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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 10 4616-4620
Copyright © 2002 by The Endocrine Society

Original Article

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

S. Grottoli, R. Giordano, B. Maccagno, M. Pellegrino, E. Ghigo and E. Arvat

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 {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/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.

THE ACTIVITY OF the hypothalamus-pituitary-adrenal (HPA) axis is mainly regulated by the neurohormones CRH and arginine vasopressin (AVP), which, in turn, are under the influence of several neurotransmitters and neuropeptides (1, 2). Glucocorticoid feedback, however, is the most important influence modulating the circadian activity of HPA axis as well as its response to stress by acting at the pituitary, hypothalamic, and hippocampal levels (3, 4).

Glucocorticoid actions in the brain are mediated by the activation of glucocorticoid (GRs) and mineralocorticoid (MRs) receptors. GRs are distributed throughout the brain, but mostly in hypothalamic neurons and corticotroph cells in the pituitary gland (3, 4, 5). MRs are present in the hypothalamus, but their highest expression has been detected in the hippocampus. At this level MRs have lost aldosterone selectivity and bind glucocorticoids 10-fold more than GRs (3, 4, 5).

Animal studies showed that hippocampal MRs play a major role in the control of HPA axis. In rats, they mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity (3, 4) through inhibitory projections to the paraventricular nucleus (PVN) (6, 7, 8, 9). On the other hand, there is evidence that hippocampal activation of GRs after the increase in glucocorticoid concentrations suppresses the inhibitory hippocampal output, leading to disinhibition of the PVN (4), indicating a complex interplay between GRs and MRs in the hippocampal control of HPA activity.

A stimulatory effect of intracerebroventricular (icv) and intrahippocampal MR blockade on the HPA axis in animals has been clearly shown (10, 11, 12). Similarly, the systemic administration of canrenoate (CAN), an MR antagonist, enhances both spontaneous and CRH-stimulated ACTH and cortisol secretion in humans (13, 14, 15, 16, 17), indicating that study of the effects of mineralocorticoid antagonists on ACTH and cortisol secretion could represent a new tool to investigate the glucocorticoid feedback effect at the hippocampal level.

There is evidence that hippocampus-mediated mechanisms of glucocorticoid feedback are mediated by the modulation of hypothalamic CRH secretion and could involve {gamma}-aminobutyric acid (GABA)ergic pathways (3, 4). Benzodiazepines (BDZ), namely alprazolam (ALP), activate central GABAergic receptors, which are mainly distributed in the hippocampus (18, 19, 20, 21, 22, 23, 24). Alprazolam possesses a clear inhibitory effect on the HPA axis either in basal conditions or after central nervous system (CNS)-mediated stimuli such as stress, naloxone, hexarelin, and AVP, but not CRH (25, 26, 27, 28, 29, 30, 31, 32, 33, 34). In humans, ALP strongly reduces the corticotroph responsiveness to metyrapone, stressing that GABAergic pathways are involved in the mechanisms underlying the negative glucocorticoid feedback (35). It has been hypothesized that the effects of GABA/BDZ on HPA activity are mediated by CRH and/or AVP.

To clarify the interaction between MRs and BDZ on HPA axis in humans, we studied the effect of ALP on ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels during placebo or CAN infusion in normal young volunteers. The study was performed at the lowest point of corticotroph and adrenal secretion, i.e. late evening and early night hours, because during this time period hippocampal MRs, but not GRs, are mostly occupied and play a major role in the tonic inhibitory effect of glucocorticoids (3, 4, 17).

Subjects and Methods

Drugs

Vials containing 200 mg potassium CAN were purchased from Knoll Farmaceutici Spa (Milan, Italy). Tablets containing 0.5 mg ALP (Xanax) were purchased from Pharmacia & Upjohn, Inc. (Milan, Italy).

Study protocol

Six normal young women (aged 25–32 yr; weight, 50.0–59.5 kg) were studied in the early follicular phase. The study was approved by the ethical committee of University of Turin, and informed consent to participate in it was obtained from all subjects. All subjects received the following treatments in random order and at least 3 d apart: 1) placebo plus placebo (placebo orally at 1830 h, 1.0 ml saline as an iv bolus at 2000 h, followed by 250-ml infusion over 4 h up to 2400 h), 2) placebo plus CAN (200 mg as an iv bolus at 2000 h, followed by 200 mg infused in 250 ml saline over 4 h up to 2400 h), and 3) ALP (1.0 mg, orally, at 1830 h, i.e. ~0.02 mg/kg) plus CAN. The tests started at 1830 h after at least 6 h of fasting and 30 min after venous cannulation, kept patent by a slow infusion of isotonic saline. Blood samples were taken basally at 1830 h and every 15 min from 2000–2400 h. At each time point in each testing session ACTH, cortisol, and DHEA levels were assayed. Samples from individual subjects were analyzed together.

Plasma ACTH levels (picomoles per liter) were measured in duplicate by immunoradiometric assay (Allegro HS-ACTH, Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity of the assay was 0.2 pmol/liter. The inter- and intraassay coefficients of variation ranged from 6.9–8.9% and from 1.1–3.0%, respectively.

Serum cortisol levels (nanomoles per liter) were measured in duplicate by RIA (CORT-CTK 125, immunoradiometric assay, Sorin, Saluggia, Italy). The sensitivity of the assay was 11.0 nmol/liter. The inter- and intraassay coefficients of variation ranged from 6.6–7.5% and from 3.8–6.6%, respectively.

Serum DHEA (nanomoles per liter) was measured in duplicate by RIA (DSL-9000 Active DHEA, Diagnostic Systems Laboratories, Inc., Webster, TX). The sensitivity of the assay was 0.068 nmol/liter. The inter- and intraassay coefficients of variation ranged from 5.6–10.6% and from 7.0–10.2%, respectively.

The hormone levels (mean ± SEM) are expressed as absolute peaks and areas under curves from 2200–2400 h (AUC2200–2400), which is the time interval following the start of the effect of CAN infusion.

Statistical analysis was carried out using nonparametric ANOVA (Friedman’s test), followed by Wilcoxon test, to evaluate the effects of treatments with placebo, CAN alone, or CAN preceded by ALP on the hormone levels and then with analysis of covariance test, calculated on areas under the curve and each time point, to evaluate the different effects exerted by placebo, CAN alone, or CAN preceded by ALP.

Results

Hormonal levels at 1830 and 2000 h in different testing sessions were not significantly different.

During placebo administration, ACTH, cortisol, and DHEA secretion showed a decrease from 1830–2400 h (baseline vs. nadir, mean ± SEM, 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; AUC2200–2400, 95.0 ± 11.3 pmol/liter·h, 3388.6 ± 395.1 nmol/liter·h, and 1223.9 ± 145.6 nmol/liter·h, respectively), although statistical significance was obtained for ACTH and cortisol only (P < 0.05; Figs. 1–3GoGoGo).



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  		Figure 1. Mean (±SEM) ACTH levels and AUCs after placebo plus placebo, placebo plus CAN (200 mg as an iv bolus at 2000 h, followed by 200 mg infused in 250 ml saline over 4 h up to 2400 h), or ALP (0.02 mg/kg, orally, at 1830 h) plus CAN in normal subjects. •, P < 0.05 vs. the same time points.

 


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  		Figure 2. Mean (±SEM) cortisol levels and AUCs after placebo plus placebo, placebo plus CAN (200 mg as an iv bolus at 2000 h, followed by 200 mg infused in 250 ml saline over 4 h up to 2400 h), or ALP (0.02 mg/kg, orally, at 1830 h) plus CAN in normal subjects. •, P < 0.05 vs. the same time points.

 


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  		Figure 3. Mean (±SEM) DHEA levels and AUCs after placebo plus placebo, placebo plus CAN (200 mg as an iv bolus at 2000 h, followed by 200 mg infused in 250 ml saline over 4 h up to 2400 h), or ALP (0.02 mg/kg, orally, at 1830 h) plus CAN in normal subjects. •, P < 0.05 vs. the same time points.

 
During CAN administration, 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 vs. the same time points during placebo; Fig. 4Go).



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  		Figure 4. Individual ACTH (upper panel), cortisol (middle panel), and DHEA (lower panel) levels at 2400 h after placebo, CAN alone, or CAN preceded by ALP in normal subjects.

 
ACTH, cortisol, and DHEA AUCs after CAN (135.0 ± 7.4 pmol/liter·h, 7245.2 ± 919.4 nmol/liter·h, and 2178.4 ± 315.5 nmol/liter·h) were higher (P < 0.05) than those after placebo (Figs. 1–3GoGoGo).

ALP 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; 92.0 ± 10.6 pmol/liter·h, 3882.6 ± 517.8 nmol/liter·h, and 1290.0 ± 328.9 nmol/liter·h; P < 0.05; Figs. 1–3GoGoGo).

The hormonal levels at each time point during ALP plus CAN treatment were not different from those observed during placebo.

Side effects

CAN administration did not induce significant side effects, whereas ALP induced mild sleepiness in all subjects. Neither stopping the testing nor medication was required.

Discussion

The results of the present study show that the administration of ALP, a BDZ, abolishes the stimulatory effect of CAN, an MR blocker, on evening ACTH, cortisol, and DHEA secretion in humans.

It has widely been demonstrated that hippocampal MRs play a major role in glucocorticoid feedback control of the HPA axis (4). Animal studies clearly showed that MRs mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity (3, 4) through inhibitory projections to the PVN (6, 7, 8, 9). In fact, the stimulatory effect of both icv and intrahippocampal MR blockade on basal HPA activity has been shown in rats (10, 11, 12). In agreement with animal studies, the stimulatory effect of MR blockade by spironolactone or CAN on the HPA axis has been demonstrated in humans (13, 14, 15, 16, 17). Our present findings confirm our previous results, showing a stimulatory effect of CAN on evening ACTH, cortisol, and even DHEA secretion in normal young adults (17). As in previous studies the most prominent stimulatory effect was recorded for cortisol secretion, which was increased about 200% at 2400 h. The stimulatory effect of CAN was maximal after 3–4 h, in agreement with the delay in the effects of other ACTH secretagogues that act by modulation of glucocorticoid-mediated feedback in the CNS, i.e. metyrapone and RU-486 (25, 26).

There is evidence that ALP, a BDZ, exerts a remarkable inhibitory effect on the activity of the HPA axis in both humans and animals (27, 28, 29, 30, 31, 32, 33, 35, 36) through the activation of central GABAergic receptors (18, 19, 20). In fact, GABA plays a major influence in the neural control of HPA axis (21). Besides the inhibitory activity on ACTH and cortisol responses to various stimuli, the notable exception being human CRH (27, 29, 30, 31, 32, 33, 34, 37), ALP has been found to markedly inhibit the ACTH and deoxycortisol responses to metyrapone, indicating that GABAergic activation has an inhibitory effect on the HPA axis, overriding the stimulatory effect produced by the removal of negative cortisol feedback (35).

The results of the present study show for the first time that the stimulatory effect of CAN on the HPA axis is abolished by ALP, thus providing further evidence that GABAergic mechanisms are involved in mediating the HPA response to glucocorticoid feedback action.

There is evidence that hypothalamic CRH plays a major role in hippocampal-mediated glucocorticoid feedback (2), which is likely to involve GABAergic activation (4, 21). In this regard it has been shown that the stimulatory effect of mineralocorticoid antagonists on the HPA axis includes concomitant activation of CRH- and AVP-secreting neurons, although other mechanisms cannot be ruled out (17). In agreement with studies in animals, CAN has been found to enhance CRH- or AVP-induced ACTH and cortisol secretion in humans (17). On the other hand, the activation of central GABA/BDZ receptors has been demonstrated to clearly inhibit CRH release in rats (28, 36); moreover, both BDZ and GABA are, in turn, able to inhibit hypothalamic AVP release (37, 38, 39). Moreover, probably acting as an {alpha}2-adrenergic agonist, ALP inhibits noradrenergic activity (40, 41, 42), thus removing another well known stimulatory influence on corticotroph function.

Thus, the results of the present study suggest that GABAergic enhancement by ALP abolishes the stimulatory effect of mineralocorticoid blockade by CAN because it blocks the activation of CRH- and AVP-secreting neurons. It is remarkable that the GABAergic influence seems to override the lack of proactive feedback induced by blocking MRs, in agreement with the evidence that the stimulatory effect of metyrapone on corticotroph function is markedly inhibited by ALP (35). The CNS level by which GABA blocks HPA activity could be within the hypothalamus in the PVN (28, 36) or at a suprahypothalamic level within the hippocampus (4, 43). In fact, at both hypothalamic and hippocampal levels high GABA, MR, and CRH receptor density has been demonstrated (2, 4), and both of these CNS areas have been shown to play a critical role in the negative glucocorticoid feedback mechanisms (3, 4).

In conclusion, this study emphasizes the major effects of mineralocorticoid antagonists and BDZs on the HPA axis in humans, showing that the inhibitory effect of GABAergic activation by ALP overrides the stimulatory effect of CAN on ACTH and cortisol secretion in humans. As both CAN and ALP are drugs commonly used in clinical practice, the effects of these substances have to be taken into account when endocrinological investigations are performed as well as before treating patients with suspected adrenal impairment.

Acknowledgments

We thank Prof. Franco Camanni for his support of this study, and Dr. A. Bertagna and Mrs. A. Barberis for their skillful technical assistance.

Footnotes

This work was supported by Ministero dell’Università e della Ricerca scientifica (Grant 9906153187) and the Foundation for the Study of Endocrinological and Metabolic Diseases.

Abbreviations: ALP, Alprazolam; AUC, area under the curve; AVP, arginine vasopressin; BDZ, benzodiazepine; CAN, canrenoate; CNS, central nervous system; DHEA, dehydroepiandrosterone; GABA, {gamma}-aminobutyric acid; HPA, hypothalamus-pituitary-adrenal; icv, intracerebroventricular; MR, mineralocorticoid receptors; PVN, paraventricular nucleus.

Received March 4, 2002.

Accepted June 28, 2002.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals