Does glucocorticoid receptor blockade exacerbate tissue damage after mineralocorticoid/salt administration?

Amanda J. Rickard, John W. Funder, James Morgan, Peter J. Fuller, Morag J. Young

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19 Citations (Scopus)


Mineralocorticoid receptor (MR) antagonism reverses established inflammation, oxidative stress, and cardiac fibrosis in the mineralocorticoid/ salt-treated rat, whereas withdrawal of the mineralocorticoid deoxycorticosterone (DOC) alone does not. Glucocorticoid receptors (GRs) play a central role in regulating inflammatory responses but are also involved in cardiovascular homeostasis. Physiological glucocorticoids bind MR with high affinity, equivalent to that for aldosterone, but are normally prevented from activating MR by pre-receptor metabolism by 11β-hydroxysteroid dehydrogenase 2. We have previously shown a continuing fibrotic and hypertrophic effect after DOC withdrawal, putatively mediated by activation of glucocorticoid/MR complexes; the present study investigates whether this effect is moderated by antiinflammatory effects mediated via GR. Uninephrectomized rats, drinking 0.9% saline solution, were treated as follows: control; DOC (20 mg/wk) for 4 wk; DOC for 4 wk and no steroid wk 5-8; DOC for 4 wk plus the MR antagonist eplerenone (50 mg/kg·d) wk 5-8; DOC for 4 wk plus the GR antagonist RU486 (2 mg/d) wk 5-8; and DOC for 4 wk plus RU486 and eplerenone for wk5-8. After steroid withdrawal, mineralocorticoid/salt-induced cardiac hypertrophy is sustained, but not hypertension. Inflammation and fibrosis persist after DOC withdrawal, and GR blockade with RU486 has no effect on these responses. Rats receiving RU486 for wk 5-8 after DOC withdrawal showed marginal blood pressure elevation, whereas eplerenone alone or coadministered with RU486 reversed all DOC/salt-induced circulatory and cardiac pathology. Thus, sustained responses after mineralocorticoid withdrawal appear to be independent of GR signaling, in that blockade of endogenous antiinflammatory effects via GR does not lead to an increase in the severity of responses in the mineralocorticoid/ salt-treated rat after steroid withdrawal.

Original languageEnglish
Pages (from-to)4829-4835
Number of pages7
Issue number10
Publication statusPublished - Oct 2007
Externally publishedYes

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