Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists
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
References (102)
- et al.
Angiotensin II: an intraovarian regulatory peptide
Am. J. Med. Sci.
(1988) Blood, pituitary, and brain renin–angiotensin systems and regulation of secretion of anterior pituitary gland
Front. Neuroendocrinol.
(1993)- et al.
Skeletal muscle RAS and exercise performance
Int. J. Biochem. Cell Biol.
(2003) - et al.
Radioautographic localization of specific binding sites for blood-borne angiotensin II in the rat brain
Brain Res.
(1980) - et al.
Angiotensin II in central nervous system physiology
Regul. Pept.
(1998) - et al.
Brain angiotensin: on the way to becoming a well-studied neuropeptide system
Biochem. Pharmacol.
(1984) - et al.
Distribution of [125I] angiotensin II binding sites in the rat brain: a quantitative autoradiographic study
Neuroscience
(1986) - et al.
Quantitative distribution of angiotensin II binding sites in rat brain by autoradiography
Peptides
(1986) - et al.
Angiotensin receptor binding in human hypothalamus: autoradiographic localization
Brain Res.
(1987) - et al.
Angiotensin II binding site in the anteroventral-third ventricle (AV3V) area and related structures of the rat brain
Neurosci. Lett.
(1986)
Angiotensin II type-1 receptor subtype cDNAs: differential tissue expression and hormonal regulation
Biochem. Biophys. Res. Commun.
The AT2 receptor: fact, fancy and fantasy
Regul. Pept.
Localization of AT2 angiotensin receptor gene expression in rat brain by in situ hybridization histochemistry
Brain Res. Mol. Brain Res.
Characterization and distribution of angiotensin II receptor subtypes in the mouse brain
Eur. J. Pharm.
Identification and characterization of angiotensin II receptors subtypes in human brain
Eur. J. Pharmacol.
Angiotensin II receptor subtypes and phosphoinositide hydrolysis in rat adrenal medulla
Brain Res. Bull.
Opposite regulation of brain angiotensin type1 and type 2 receptors in cold-induced hypertension
Regul. Pept.
Emerging features of brain angiotensin receptors
Regul. Pept.
Chronic peripheral administration of the angiotensin II AT1 receptor antagonist Candesartan blocks brain AT1 receptors
Brain Res.
Effect of electrolytic and neurotoxic lesions of the median rafe nucleus on anxiety and stress
Pharmacol. Biochem. Behav.
Role of neutrophil elastase in stress-induced gastric mucosal injury in rats
J. Lab. Clin. Med.
Role of angiotensin II-induced cAMP in mesangial TNF-alpha production
Cytokine
Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain
Exp. Neurol.
Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders
Peptides
Benzodiazepine receptors in rat cerebral cortex and hippocampus undergo rapid and reversible changes alter acute stress
Neuroscience
Antagonism by pivagabine of stress-induced changes in GABAA receptor function and corticotropin-releasing factor concentrations in rat brain
Psychoneuroendocrinology
The substance causing renal hypertension
J. Physiol. (Lond)
A crystalline pressor substance (angiotensin) resulting from the reaction between renin and renin activator
J. Exp. Med.
Hypertension mechanisms
The renin–angiotensin systems
Trends Pharmacol. Sci.
Angiotensin II receptors in testes
Endocrinology
The tissue renin–angiotensin system: a target for angiotensin-converting enzyme inhibitors
J. Hum. Hypertens.
The renin–angiotensin system: renal actions and blood pressure regulation
Compr. Ther.
Protective effects of the inhibition of the renin–angiotensin system against gastric mucosal lesions induced by cold-restraint in the rat
Acta Physiol. Hung.
The expression and localization of the angiotensin-converting enzyme mRNA in human adipose tissue
Blood Pressure
Expression of renin–angiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure
Circulation
Tissue renin–angiotensin system: its expression, localization, regulation and potential role in the pancreas
J. Mol. Endocrinol.
Immunohistochemical localization of angiotensin II receptor and local renin–angiotensin system in human colonic mucosa
J. Histochem. Cytochem.
The central effects of the renin–angiotensin system
Clin. Exp. Hypertens. [A]
Brain and pituitary angiotensin
Endocr. Rev.
Autoradiographic localization of angiotensin II receptors in rat brain
Proc. Natl. Acad. Sci. U. S. A.
Localization of central angiotensin II receptors with [125I-sarl, ile8-angiotensin II: periventricular sites of the anterior third ventricle
Neuroendocrinology
Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain
Am. J. Physiol.
Organization of angiotensin II immunoreactive cells and fibers in the rat central nervous system
Neuroendocrinology
Angiotensin II receptors and angiotensin II receptors antagonists
Pharmacol. Rev.
International Union of Pharmacology: XXIII. The angiotensin receptors
Pharmacol. Rev.
Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor
Nature
Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition
J. Biol. Chem.
Angiotensin II receptors: protein and gene structure, expression and potential pathological involvement
Eur. J. Endocrinol.
Molecular biology of angiotensin II receptors: an overview
J. Hypertens.
Cited by (109)
A high salt intake in early life affects stress-coping response in males but not in female rats
2024, Physiology and BehaviorAssociation between anxiety and hypertension in adults: A systematic review and meta-analysis
2021, Neuroscience and Biobehavioral ReviewsOverexpression of angiotensin converting enzyme 2 reduces anxiety-like behavior in female mice.
2020, Physiology and BehaviorCitation Excerpt :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.