title: A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH.
abstract: The physiological actions of brain Angiotensin II AT(2) receptors and their relationship to Angiotensin II AT(1) receptors remain controversial. To further clarify their role, we determined to what extent systemic administration of an AT(2) receptor antagonist affected AT(2) receptor binding within the brain and the expression of AT(1) receptors. For this purpose, we subcutaneously administered the AT(2) receptor antagonist PD123319 (1 mg/kg/day) to adult male rats for two weeks via osmotic minipumps. We also studied the content of pituitary adrenocorticotropic hormone and vasopressin, representative of hypothalamic-pituitary-adrenal axis activation, and the tyrosine hydroxylase gene expression in the locus coeruleus as a measure of central norepinephrine function. We found significant decreases in AT(2) receptor binding in brain areas inside the blood brain barrier, the inferior olive and the locus coeruleus. AT(2) receptor blockade increased AT(1) receptor binding and mRNA expression not only in the subfornical organ and the median eminence, situated outside the blood brain barrier, but also in the hypothalamic paraventricular nucleus, located inside the blood brain barrier. These changes paralleled decreased expression of tyrosine hydroxylase mRNA in the locus coeruleus and decreased pituitary adrenocorticotropic and vasopressin content. Our results demonstrate that sustained peripheral administration of an AT(2) antagonist decreases binding to brain AT(2) receptors, indicating that this drug is a useful tool for the study of their central role. AT(2) receptor activity inhibition up-regulates AT(1) receptor expression in specific brain areas. Blockade of brain AT(2) receptors is compatible with enhanced hypothalamic-pituitary-adrenal axis and decreased central sympathetic system activity.
authors.affiliation: Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Macova
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pavel
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008473:Median Eminence / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D010913:Pituitary-Adrenal System; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013356:Subfornical Organ / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014667:Vasopressins; C073402:PD 123319; D000324:Adrenocorticotropic Hormone; D014446:Tyrosine 3-Monooxygenase