Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor

The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4–5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor.

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Hypothalamic-Pituitary-Adrenal Axis Activity of Newborn Mice Rapidly Desensitizes to Repeated Maternal Absence but Becomes Highly Responsive to Novelty

Endocrinology ◽

10.1210/en.2008-0238 ◽

2008 ◽

Vol 149 (12) ◽

pp. 6366-6377 ◽

Cited By ~ 39

Author(s):

L. Enthoven ◽

M. S. Oitzl ◽

N. Koning ◽

M. van der Mark ◽

E. R. de Kloet

Keyword(s):

Glucocorticoid Receptor ◽

Receptor Antagonist ◽

Hpa Axis ◽

Mineralocorticoid Receptor ◽

Maternal Separation ◽

Mineralocorticoid Receptor Antagonist ◽

Newborn Mice ◽

Hypothalamic Pituitary Adrenal ◽

The Third ◽

Corticosterone Response

In CD1 mice we investigated the hypothalamic-pituitary-adrenal (HPA) axis response to maternal separation for 8 h daily from postnatal d 3 to 5. At d 3 a slow separation-induced corticosterone response developed that peaked after 8 h, and the pups became responsive to stressors. On the second and third day, the response to 8 h separation rapidly attenuated, whereas the response to novelty did not, a pattern reflected by the hypothalamic c-fos mRNA response. If maternal separation and exposure to novelty were combined, then after the third such daily exposure, the sensitivity to the stressor was further enhanced. Meanwhile, basal corticosterone and ACTH levels were persistently suppressed 16 h after pups were reunited with their mothers. To explain the HPA axis desensitization after repeated separation, we found that circulating ghrelin levels increased and glucose levels decreased after all periods of maternal separation, ruling out a role of altered metabolism. Glucocorticoid feedback was not involved either because a glucocorticoid receptor antagonist amplified the corticosterone response after the first but became ineffective after the third separation. In contrast, a mineralocorticoid receptor antagonist decreased and increased corticosterone levels after the first and third period of separation, respectively. In conclusion, the newborn’s HPA axis readily desensitizes to repeated daily maternal separation, but continues to respond to novelty in a manner influenced by a central mineralocorticoid receptor- rather than glucocorticoid receptor-mediated mechanism.

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Regulation of the Hypothalamic-Pituitary-Adrenal Axis Circadian Rhythm by Endocannabinoids Is Sexually Diergic

Endocrinology ◽

10.1210/en.2010-0101 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3720-3727 ◽

Cited By ~ 38

Author(s):

Helen C. Atkinson ◽

James D. Leggett ◽

Susan A. Wood ◽

Emma S. Castrique ◽

Yvonne M. Kershaw ◽

...

Keyword(s):

Hpa Axis ◽

Cannabinoid Receptor ◽

Time Of Day ◽

Female Rats ◽

Male Rats ◽

Acute Administration ◽

Sampling System ◽

Hypothalamic Pituitary Adrenal ◽

Male And Female Rats ◽

Cb1 Antagonist

We have examined the effects of acute administration of the cannabinoid receptor type 1 (CB1) antagonist AM251 on the rat hypothalamic-pituitary-adrenal (HPA) axis with respect to both gender and time of day. Blood samples were collected from conscious male and female rats every 5 min using an automated blood sampling system, and corticosterone concentrations were determined. In male rats, there was a distinct diurnal effect of AM251 with a greater activation of the HPA axis in the morning (diurnal trough) compared with the evening (diurnal peak). At both times of the day, circulating corticosterone concentrations were elevated for approximately 4 h after AM251 administration. In female rats, there was also diurnal variation in the activation of the HPA axis; however, these effects were not as profound as those in males. Corticosterone concentrations were only slightly elevated at the diurnal trough and for a shorter time period than in males (2 compared with 4 h). Moreover, there was no effect of AM251 on corticosterone concentrations when administered at the diurnal peak. Subsequent studies, only in males, in which both ACTH and corticosterone were measured, confirmed that the effects of AM251 on corticosterone were mediated by ACTH. Moreover, the elevation of both ACTH and corticosterone could be replicated using another CB1 antagonist, AM281. These data demonstrate that the extent and duration of HPA axis activation after CB1 blockade are clearly dependent on both gender and time of day.

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Rapid effects of the mineralocorticoid receptor antagonist canrenoate on basal activity of the HPA axis in the rat

Frontiers in Neuroendocrinology ◽

10.1016/j.yfrne.2006.03.101 ◽

2006 ◽

Vol 27 (1) ◽

pp. 49-50

Author(s):

H.C. Atkinson ◽

S.A. Wood ◽

Y.M. Kershaw ◽

E.S. Castrique ◽

S.L. Lightman

Keyword(s):

Receptor Antagonist ◽

Hpa Axis ◽

Mineralocorticoid Receptor ◽

Mineralocorticoid Receptor Antagonist ◽

Basal Activity

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Protective Effect of Spironolactone on Endothelial Cell Apoptosis

Endocrinology ◽

10.1210/en.2005-1318 ◽

2006 ◽

Vol 147 (5) ◽

pp. 2496-2505 ◽

Cited By ~ 28

Author(s):

Tracy A. Williams ◽

Andrea Verhovez ◽

Alberto Milan ◽

Franco Veglio ◽

Paolo Mulatero

Keyword(s):

Cytochrome C ◽

Receptor Antagonist ◽

Mineralocorticoid Receptor ◽

Caspase 3 ◽

Umbilical Vein ◽

Inhibitory Effect ◽

Serum Deprivation ◽

Parp Cleavage ◽

Cytochrome C Release ◽

Mineralocorticoid Receptor Antagonist

Human umbilical vein endothelial cells (HUVECs) undergo apoptosis in response to serum deprivation. We show that the nonspecific mineralocorticoid receptor antagonist, spironolactone, protects from caspase-3 activation induced by serum deprivation in contrast to the selective mineralocorticoid receptor antagonist, eplerenone, that is nonprotective. We also demonstrate that progesterone, hydrocortisone, and dexamethasone all protect HUVECs from serum-deprivation-induced caspase-3 activation, whereas aldosterone and dihydrotestosterone have no effect. Spironolactone has been demonstrated to display agonist activity only to the progesterone receptor (PR), and we additionally show that spironolactone and progesterone, but not eplerenone, inhibit mitochondrial cytochrome c release and cleavage of nuclear poly (ADP-ribose) polymerase (PARP) and increase cell viability. Additionally, the PR antagonist mifepristone (RU486) partially blocked the inhibitory effect of both spironolactone and progesterone on caspase-3 activation, cytochrome c release, and nuclear PARP cleavage. Nitric oxide (NO) protects HUVECs from apoptosis in response to various stimuli including serum-deprivation; however, the NO synthase inhibitor N-monomethyl-l-arginine, did not abolish inhibition of caspase-3 activation or PARP cleavage by spironolactone. Thus, we demonstrate that spironolactone protects HUVECs from serum-deprivation-induced apoptosis by inhibition of caspase-3 activity, cytochrome c release and PARP cleavage by a NO-independent mechanism; further, this effect is likely mediated by the agonist properties of spironolactone toward the PR.

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