Oral administration of an AT 1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats

Document Type

Journal Article

Publication Date

11-26-2004

Journal

Brain Research

Volume

1028

Issue

1

DOI

10.1016/j.brainres.2004.06.079

Keywords

Angiotensin II; AT receptor antagonist 1; Spontaneously hypertensive rat

Abstract

Peripheral and brain angiotensin II AT 1 receptor blockade decreases high blood pressure, stress, and neuronal injury. To clarify the effects of long-term brain Ang II receptor blockade, the AT 1 blocker, candesartan, was orally administered to spontaneously hypertensive rats (SHRs) for 40 days, followed by intraventricular injection of 25 ng of Ang II. Before Ang II injection, AT 1 receptor blockade normalized blood pressure and decreased plasma adrenocorticotropic hormone (ACTH) and corticosterone. After central administration of excess Ang II, the reduction of ACTH and corticosterone release induced by AT 1 receptor blockade no longer occurred. Central Ang II administration to vehicle-treated SHRs further increased blood pressure, provoked drinking, increased tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus, and stimulated sympathoadrenal catecholamine release. Pretreatment with the AT 1 receptor antagonist eliminated Ang II-induced increases in blood pressure, water intake, and sympathoadrenal catecholamine release; inhibited peripheral and brain AT 1 receptors; increased AT 2 receptor binding in the locus coeruleus, inferior olive, and adrenal cortex; and decreased AT 2 receptor binding in the adrenal medulla. Inhibition of brain AT 1 receptors correlated with decreased TH transcription in the locus coeruleus, indicating a decreased central sympathetic drive. This, and the diminished adrenomedullary AT 1 and AT 2 receptor stimulation, result in decreased sympathoadrenomedullary stimulation. Oral administration of AT 1 antagonists can effectively block central actions of Ang II, regulating blood pressure and reaction to stress, and selectively and differentially modulating sympathoadrenal response and the hypothalamic- pituitary-adrenal stimulation produced by brain Ang II - effects of potential therapeutic importance.

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