Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation stress

Angiotensin II, which stimulates AT, receptors, is a brain and peripheral s tress hormone. We pretreated rats with the AT, receptor antagonist candesar tan for 13 d via sc-implanted osmotic minipumps, followed by 24-h isolation in individual metabolic cages. We measured angiotensin II receptor-type bi nding and mRNAs and tyrosine hydroxylase mRNA by quantitative autoradiograp hy and in situ hybridization, catecholamines by HPLC, and hormones by RIA. Isolation increased AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituita ry AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) m RNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catec holamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Cand esartan blocked AT(1) 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 i ncrease in AT(2) binding in adrenal medulla; and substantially decreased ur inary AVP, corticosterone, aldosterone, and catecholamines during isolation . Peripheral pretreatment with an AT(1) receptor antagonist blocks brain an d peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrena l response to stress, suggesting a physiological role for peripheral and br ain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders.