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.

Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

“…Mice were randomly allocated to treatment with vehicle (sterile isotonic saline), CGP42112A (Sigma Aldrich, St. Louis, MO, USA) an AT 2 agonist, which is a peptide with a short half-life [25], or PD 123319, an AT 2 antagonist [36,37]. CGP42112A was delivered in 1 of 3 doses: 0.1, 1.0, or 10.0 ng/kg/min [31].…”

Effects of angiotensin type 2 receptor on secretion of the locus coeruleus in stress-induced hypertension rats

“…*P < 0.05, **P < 0.01 vs before reagent administration, respectively. administrated peripherally to study the role of AT 2 receptors (Macova et al, 2009). CGP42112 is a selective peptide AT 2 receptor agonist that is hard to cross the blood-brain barrier, so it is usually injected intracerebroventricularly to study the role of central AT 2 receptors.…”

“…The central angiotensin system contributes to the ontogenesis of hypertension and other sympathy-excitatory states (Gao and Zucker, 2011). Two main receptor subtypes of angiotensin II have been identified, angiotensin II type 1 receptor (AT 1 receptor) and type 2 receptor (AT 2 receptor), which are expressed throughout the brain, there appears to be a high density in the brain areas such as the medulla and hypothalamus that regulate arterial baroreflex function, sympathetic outflow and blood pressure (Macova et al, 2009). In the rat, the LC expresses large numbers of AT 2 receptors (Tsutsumi and Saavedra, 1991), indicating that this receptor type may be involved in central norepinephrine function.…”

Angiotensin II, Vasopressin, and Collagen-IV Expression in the Subfornical Organ in a Case of Syndrome of Inappropriate ADH

“…On the other hand, the presence of VAS, AGII, and TH and their implication in cardiovascular, salt water balance and blood pressure regulation have long been described in the hypothalamus in man and different animal species [7][8][9][10]. Several authors have also described the detection of tyrosine hydroxylase-immunoreactivity and vasopressin mRNA and ANGII in the hypothalamus that could be related to hypertension and SIADH [11][12][13][14]. Furthermore, the subfornical organ (SFO) is a circumventricular organ located in the medial plane, below the commissure of fornix (Figures 1(a) and 1(b)), which contains neurons, glia, and a dense plexus of highly fenestrated capillaries, and is covered by an ependymal layer [15,16].…”