Elsevier

Regulatory Peptides

Volume 128, Issue 3, 30 June 2005, Pages 227-238
Regulatory Peptides

Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists

https://doi.org/10.1016/j.regpep.2004.12.015Get rights and content

Abstract

The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT1 receptors is required for the stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of the central sympathetic activity. Long-term peripheral administration of the angiotensin II AT1 antagonist candesartan blocks not only peripheral but also brain AT1 receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT1 receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-α) in the gastric mucosa and a partial blockade of the stress-induced sympathoadrenal stimulation, while the protective effect of the glucocorticoid release during stress is maintained. AT1 receptor antagonism prevents the stress-induced decrease in cortical CRH1 and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT1 receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.

Section snippets

Angiotensin II was discovered as a pro-hypertensive, circulating hormone produced by the peripheral renin–angiotensin system

The octapeptide angiotensin II (Ang II) was initially described as a hormone of peripheral origin [1], [2], the active end principle of the classical renin–angiotensin system (RAS) [3]. The precursor molecule, angiotensinogen, originates in the liver and is cleaved by kidney renin forming the inactive decapeptide angiotensin I (Ang I). Ang I is converted into Ang II by the angiotensin-converting enzyme (ACE) predominantly located in the lung [4]. Circulating Ang II produces vasoconstriction,

There are multiple local angiotensin II systems in many organs

The subsequent discovery that Ang II was locally formed and selectively regulated in many organs [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] indicated that tissue Ang II might play multiple important roles in local tissues.

The brain angiotensin II system: angiotensin II is a brain neurohormone and neuromodulator

The demonstration that injection of Ang II into the circulation elicited effects in the central nervous system indicated the presence of receptors for this peptide in the brain [16]. Circulating Ang II does not penetrate the blood brain barrier and receptors responding to blood borne Ang II were located in the circumventricular organs outside this barrier [17]. The result of receptor stimulation was the induction of fluid and salt intake and increase in blood pressure [18], [19], [20]. The

There are two angiotensin II receptor types. The AT1 receptors mediate the physiological effect of angiotensin II

There are two distinct binding sites for Ang II, the AT1 and AT2 receptors, initially characterized pharmacologically on the basis of their affinities for different peptidic and non-peptidic ligands [29], [30]. Cloning of the AT1 and AT2 receptors revealed that they belong to the superfamily of seven membrane-spanning G-protein coupled receptors [31], [32]. The AT1 and AT2 receptors have a similar binding affinity for Ang II although they only share a 32–34% identity at the amino acid level [33]

Peripheral AT1 receptor blockade is therapeutically effective

Inhibition of Ang II formation by angiotensin-converting enzyme (ACE) inhibitors is of major therapeutic importance in the treatment of hypertension [38]. Similar effects and higher specificity in the treatment of human hypertension is achieved by the use of specific nonpeptide Ang II receptor antagonists that selectively block the AT1 receptors, such as losartan and candesartan [29], [38]. Ang II regulates its own synthesis trough AT1 receptor stimulation, by decreasing renin formation and

AT1 and AT2 receptors are expressed in the brain and mediate specific brain functions

With the use of the specific AT1 and AT2 receptor ligands [26] and selected riboprobes for the AT2 receptor and for the untranslated regions (UTRs) of the AT1A and AT1B receptor subtypes [40], it was possible to identify the receptor type expressed in the brain. Both AT1 and AT2 receptor types were found, with a distribution similar, although not identical, in all mammalian species studied [26], [40], [41], [42], [43], [44], [45], including humans [46]. While AT1 receptors predominate in adult

Peripheral and brain AT1 receptors participate in the regulation of the stress reaction

There is a role of brain Ang II, and in particular of its AT1 receptors, in the regulation of the response to stress. First, there is a suggestive distribution of AT1 receptors, remarkably concentrated in all key hypothalamic areas belonging to the hypothalamic–pituitary–adrenal axis, the stimulation of which is the hallmark of the stress reaction. AT1 receptors are concentrated in the parvocellular portion of the hypothalamic paraventricular nucleus, the site of corticotrophin-releasing

Effects of AT1 receptor blockade during stress. Peripheral administration of the AT1 antagonist candesartan blocks brain AT1 receptors and prevents the hormonal and sympathoadrenal response to isolation stress

To determine whether or not Ang II and AT1 receptors played significant roles in the regulation of the stress reaction, we studied the response of the organism to stress after sustained blockade of peripheral and brain AT1 receptors. We first developed an animal model of brain AT1 receptor blockade after peripheral administration of the receptor antagonist, a model necessary to relate our findings in a meaningful way to clinical conditions in human populations. We found that peripheral

Effect of pretreatment with candesartan on an acute stress-induced disorder

To establish whether or not AT1 receptor blockade could be of therapeutic benefit, we initiated a study of the effects of candesartan on the development of stress-induced disorders. We first studied the effect of candesartan on the incidence of gastric ulcers induced by cold-restraint [74], a commonly used and clinically relevant experimental model for acute stress-induced gastric damage [75].

Stress induces acute gastric mucosa lesions by a variety of mechanisms, including psychological factors

Centrally-acting AT1 receptor antagonists are anxiolytics and prevent stress-induced alterations in cortical CRH1 and benzodiazepine receptors

The regulation of the stress response by AT1 receptors is not limited to their influence on the HPA axis and the sympathoadrenal system and includes regulatory effects at higher central levels. CRH acts as a modulator, predominantly through CRH1 receptor stimulation, in centers higher than the hypothalamus, to influence and integrate stress-induced behaviors [93]. We found that isolation stress in the rat decreases CRH1 receptor expression in the frontal, parietal and cingulate cortex, an

Conclusions

Recent experiments indicate possible novel therapeutic effects of Ang II AT1 receptor blockade. AT1 receptor blockade antagonizes the effects of AT1 receptor stimulation in peripheral organs integrating, together with hypothalamic structures, the HPA axis, and in higher brain centers such as the amygdala [99] involved in the processing of sensory information and the behavioral response to stress (Fig. 12). In this way, the AT1 receptor antagonist modulates the stress-induced glucocorticoid

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      The effector peptide of the RAS, angiotensin II (Ang-II), is synthesized through proteolytic cleavage events whereby renin converts angiotensinogen into angiotensin I, which is cleaved by angiotensin converting enzyme into Ang-II, which in turn, activates the angiotensin type 1a receptor (AT1aR). Prior studies have found that stressful stimuli induce Ang-II binding to AT1aR(s) but antagonizing this interaction attenuates indices of stress and anxiety-like behavior in male rodents [5, 19, 22, 26]. More recently, the therapeutic utility of angiotensin converting enzyme 2 (ACE2) and the counter-regulatory limb of the RAS has been pursued as an experimental therapeutic for stress-related disease.

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