Peripheral administration of an angiotensin II AT(1) receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation Stress.
Angiotensin II, which stimulates AT(1) receptors, is a brain and peripheral stress hormone. We pretreated rats with the AT(1) 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 AT(1) receptor binding in hypothalamic paraventricular nucleus as well as anterior pituitary ACTH, and decreased posterior pituitary AVP. Isolation stress also increased AT(1) receptor binding and AT(1B) mRNA in zona glomerulosa and AT(2) binding in adrenal medulla, adrenal catecholamines, tyrosine hydroxylase mRNA, aldosterone, and corticosterone. Candesartan 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 increase in AT(2) binding in adrenal medulla; and substantially decreased urinary AVP, corticosterone, aldosterone, and catecholamines during isolation. Peripheral pretreatment with an AT(1) receptor antagonist blocks brain and peripheral AT(1) receptors and inhibits the hypothalamic-pituitary-adrenal response to stress, suggesting a physiological role for peripheral and brain AT(1) receptors during stress and a possible beneficial effect of AT(1) antagonism in stress-related disorders.
Armando
I
I
Centro de Investigaciones Endocrinologicas, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Buenos Aires 1013, Argentina. saavedrj@irp.nimh.nih.gov
Carranza
A
A
Nishimura
Y
Y
Hoe
K L
KL
Barontini
M
M
Terrón
J A
JA
Falcón-Neri
A
A
Ito
T
T
Juorio
A V
AV
Saavedra
J M
JM
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001921:Brain / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism / Q000652:urine; D006728:Hormones / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology*; D007260:Infusion Pumps; D007279:Injections, Subcutaneous; D008297:Male; D010907:Pituitary Hormones / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012934:Social Isolation / Q000523:psychology*; D013315:Stress, Psychological / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D000305:Adrenal Cortex Hormones; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002395:Catecholamines; D006728:Hormones; D010907:Pituitary Hormones; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014446:Tyrosine 3-Monooxygenase; C081643:candesartan