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Peripheral Administration of an Angiotensin II AT₁ Receptor Antagonist Decreases the Hypothalamic-Pituitary-Adrenal Response to Isolation Stress

Centro de Investigaciones Endocrinologicas, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires (I.A., A.C., M.B.), Buenos Aires 1013, Argentina; and Section on Pharmacology, National Institute of Mental Health, National Institutes of Health (I.A., Y.N., K.-L.H., J.A.T., A.F.-N., T.I., A.V.J., J.M.S.), Bethesda, Maryland 20814

Address all correspondence and requests for reprints to: Dr. Ines Armando, Section on Pharmacology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20814. E-mail: saavedrj{at}irp.nimh.nih.gov

Angiotensin II, which stimulates AT₁ receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT₁ receptor antagonist candesartan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type binding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiography and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT₁ receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT₁ receptor binding and AT_1B mRNA in zona glomerulosa and AT₂ binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan blocked AT₁ binding in paraventricular nucleus and adrenal gland; prevented the isolation-induced alterations in pituitary ACTH and AVP and in adrenal corticosterone, aldosterone, and catecholamines; abolished the increase in AT₂ binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT₁ receptor antagonist blocks brain and peripheral AT₁ receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT₁ receptors during stress and a possible beneficial effect of AT₁ antagonism in stress-related disorders.

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