Elsevier

Brain Research

Volume 1028, Issue 1, 26 November 2004, Pages 9-18
Brain Research

Research report
Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats

https://doi.org/10.1016/j.brainres.2004.06.079Get rights and content

Abstract

Peripheral and brain angiotensin II AT1 receptor blockade decreases high blood pressure, stress, and neuronal injury. To clarify the effects of long-term brain Ang II receptor blockade, the AT1 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, AT1 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 AT1 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 AT1 receptor antagonist eliminated Ang II-induced increases in blood pressure, water intake, and sympathoadrenal catecholamine release; inhibited peripheral and brain AT1 receptors; increased AT2 receptor binding in the locus coeruleus, inferior olive, and adrenal cortex; and decreased AT2 receptor binding in the adrenal medulla. Inhibition of brain AT1 receptors correlated with decreased TH transcription in the locus coeruleus, indicating a decreased central sympathetic drive. This, and the diminished adrenomedullary AT1 and AT2 receptor stimulation, result in decreased sympathoadrenomedullary stimulation. Oral administration of AT1 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.

Introduction

Angiotensin II (Ang II), the acting principal of the renin–angiotensin system, (RAS) is a circulating and local hormone and paracrine factor that regulates blood pressure and fluid metabolism [15], [47]. The physiologically active receptors mediating the peripheral actions of Angiotensin belong to the AT1 type [47]. Peripheral AT2 receptors are not well characterized [12], perhaps mediating angiotensin formation and release of catecholamines in the adrenal gland [26], [32], and contributing to protect the kidney from ischemia [5].

Circulating Ang II, however, also affects the brain through stimulation of receptors located outside the blood–brain barrier [38], [40]. In addition, there is a brain Ang II system that contributes to the regulation of hormone release, central sympathetic activity, central response to stress, and many other brain functions [40]. Brain Ang II contributes to the development and maintenance of genetic hypertension, even in models where the circulating RAS is not stimulated, such as spontaneously hypertensive rats (SHRs) [40]. Whereas brain AT1 receptors mediate most of the central effects of Ang II, the role of brain AT2 receptors is not well understood, and they are probably involved in brain development and the regulation of sensory and motor systems [12], [41]. In addition, the brain AT2 receptors have been recently proposed to regulate blood pressure and drinking response to centrally administered Ang II [31].

We have demonstrated that peripheral administration of selective Ang II AT1 receptor antagonist blocks not only peripheral receptors but also central AT1 receptors [36]. Such a treatment prevents the central and peripheral components of the hormonal and sympathoadrenal response to stress [2] and protects the brain against ischemia [25], [37]. These results indicated that administration of AT1 antagonists could not only control systemic blood pressure but also exert central effects of additional therapeutic value.

We wished to clarify whether long-term oral administration of an AT1 receptor antagonist inhibiting both peripheral and brain receptors could selectively affect specific central actions of Ang II. We selected the AT1 antagonist, candesartan, an insurmountable antagonist [44] which, when administered peripherally, readily crosses the blood–brain barrier and significantly inhibits brain AT1 receptors [36]. To further establish the possibility that blockade of brain AT1 receptors could be considered therapeutically useful, we studied the effect of AT1 receptor blockade after the central administration of Ang II to SHRs, an animal model with increased activation of the brain sympathetic and Ang II systems, and with increased susceptibility to stress [22], [40]. In this study, we did not submit the SHRs to specific stress protocols; we focused on the effects of brain AT1 receptor blockade with or without intracerebroventricular (i.c.v.) administration of Ang II.

Section snippets

Animals and surgical preparation

The Animal Care and Use Committee of the National Institute of Mental Health, National Institutes of Health approved all experimental procedures. We studied male SHRs, 200–250 g weight, 8 weeks old, housed three to five per cage at a room temperature of 20 °C, with food and water available ad libitum, under a 12-h light/dark cycle. Animals were randomly divided into groups of eight animals each, and were treated with oral candesartan-celexetil (TCV 116; ASTRA, Mölndal, Sweden), 10 mg/kg/day,

Systolic blood pressure, plasma catechols, and plasma hormones after treatment of SHRs with the AT1 receptor antagonist

Systolic arterial blood pressure was high in SHRs treated with vehicle and decreased to normal levels in animals treated with the AT1 receptor antagonist (Fig. 1A). This treatment parallels the normalization of the increased blood pressure in SHRs, as described earlier, from 180 to 240 mm Hg before the treatment to values about 100–110 mm Hg after treatment [25], [37]. Levels of plasma catecholamines, as measured here in SHRs treated with vehicle, were consistent to, and in the same range of,

Discussion

Long-term oral administration of the AT1 receptor antagonist, candesartan, normalizes the increased blood pressure in SHRs [25], [37] and inhibits binding to brain AT1 receptors in addition to peripheral AT1 sites in a manner similar to that of subcutaneously injected candesartan in normotensive rats [36]. Candesartan, an insurmountable AT1 receptor antagonist [44], was administered until the day of the experiment, and inhibition of binding as detected in vitro was probably due, at least in

Acknowledgements

A.S. is a member of the Argentinean National Research Council (CONICET).

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