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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 4 1106-1110
Copyright © 1997 by The Endocrine Society

Clinical Studies

Blocking of Central Nervous Mineralocorticoid Receptors Counteracts Inhibition of Pituitary-Adrenal Activity in Human Sleep1

Jan Born, Dirk Steinbach, Christoph Dodt and Horst-Lorenz Fehm

Clinical Neuroendocrinology (J.B., D.S., H.-L.F.), and Department of Internal Medicine (C.D., H.-L.F.), University of Lübeck, 23538 Lübeck, Germany; and Physiological Psychology (J.B.), University of Bamberg, 96045 Bamberg, Germany

Address all correspondence and requests for reprints to: Jan Born, Ph.D., Medizinische Universität Lübeck, Klinische Forschergruppe: Klinische Neuroendokrinologie, Haus 23a, Ratzeburger Allee 160, 23538 Lübeck, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Pituitary-adrenal activity has been found to be inhibited during early nocturnal sleep in humans. This inhibition was supposed to reflect a regulatory influence of hippocampal cells characterized by the expression of mineralocorticoid receptors (MR). Pituitary adrenal responsiveness to bolus injections of CRH (50 µg) was examined in each of nine healthy men on four occasions: CRH was injected either during early nocturnal sleep or at the same time of night while the subject was kept awake. Both of these conditions were run after pretreatment with the selective MR antagonist, canrenoate (2 x 200 mg, 0800 and 1700 h, preceding the experimental night) and after placebo administration. After placebo, sleep reduced ACTH and cortisol secretory responses to CRH to about 65% of the size observed during wakefulness (P < 0.05). After canrenoate, ACTH and cortisol secretory responses during sleep and wakefulness did not differ and were comparable with those obtained in placebo-treated subjects during wakefulness. Compared with placebo, canrenoate also distinctly reduced the time spent in slow-wave sleep (P < 0.005). The findings confirm an inhibition of pituitary-adrenal responsiveness during early sleep. The inhibition disappearance after blockage of MR suggests that sleep exerts this influence via central nervous MR-expressing cells. These cells seem to be simultaneously involved in the generation of slow-wave sleep.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PITUITARY-ADRENAL secretory activity displays strong diurnal variations. In humans, ACTH/cortisol secretory activity typically is reduced to a minimum (nadir) during the early hours of nocturnal sleep. This nadir seems to reflect the coordinate activation of hypothalamic and hippocampal mechanisms inhibiting pituitary-adrenal secretion.

Occurrence of the ACTH/cortisol nadir during the first hours of the night, even in waking subjects, primarily reflects activity of the circadian oscillator (1). However, nocturnal sleep strengthens the influence of the circadian rhythm. Several studies have reported on a temporary decline in plasma concentrations of cortisol occurring, contingent upon sleep onset at night, as well as during daytime sleep (2, 3, 4). In conditions of regular nighttime sleep, a decrease in plasma ACTH/cortisol after sleep onset may not readily be discerned (because of the circadian influence) because, in healthy young subjects, plasma ACTH/cortisol concentrations already are typically rather low before sleep onset. Yet, a substantial contribution of nighttime sleep to the inhibitory control over pituitary-adrenal activity around the nadir time can be demonstrated under conditions of stimulated ACTH/cortisol release. A decreased stimulation of ACTH/cortisol during early sleep [especially slow-wave sleep (SWS)] has been revealed in subjects constantly infused with CRH (5). Moreover, ACTH/cortisol secretory responses to iv bolus administrations of CRH and vasopressin during early epochs of nocturnal NonREM (nonrapid eye movement) sleep were markedly diminished, compared with secretory responses obtained during the same time of night but in subjects kept awake (5, 6, 7). Together, these results indicate an inhibition of pituitary-adrenal secretory activity during early sleep, possibly mediated via the hypothalamic release of an as-yet unknown release inhibiting factor of ACTH.

A hippocampal control over diurnal oscillations of hypothalamic-pituitary-adrenal secretion has been proposed on the basis of data from animal studies (8, 9). The hippocampus has been demonstrated to process corticosteroid feedback signals via two different types of receptors, type I mineralocorticoid receptors (MR) and type II glucocorticoid receptors (8, 10, 11). In rats, corticosterone has been shown to inhibit pituitary-adrenal secretion via hippocampal MR. Blocking of this receptor enhanced basal and stress-induced pituitary-adrenal activity (12). Likewise, administration of the selective MR antagonist, canrenoate, enhanced plasma cortisol concentrations around the time of the nadir in human subjects (13). Although these data suggest a contribution of MR to the circadian control of ACTH/cortisol release, it is unclear to what extent the MR system is involved also in mediating the inhibitory effect of early sleep on pituitary-adrenal secretion.

A working hypothesis for this study was that the hippocampal MR neuronal system contributes specifically to the sleep-related inhibition of pituitary-adrenal secretion in humans. It was believed that blocking of the central nervous MR, after canrenoate, would enhance pituitary-adrenal secretory responsiveness to CRH selectively during early nocturnal sleep. Hereby, secretory responsiveness should reach a level normally present during wakefulness. No such enhancing effect of canrenoate was expected during wakefulness.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Nine healthy men (22–30 yr old, mean 24.1 yr) participated in the study. The men were nonsmokers, were not under medication during the period of the experiments, and had no history of sleep disturbances. They had normal sleep-wake rhythms for at least 4 weeks before the experiments. The study took place in the sleep laboratory of the Neuroendocrinology Department at the University of Lübeck. The experimental protocol was approved by the local ethics committee, and each man gave written informed consent before participation.

The subjects were acclimatized to the experimental setting by an adaptation night. They were required to arise between 0700 and 0730 h on the day before experimental nights and not to take any naps and to abstain from alcoholic drinks, coffee, and black tea throughout the day.

Each man was examined on four occasions. On two of these occasions, he received iv 200 mg potassium canrenoate (AldactoneR, Boehringer, Mannheim, FRG), once at 0800 h and a second time at 1700 h before the experimental night. On the other occasions, placebo (saline solution) was injected. The order of placebo and canrenoate conditions was balanced across subjects. On the nights after canrenoate and placebo, respectively, a bolus of 50 µg human CRH (Ferring, Kiel, FRG) was injected iv, once while the subject was asleep (conditions Placebo/Sleep and Canrenoate/Sleep) and once while the subject was kept awake (conditions Placebo/Wake and Canrenoate/Wake).

During the sleep conditions, subjects were prepared for standard polysomnographical recordings and blood sampling procedures between 2100 and 2200 h. Continuous recordings were obtained between 2300 h (when lights were switched off) until 2 h after CRH administration. CRH was given within 60 min after sleep onset, when extemporaneous examination of sleep recordings indicated the presence of sleep stage 2 occurring after the first epoch of SWS. On 2 nights (of each canrenoate and placebo), CRH was given exactly 60 min after sleep onset, because until this time, either SWS had not occurred or the first epoch of SWS still persisted. In these latter cases, sleep stage 2 or 3 was present during CRH administration. The average time of CRH stimulation was at 0005 h (range 2350–0045 h) after canrenoate and at 2358 h (range 2334–0024 h) after placebo. The latency of CRH administration, with reference to sleep onset, averaged (mean ± SEM) 55.0 ± 1.9 min after canrenoate and 46.7 ± 6.0 min after placebo. Blood for determination of plasma ACTH and cortisol was sampled (beginning at 2300 h) every 15 min during the time preceding CRH administration, immediately before CRH administration (zero min), and 15, 30, 45, 60, 75, 90, 105, and 120 min after CRH injection. Blood samples were drawn from an iv catheter connected to a long thin tube, which enabled blood collection from an adjacent room without disturbing the subject’s sleep. To prevent clotting, about 250 mL saline (0.9%) were infused throughout the study period. The catheter was flushed with 3 mL of a solution containing 10% albumin in 0.9% saline before and after each CRH administration.

When the subject was kept awake, CRH was administered at a time of night corresponding to the time CRH had been administered during the sleep condition(s) of the individual, in cases when the sleep condition(s) preceded the wake condition. When the wake condition was first, stimulation was performed at 2400 h. The average time of CRH stimulation was at 0006 h (range 2350–0030 h) after canrenoate and at 0001 h (range 2345–0015 h) after placebo. Blood sampling was as described for the sleep conditions. During the wake period, subjects could read a magazine or talk to the experimenter. They remained in a supine position throughout the experimental epoch.

Recording and data analysis

Sleep stages were determined from electroencephalographic, electrooculographic, and electromyographic recordings that were scored according to the criteria described by Rechtschaffen and Kales (14). Subsequent 30-sec epochs of recordings were scored visually as stage wake or as stage 1, 2, 3, 4, or REM sleep.

Blood samples were centrifuged immediately after collection, and plasma was stored at -20 C until assay. Plasma ACTH was measured by immunoradiometric assay (Lumitest, Brahms, Berlin, FRG), detecting only intact ACTH. Assay sensitivity was 2 pg/mL. Intrassay precision was below 8%. Cortisol also was determined by RIA (Hermann Biermann, Bad Nauheim, FRG). The sensitivity was 0.2 µg/dL, the intraassay coefficient of variation was below 3%, between 1 and 50 µg/dL. The cross-reactivity against potassium canrenoate was less than 1%. The interassay coefficient of variation for both the ACTH and cortisol assay was below 10%. All samples from an individual subject were analyzed in duplicate in the same assay.

Differences in plasma ACTH and cortisol concentrations after CRH administration were statistically evaluated using analysis of covariance [ANCOVA; (15)], including the concentration immediately before CRH administration (at zero min) as covariate. ANCOVA included the repeated measures factors Pretreatment (canrenoate vs. placebo) and Mental state (sleep vs. wake). ANCOVA was run separately on values for each point in time after CRH administration and on area measures (area under response curve between zero and 90 min after CRH administration). In addition, ANOVA was used to compare preinjection baseline concentrations of cortisol and ACTH among the four experimental conditions. Finally, pairwise comparisons were performed between the effects of any two conditions. A (Greenhouse-Geisser corrected) P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After placebo, plasma concentrations of cortisol and ACTH during the 15-min baseline interval preceding the administration of CRH were low and close to the detection limit, even when subjects were kept awake (mean ± SEM; ACTH: 7.3 ± 0.6 pg/mL; cortisol: 2.5 ± 0.4 µg/dL). During sleep, respective baseline concentrations were 6.2 ± 0.7 pg/mL for ACTH and 2.3 ± 0.4 µg/dL for cortisol. Pretreatment with canrenoate significantly enhanced baseline concentrations of cortisol. Compared with the respective placebo conditions, the increase was significant in subjects when asleep [3.5 ± 0.5 µg/dL, F (1, 8) = 8.2, P < 0.05] but failed to reach significance during wakefulness (3.6 ± 0.4 µg/dL, not significant). Plasma ACTH concentrations during the preinjection baseline interval were, on average, also slightly elevated after canrenoate (6.3 ± 1.0 pg/mL during sleep, 8.0 ± 0.6 pg/mL during wakefulness). However, compared with the respective placebo conditions, the increases in ACTH concentration remained nonsignificant.

Sleep, as well as administration of canrenoate, distinctly influenced the ACTH/cortisol secretory response to CRH. On each occasion, the bolus injection of CRH triggered a substantial elevation of plasma ACTH and cortisol concentrations. Individual maximum concentrations of ACTH were reached between 15 and 45 min after injection. Maximum concentrations of the cortisol response were reached between 30 and 60 min after CRH injection. Figure 1Go shows ACTH/cortisol secretory responses during sleep and wakefulness, comparing the effects of pretreatment with placebo vs. canrenoate. Figure 2Go summarizes area under curve measures of the secretory responses obtained in the four experimental conditions.



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  		Figure 1. Mean (±SEM) ACTH (left) and cortisol (right) secretory responses to a bolus injection of 50 µg CRH (at zero min). CRH was administered either during early nocturnal sleep (top) or at the same time of night while the subject was kept awake (bottom). Both of these conditions were run after pretreatment with placebo (solid lines) and the selective MR antagonist canrenoate (2 x 200 mg, dashed lines). Means represent baseline-adjusted values derived from ANCOVA. *, P < 0.05; **, P < 0.01, for pairwise comparisons between effects of canrenoate and placebo.

 


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  		Figure 2. Mean (±SEM) areas under ACTH (top) and cortisol (bottom) secretory response curves between zero and 90 min after bolus injection of 50 µg CRH. CRH was injected during early nocturnal sleep and at the same time of night when subjects were kept awake. Both of these conditions were run after pretreatment with placebo (solid lines) and after administration of the selective MR antagonist canrenoate (2 x 200 mg, dashed lines). *, P < 0.05; **, P < 0.01, for pairwise comparisons between the effects of any two of the conditions.

 
Comparison of the two placebo conditions indicated (as expected) a substantial reduction of ACTH and cortisol secretory responses during early sleep, as compared with the responses obtained at the same time of night in waking subjects. Suppression of the ACTH secretory response during sleep reached statistical significance persistently between 15 and 105 min after CRH injection, except for the 30-min postinjection time. The parallel effect of sleep on cortisol secretion was confirmed statistically between 30 and 120 min post injection. The area under the curve between zero and 90 min after CRH injection was reduced during sleep, on average, by 33%, for plasma ACTH concentrations [F (1, 7) = 5.5, P < 0.05] and by 35% for plasma cortisol concentrations [F (1, 7)= 5.8, P < 0.05].

During sleep, pretreatment with canrenoate enhanced ACTH and cortisol secretory responses so that the sizes of these responses were comparable with those obtained in placebo-treated subjects during wakefulness (Fig. 1Go). The enhancing effect of canrenoate on the sleep-associated responses was observed between 15 and 75 min post injection for ACTH and between 45 and 120 min post injection for cortisol. Area measures indicated, on average, an increase of 24% for ACTH responses and of 31% for cortisol responses during early sleep, after canrenoate, as compared with placebo (Fig. 2Go). In contrast to the effects of canrenoate during sleep, during wakefulness, canrenoate did not enhance ACTH/cortisol secretory responses. In awake subjects, secretory responses, as determined by area under the curve measures, were completely comparable after pretreatment with canrenoate and placebo (Fig. 2Go). Inspection of the time course of secretory responses even revealed a somewhat faster recovery of baseline ACTH and cortisol levels after pretreatment with canrenoate than placebo. During the 2nd hour after CRH injection, this difference temporarily reached significance (Fig. 1Go).

Statistically, the enhancing effect of canrenoate on pituitary-adrenal responsiveness to CRH, being restricted to stimulation during sleep but absent in waking subjects, was confirmed by significant Pretreatment x Mental state interaction terms for the area under the curve measures of ACTH [F (1, 7) = 6.03, P < 0.05] and cortisol [F (1, 7) = 8.75, P < 0.025]. Moreover, pairwise comparisons of the areas indicated significant differences between the effects of canrenoate and placebo for the sleep conditions but not for the wake conditions (Fig. 2Go).

Sleep during the time of endocrine analysis (i.e. between 15 min before and 120 min after CRH administration) was characterized by a pronounced decrease in the time spent in SWS after canrenoate (21.0 ± 3.5 min), compared with the effects of pretreatment with placebo (40.8 ± 3.1 min, P < 0.005). Time spent in sleep stage 1 was enhanced after canrenoate (29.3 ± 7.2 min vs. placebo: 11.3 ± 4.4 min, P < 0.005). Differences in time awake after canrenoate (2.8 ± 1.1 min) and placebo (1.0 ± 0.6 min) were marginal and did not reach significance. Also, time spent in sleep stage 2 and REM sleep were comparable for both conditions (canrenoate vs. placebo, stage 2 sleep: 61.1 ± 8.4 vs. 60.8 ± 4.7 min; REM sleep: 20.8 ± 4.3 vs. 20.9 ± 3.2 min, not significant).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study aimed to demonstrate a role of the central nervous MR system for the inhibition of pituitary-adrenal secretory activity during early sleep in humans. The data confirmed a blunted ACTH/cortisol secretory response to bolus injection of CRH during early nocturnal epochs of NonREM sleep, as compared with responses obtained in awake subjects. Blocking of central nervous MR after administration of canrenoate compensated for the sleep-associated inhibition of pituitary-adrenal responsiveness but did not enhance the secretory response to CRH during wakefulness.

A suppression of ACTH/cortisol secretory responsiveness to CRH and also to vasopressin during early nocturnal NonREM sleep has been likewise shown in previous human studies (6, 7). Considering that early sleep influenced cortisol and ACTH secretory responses in parallel, the inhibitory mechanism mediating this influence probably is not located at the adrenocortical level. Also, cortisol secretory responses to ACTH administration were found to be unchanged during early sleep (16). It may be that reduced pituitary-adrenal responsiveness during early nocturnal sleep represents a consequence of an inhibited hypothalamic release of CRH and vasopressin, which are the main secretagogues of ACTH release in the human (17, 18). However, in a recent study, the sleep-related suppression of pituitary-adrenal responsiveness was found even after combined administration of CRH and vasopressin at doses expected to mask any possible differences in basal endogenous release of both secretagogues (5). Those findings favored the view that the ACTH response during early sleep is diminished because of hypothalamic secretion of an as-yet unknown release-inhibiting factor of ACTH.

Because cross-reactivity of canrenoate with antibodies of the cortisol assay was below 1%, cross-reactivity of the RIA can be excluded as a contaminating source for the effects of the MR antagonist. Also, enhancing effects of canrenoate on ACTH and cortisol secretory responses cannot be explained by metabolic changes. Canrenoate, at high concentrations, has been shown to inhibit, rather than to stimulate, steroid synthesis, and the substance does not seem to change degradation of cortisol (19, 20). Moreover, there is, at present, no evidence supporting any effect of canrenoate on synthesis and degradation of ACTH. Potassium canrenoate is not active per se but, in the body, is converted to canrenone, which has a half-life of approximately 16.5 h and is considered the main functional active derivate (21). Both potassium canrenoate and canrenone pass the blood brain barrier (22, 23). Given that canrenoate and its main metabolites reached the brain, hormonal changes after canrenoate most likely resulted from an action on central nervous MR, which in humans, are also located primarily in the hippocampus and septal regions but also in the hypothalamus and pituitary (9, 24, 25, 26). Strongest support for this conclusion derived from the fact that the effect of canrenoate depended upon the subject’s mental state, i.e. sleep or wakefulness. The MR antagonist enhanced pituitary-adrenal responsiveness exclusively during sleep, to a level comparable with that during normal wakefulness. During wakefulness, canrenoate virtually had no enhancing effect on ACTH/cortisol secretory responses to CRH. This pattern fits the working hypothesis for the present experiments, proposing an inhibitory control of the central nervous MR system on pituitary-adrenal activity that is selectively active during early nocturnal sleep. Nevertheless, in light of the largely unknown role of pituitary MR in humans, a contribution to the observed effects of canrenoate binding to receptors at these peripheral sites presently cannot be ruled out.

A finding further supporting a primary influence of canrenoate on the central nervous system was the substantial change in sleep during the epoch of hormonal analysis. Canrenoate decreased the time of SWS to about 50% of that observed after pretreatment with placebo, and these results agree with a previous study on canrenoate effects on human sleep (27). The decrease in SWS was compensated mainly by an increased time spent in stage 1 sleep after administration of the MR antagonist. On this background, it is conceivable that the elevation of pituitary responsiveness during sleep did not reflect a primary effect of the MR antagonist but was secondary to its suppressive effect on SWS. SWS itself is supposed to suppress pituitary-adrenal secretory activity (5, 28). However, in a foregoing human study, selective suppression of SWS during the first 3 h of nocturnal sleep did not affect basal plasma cortisol concentrations (29). Yet, these data on basal concentrations do not exclude the possibility that SWS may be essential for the canrenoate-induced effects on pituitary release stimulated by exogenous CRH.

Considering findings from rat and human studies that the blockade of MR-enhanced diurnal nadir concentrations of corticosteroid, even in awake subjects (12, 13), it may have been expected that canrenoate also would enhance pituitary responsiveness to CRH in the wake condition of this experiment. On the other hand, it could be argued that in the present study, no such an enhancement was obtained because during wakefulness, the ACTH/cortisol responses to CRH already were at a maximum, thus preventing any further increase of these responses after canrenoate. However, the dose of 50 µg CRH was chosen to induce only intermediate increases in ACTH plasma concentrations. Moreover, foregoing experiments (6) have shown in awake subjects that ACTH/cortisol responses to CRH injections were almost identical in the first, as compared with the second part of the night, i.e. during times when basal pituitary-adrenal activity substantially differs because of circadian rhythm. Those results indicate that regulation of pituitary responsiveness to CRH apparently relies on mechanisms different from those regulating circadian nadir and peak concentrations. Further, they indicated that the decrease in pituitary responsiveness to CRH during early sleep is indeed specifically linked to sleep (and not to circadian control over pituitary-adrenal activity). This view fits well with the present findings that the enhancing effects of canrenoate on pituitary responses to CRH were clearly limited to sleep. (In a related experiment on awake subjects, canrenoate likewise failed to enhance the ACTH/cortisol response to CRH obtained in the afternoon; Dodt et al., unpublished). During wakefulness, in the present study, ACTH/cortisol secretory responses, on the contrary, seemed to decrease somewhat faster after pretreatment with canrenoate than placebo. This effect even temporarily reached significance during the 2nd hour of the poststimulation epoch. This tendency towards a reversed effect of canrenoate on pituitary responsiveness in awake subjects cannot be explained presently and needs further exploration. With respect to basal circadian levels, canrenoate slightly enhanced plasma cortisol concentrations before administration of CRH. Although somewhat less consistent during wakefulness, on average, the increase was comparable in awake and sleeping subjects, which agrees with data in animals and humans, indicating a contribution of MR also to the circadian control of basal pituitary-adrenal secretory activity (12, 13).


   Acknowledgments
 
The authors are grateful to A. Otterbein and S. Baxmann for technical assistance.


   Footnotes
 
1 This work was supported by a grant from the Deutsche Forschungs-geineinschaft (to J.B. and H.-L.F.). Back

Received September 5, 1996.

Revised November 20, 1996.

Accepted December 16, 1996.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Am J Physiol Endocrinol Metab, July 1, 1998; 275(1): E94 - E100.
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C. Bierwolf, A. Burgemeister, K. Lüthke, J. Born, and H. L. Fehm
Influence of Exogenous Atrial Natriuretic Peptide on the Pituitary-Adrenal Response to Corticotropin-Releasing Hormone and Vasopressin in Healthy Men
J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1151 - 1157.
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