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Table of Contents
Vol. 64, No. 6, 1996
Issue release date: 1996
Section title: Ontogeny of Neuroendocrine Cells
Neuroendocrinology 1996;64:412–418
(DOI:10.1159/000127146)

Dexamethasone in the Last Week of Pregnancy Attenuates Hippocampal Glucocorticoid Receptor Gene Expression and Elevates Blood Pressure in the Adult Offspring in the Rat

Levitt N.S. · Lindsay R.S. · Holmes M.C. · Seckl J.R.
Molecular Endocrinology Laboratory, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK

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Article / Publication Details

First-Page Preview
Abstract of Ontogeny of Neuroendocrine Cells

Received: February 22, 1996
Accepted: July 22, 1996
Published online: April 09, 2008
Issue release date: 1996

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN

Abstract

Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribed to ‘fetal programming’. In rats, fetoplacental exposure to maternally administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is unclear. Pre- and postnatal stress programmes hypothalamic-pituitary-adrenal (HPA) axis responses throughout the lifespan, an effect thought to be mediated via permanent effects on glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) gene expression in the hippocampus. Corticosteroids also have specific central effects on blood pressure control mediated by GR and MR. This study investigated corticosterone (CORT) responses to restraint stress and GR and MR gene expression in areas of the brain postulated to mediate the central effects of corticosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commissural organ, area postrema and nucleus tractus solitarius). Pregnant Wistar rats received dexamethasone (100 µg/kg·day–1) or vehicle on days 15–20 of gestation. This reduced birth weight by 11 %. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pressure was significantly elevated in the adult offspring of dexamethasone-treated pregnancies (dexamethasone 144 ± 2/125 ± 2 mm Hg vs. control 133 ± 2.7/ 112 ± 2.8 mm Hg; both p < 0.01). Offspring of dexamethasone-treated pregnancies had increased basal plasma CORT (155 ± 29 nmol/l) compared to offspring of controls (79 ± 15 nmol/l, p < 0.05), but the CORT response to stress was similar. Hippocampal neuronal GR mRNA expression was significantly lower in the offspring of dexamethasone-treated pregnancies (dentate gyrus 20% lower, CA1 15% lower; p < 0.01). Similarly, hippocampal MR gene expression was decreased in CA1 and CA2 by 24 and 25%, respectively (p < 0.05). No differences in GR or MR mRNA expression were found in the OVLT, subcommissural organ, area postrema or nucleus tractus solitarius. These findings suggest that glucocorticoid excess in the last trimester of rat pregnancy (i) is sufficient to programme offspring hypertension; (ii) also increases basal plasma CORT levels, and (iii) permanently attenuates GR and MR mRNA expression in specific hippocampal subfields. This, if translated into protein, may reduce sensitivity to glucocorticoid feedback and thus contribute to the CORT excess. However, hypertension in this model is unlikely to be mediated by similar changes in GR or MR gene expression in the examined areas of the brain putatively involved in the more direct central regulation of blood pressure.

© 1996 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Ontogeny of Neuroendocrine Cells

Received: February 22, 1996
Accepted: July 22, 1996
Published online: April 09, 2008
Issue release date: 1996

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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