A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH

Autor: Jaroslav Pavel, Juan M. Saavedra, Miroslava Macova
Rok vydání: 2009
Předmět:
Male
Hypothalamo-Hypophyseal System
endocrine system
medicine.medical_specialty
Angiotensin receptor
Vasopressin
Transcription
Genetic
Tyrosine 3-Monooxygenase
Pyridines
Vasopressins
medicine.drug_class
Pituitary-Adrenal System
Angiotensin II Type 2 Receptor Blockers
Biology
Article
Receptor
Angiotensin
Type 1
Adrenocorticotropic Hormone
Internal medicine
medicine
Animals
RNA
Messenger
Rats
Wistar
Receptor
Molecular Biology
Arginine vasopressin receptor 1B
Angiotensin II receptor type 1
General Neuroscience
Imidazoles
Median Eminence
Brain
Receptor antagonist
Angiotensin II
Subfornical organ
Rats
Endocrinology
medicine.anatomical_structure
Blood-Brain Barrier
Pituitary Gland
cardiovascular system
Locus Coeruleus
Neurology (clinical)
hormones
hormone substitutes
and hormone antagonists
Paraventricular Hypothalamic Nucleus
Subfornical Organ
circulatory and respiratory physiology
Developmental Biology
Zdroj: Brain Research. 1250:130-140
ISSN: 0006-8993
DOI: 10.1016/j.brainres.2008.11.006
Popis: 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.
Databáze: OpenAIRE
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