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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

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Prof. Emanuela Arvat, Divisione di Endocrinologia e Malattie del Metabolismo, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy. E-mail: emanuela.arvat{at}unito.it.

Abstract

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 -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/m²). 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 alprazolam 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.

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