Submitted on November 14, 2007
Accepted on March 13, 2008
Corticosteroids mediate fast feedback of the rat hypothalamic-pituitary-adrenal axis via the mineralocorticoid receptor
Helen Caroline Atkinson1*, Susan Ann Wood1, Emma Suzanne Castrique2, Yvonne M Kershaw2, Crispin C Wiles2, and Stafford Lightman3
1 Henry Wellcome Laboratories for Integrative Neurscience and Endocrinology, University of Bristol, Bristol, Bristol, United Kingdom
2 Henry Wellcome Laboratories for Integrative Neurscience and Endocrinology, University of Bristol, Bristol, Bristol, United Kingdom; Henry Wellcome Laboratories for Integrative Neurscience and Endocrinology, University of Bristol, United States
3 Henry Wellcome Laboratories for Integrative Neurscience and Endocrinology, University of Bristol, Bristol, Bristol, United Kingdom; Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol Division of Medicine, Bristol BS1 3NY, United Kingdom
* To whom correspondence should be addressed. E-mail: helena{at}graduate.uwa.edu.au.
The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every five minutes 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 minutes of the aldosterone bolus and 28 minutes 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, while the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (one secretory event only) whereas that of methylprednisolone persisted for 4-5 hours. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 minutes and corticosterone within 20 minutes. The inhibitory effect of aldosterone was unaffected by pre-treatment with the glucocorticoid receptor antagonist RU38486 but blocked by the mineralocorticoid receptor antagonist 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.
