，在人体中，阿普唑仑对GABA能激活的抑制作用超过了坎利酸盐对HPA轴的盐皮质激素阻断的刺激作用。这些发现强调了GABA在人类HPA轴控制中的作用。
Mineralocorticoid receptors (MR) in the hippocampus play a major role in the control of the hypothalamus-pituitary-adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids in the maintenance of basal activity. Intracerebroventricular and intrahippocampal MR blockade stimulates HPA axis in animals; the systemic administration of mineralocorticoid antagonists enhances spontaneous and CRH-stimulated ACTH and cortisol secretion in humans. Benzodiazepines, namely alprazolam, activate central gamma-aminobutyric acid (GABA)ergic receptors, which are mainly distributed in the hippocampus. Alprazolam has a inhibitory effect on HPA axis either in basal conditions or after central nervous system-mediated stimuli. In humans, alprazolam strongly reduces the corticotroph responsiveness to removal of glucocorticoid feedback by metyrapone. We studied the effect of alprazolam (0.02 mg/kg, orally) on the effect of canrenoate (CAN), an MR antagonist (200 mg as an iv bolus, followed by 200 mg infused in 250 ml saline) or placebo on ACTH, cortisol, and dehydroepiandrosterone (DHEA) secretion in six normal young women (aged 25-32 yr; body mass index, 19-23 kg/m(2)). During placebo, ACTH, cortisol, and DHEA secretion showed a progressive decrease (baseline vs. nadir, mean +/- SEM, from 1830-2400 h, 2.6 +/- 0.3 vs. 1.4 +/- 0.3 pmol/liter, 133.2 +/- 16.4 vs. 46.9 +/- 5.2 nmol/liter, and 22.6 +/- 2.3 vs. 18.6 +/- 2.3 nmol/liter, respectively), although statistical significance was obtained for ACTH and cortisol only (P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA secretion showed a progressive rise, which began at approximately 2100 h and peaked between 2300 and 2400 h (2.9 +/- 0.3 pmol/liter, 172.6 +/- 27.9 nmol/liter, and 45.3 +/- 10.7 nmol/liter, respectively; P < 0.05). Alprazolam abolished the CAN-induced increases in ACTH, cortisol, and DHEA levels (1.8 +/- 0.1 pmol/liter, 59.7 +/- 8.6 nmol/liter, and 19.8 +/- 6.7 nmol/liter; P < 0.05), inducing hormonal peaks overlapping with those recorded after placebo in the absence of any treatment. In conclusion, our study demonstrates that the inhibitory effect of GABAergic activation by alprazolant overrides the stimulatory effect of mineralocorticoid blockade by canrenoate on the HPA axis in humans. These findings emphasize the role of GABA in the control of the HPA axis in humans.