Title

Angiotensin II AT1 receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress

Document Type

Journal Article

Publication Date

4-20-2007

Journal

Brain Research

Volume

1142

Issue

1

DOI

10.1016/j.brainres.2007.01.037

Keywords

Brain angiotensin II receptor; Hypothalamic-pituitary-adrenal axis; Paraventricular nucleus; Renin-angiotensin system; Stress

Abstract

Sustained pretreatment with angiotensin II AT1 receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT1 receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT1 receptor antagonist, 0.5 mg/kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT1 receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. In rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT1 receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT1 receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT1 receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT1 receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT1 receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions. © 2007 Elsevier B.V. All rights reserved.

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