Angiotensin II AT1receptor blockade selectively enhances brain AT2receptor expression, and abolishes the cold-restraint stress-induced increase in tyrosine hydroxylase mRNA in the locus coeruleus of spontaneously hypertensive rats (original) (raw)
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The Role of AT(1A) Receptors in Cardiovascular Reactivity to Acute Aversive Stress
Hypertension
We determined whether genetic deficiency of angiotensin II Type 1A (AT 1A ) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT 1A
Peripherally Administered Angiotensin II AT 1 Receptor Antagonists Are Anti-stress Compounds in Vivo
Annals of the New York Academy of Sciences, 2008
Angiotensin II AT 1 receptor blockers (ARBs) are commonly used in the clinical treatment of hypertension. Subcutaneous or oral administration of the ARB candesartan inhibits brain as well as peripheral AT 1 receptors, indicating transport across the blood brain barrier. Pretreatment with candesartan profoundly modifies the response to stress. The ARB prevents the peripheral and central sympathetic activation characteristic of isolation stress and abolishes the activation of the hypothalamic-pituitary-adrenal axis during isolation. In addition, candesartan prevents the isolation-induced decrease in cortical corticotropin-releasing factor 1 and benzodiazepine receptors induced by isolation. When administered before cold-restraint stress, candesartan totally prevents the production of gastric ulcerations. This preventive effect of candesartan is the consequence of profound anti-inflammatory effects, reduction of sympathetic stimulation, and preservation of blood flow to the gastric mucosa. The ARB does not reduce the hypothalamicpituitary-adrenal axis stimulation during cold-restraint. Preservation of the effects of endogenous glucocorticoids is essential for protection of the gastric mucosa during cold-restraint. Administration of the ARB to non-stressed rats decreases anxiety in the elevated plus-maze. Our results demonstrate that Angiotensin II, through AT 1 receptor stimulation, is a major stress hormone, and that ARBs, in addition to their anti-hypertensive effects, may be considered for the treatment of stress-related disorders.
Hypertension
We determined whether genetic deficiency of AT1A-receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate and activity. Before stress, lower resting mean arterial pressure was recorded in AT1A-/- (85±2 mmHg) than in AT1A+/+ mice (112±2 mmHg); heart rate was not different between groups. Cage-switch stress for 90-minutes elevated blood pressure by +24±2 mmHg in AT1A+/+ and +17±2 mmHg in AT1A-/- mice (P<0.01) and heart rate increased by +203±9 bpm in AT1A+/+ and +121±9 bpm in AT1A-/- mice (P<0.001). Locomotor activation was less in AT1A-/- (3.0±0.4 units) than in AT1A+/+ animals (6.0±0.4 units), but differences in blood pressure and heart rate persisted during non-active periods. In contrast to wild-types, spontaneous baroreflex sensitivity was not inhibited by stress in AT1A-/- mice. Following cage-switch stress, c-Fos-immunoreactivity was less in the p...
Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists
Regulatory Peptides, 2005
The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT 1 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 AT 1 antagonist candesartan blocks not only peripheral but also brain AT 1 receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stressinduced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT 1 receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-a) 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. AT 1 receptor antagonism prevents the stress-induced decrease in cortical CRH 1 and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT 1 receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.
Psychoneuroendocrinology, 2011
Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT 1 receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT 1 receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT 1 receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT 1 receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT 1 receptors in humans is also neuroprotective, reducing the incidence of stroke, improving cognition and decreasing the progression of Alzheimer's disease. Blockade of AT 1 receptors offers a novel and safe therapeutic approach for the treatment of illnesses of increasing prevalence and socioeconomic impact, such as mood disorders and neurodegenerative diseases of the brain.
Hypertension Research, 2009
Pharmacological evidence suggests that angiotenisn II type 1 (AT 1 ) receptors are involved in the regulation of cardiovascular response to emotional stress and reinforcing effect of dietary salt on this response. In this study, we examined the effect of genetic deletion of AT 1A receptors on the cardiovascular effects of stress and salt in mice. AT 1A receptor knockout (AT 1A À/À ) and wild-type (AT 1A +/+ ) mice were implanted with telemetry devices and placed on a normal (0.4%) or high (3.1%) salt diet (HSD). Resting blood pressure (BP) in AT 1A À/À mice (84 ± 3 mm Hg) was lower than in AT 1A +/+ mice (107 ± 2 mm Hg). Negative emotional (restraint) stress increased BP by 33±3 mm Hg in AT 1A +/+ mice. This response was attenuated by 40% in AT 1A À/À mice (18 ± 3 mm Hg). Conversely, the BP increase caused by food presentation and feeding was similar in AT 1A À/À (25 ± 3 mm Hg) and AT 1A +/+ mice (26 ± 3 mm Hg). HSD increased resting BP by 14 ± 4 mm Hg in AT 1A À/À mice without affecting it significantly in AT 1A +/+ mice. Under these conditions, the pressor response to restraint stress in AT 1A À/À mice (30±3 mm Hg) was no longer different from that in wild-type animals (28 ± 3 mm Hg). The BP response to feeding was not altered by HSD in either AT 1A À/À or AT 1A +/+ mice (25 ± 2 and 27 ± 3 mm Hg, respectively). These results indicate that AT 1A receptor deficiency leads to a reduction in BP reactivity to negative emotional stress, but not feeding. HSD can selectively reinforce the cardiovascular response to negative stress in AT 1A À/À mice. However, there is little interaction between AT 1A receptors, excess dietary sodium and feeding-induced cardiovascular arousal.
Brain Research, 2000
In the present study, we have examined neurochemical correlates that may be involved in the differential cardiovascular responses observed in normotensive and hypertensive rats during stress. Using a restraint stress paradigm, both normotensive Wistar Kyoto (WKY) and Spontaneously Hypertensive rats (SHR) underwent acute (1 h restraint in a perspex tube), chronic (1 h restraint for ten consecutive days) or no restraint (control) stress. Following cessation of restraint, rats were processed by incubating sections of brain stem and kidney 125 2 1 but not WKY. Graded increases in V binding were measured in kidney medulla and cortex of both strains (150-60% with chronic 1A restraint). These results suggest that physiological adaptation to restraint is associated with specific changes in V , AT and AT receptor 1A 1 2 density within brain nuclei and kidney.
Brain Research, 2009
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.
Drug Development Research, 2005
The corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin II (Ang II) interact, regulating the central sympathetic system, the hypothalamic-pituitary-adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non-peptidic, orally active AVP V 1 , V 3 , or CRF 1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established. Brain Ang II, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang II AT 1 receptor stimulation determines the response to stress. An orally active, non-peptidic Ang II AT 1 receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF 1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress-induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang II system through AT 1 receptor stimulation, and should be studied together. Selective, safe antagonists of Ang II AT 1 receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti-stress, anti-anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development.