- [Show abstract] [Hide abstract] ABSTRACT: Rationale Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. Objective The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Methods Male Wistar rats (250–300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. Results The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. Conclusions AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.
Dataset: Supplementary Table 1[Show abstract] [Hide abstract] ABSTRACT: Step-through latencies 1. Statistical distribution values for step-through latencies in the training session of all experimental groups submitted to the passive avoidance test. Values are in seconds. All animals exceeding 60 s were dismissed from the statistical analyses.
Dataset: Supplementary Table 2[Show abstract] [Hide abstract] ABSTRACT: Fos-immunoreactivity analysis. Overall statistical results (F values) obtained in the two way ANOVA for Fos-IR cells patterns.
- [Show abstract] [Hide abstract] ABSTRACT: Previous results from our laboratory showed that angiotensin II AT1 receptors (AT1-R) are involved in the neuroadaptative changes induced by amphetamine. The aim of the present work was to study functional and neurochemical responses to angiotensin II (ANG II) mediated by AT1-R activation in animals previously exposed to amphetamine. For this purpose male Wistar rats (250-320g) were treated with amphetamine (2.5mg/kg/day intraperitoneal) or saline for 5 days and implanted with intracerebroventricular (i.c.v.) cannulae. Seven days after the last amphetamine administration the animals received ANG II (400pmol) i.c.v. One group was tested in a free choice paradigm for sodium (2% NaCl) and water intake and sacrificed for Fos immunoreactivity (Fos-IR) determinations. In a second group of rats, urine and plasma samples were collected for electrolytes and plasma renin activity determination and then they were sacrificed for Fos immunoreactivity determination in Oxytocinergic neurons (Fos-OT-IR). Repeated amphetamine exposure a) prevented the increase in sodium intake and Fos-IR cells in caudate-putamen and accumbens nucleus induced by ANG II i.c.v. b) potentiated urinary sodium excretion and Fos-OT-IR in hypothalamus and c) increased the inhibitory response in plasma renin activity, in response to ANG II i.c.v. Our results indicate a possible functional desensitization of AT1-R in response to ANG II, induced by repeated amphetamine exposure. This functional AT1-R desensitization allows to unmask the effects of ANG II i.c.v. mediated by oxytocin. We conclude that the long lasting changes in brain AT1-R functionality should be considered among the psychostimulant-induced neuroadaptations. Copyright © 2015. Published by Elsevier Ltd.
- [Show abstract] [Hide abstract] ABSTRACT: The renin angiotensin system (RAS) is involved not only in the regulation of blood pressure and fluid homeostasis, but also in the modulation of multiple additional functions in the brain. In this sense, it was found to be involved in many neuroadaptive responses induced by drugs such as cocaine, amphetamines, alcohol, as well as others. It is known that the dopaminergic neurotransmission in the nucleus accumbens and caudate-putamen plays a critical role in the rewarding effects of psychostimulant drugs and alcohol. The main and more studied actions of RAS are mediated by the neuropeptide Angiotensin II (Ang II) that belongs to the group of peptides known to stimulate dopamine release. There is growing evidence showing the key role of RAS in the development of neuroadaptive changes related to behavioral sensitization induced by natural reinforcers and drugs known to be abused. Recently, we found evidence involving the AT1 receptors in the neuroadaptive changes induced by amphetamine. Moreover, others found evidence that Ang II AT1 receptors are strongly involved in ethanol intake in rodents. Our goal is to present and discuss the evidence supporting an important role of brain RAS in neuroadaptive responses induced by two of the most abused drugs: amphetamine and alcohol, proposing this system as a potential therapeutic target in the treatment of disorders related to these drugs of choice for abuse.
- [Show abstract] [Hide abstract] ABSTRACT: Angiotensin II (Ang II) was described as a peripheral hormone; its synthesis and metabolism were characterized and it is currently known as the renin-angiotensin system (RAS). All the components of the RAS, including the receptors, have been found in brain tissue, indicating a role as a hormone or neuromodulator in the central nervous system. Ang II exerts its principal known actions at the AT1 receptor. Its functions related to AT2 receptors are controversial and associated with AT1 opposite effects, although there is evidence showing cross-talk between both receptors. The metabolism of Ang II generates other active peptides, such as Angiotensin 1–7 and Angiotensin IV, which will not be discussed. Neurobiological research has explained many of the different neuroendocrine and behavioral responses to stressors. Stress is a complex phenomenon in response to physical, environmental, or psychological stimulus. Stress triggers important adaptive functions improving health and survival. Meanwhile, excessive stress can be deleterious, therefore, individuals unable to cope with stress are highly vulnerable to a variety of diseases. Stress is a major contributor of cardiovascular disorders and psychiatric illness such as anxiety and depression. Many studies have confirmed that stress also increases the vulnerability to drug abuse. The role of Ang II at the periphery and in the central nervous system is vast and complex. For this reason, in this chapter we will focus on the role of brain RAS in stress responses and related pathologies from many other important aspects of Ang II research.
- [Show abstract] [Hide abstract] ABSTRACT: The neurovascular unit which comprises the microenvironment within small blood vessels in the brain parenchyma is responsible for the maintenance of normal neuronal function by a continuous supply of nutrients. Inflammatory processes and loss of brain–blood-barrier (BBB) integrity can lead to vascular dysfunction and pathological interactions between microvasculature, neurons, and astrocytes. These events have been closely related to the development of brain disorders such as cognitive decline, supported by numerous studies using hypertension animal models. There is a large body of evidence showing the implication of circulating and local renin angiotensin system in cerebral microvasculature function. Angiotensin II, trough AT1 receptor activation, has been related to elevated reactive oxygen species production, endothelial dysfunction, elevated permeability, inflammatory events, and vascular structure alterations. The angiotensin receptor blockers, used in antihypertensive treatments, are an important pharmacologic tool with neuroprotective effects because they can modify vascular damage and improve cognitive alterations. The development of vascular diseases can be influenced and promoted by external factors such as stress and drug abuse. Stress is related to induction of structural changes in arteries and cytokine production leading to endothelial damage and inflammation. It is known that psychostimulants have cardiovascular stimulant effects that can promote cerebral vasculitis and intracranial hemorrhage by direct and indirect mechanisms on the vasculature. The brain renin–angiotensin system is becoming an interesting new therapeutic target for vascular and related cognitive disorders.
- [Show abstract] [Hide abstract] ABSTRACT: A single or repeated exposure to psychostimulants induces long-lasting neuroadaptative changes. Different neurotransmitter systems are involved in these responses including the neuropeptide angiotensin II. Our study tested the hypothesis that the neuroadaptative changes induced by amphetamine produce alterations in brain RAS components that are involved in the expression of the locomotor sensitization to the psychostimulant drug. Wistar male rats, pretreated with amphetamine were used 7 or 21 days later to study AT1 receptors by immunohistochemistry and western blot and also angiotensinogen mRNA and protein in caudate putamen and nucleus accumbens. A second group of animals was used to explore the possible role of Ang II AT1 receptors in the expression of behavioral sensitization. In these animals treated in the same way, bearing intra-cerebral cannula, the locomotor activity was tested 21 days later, after an amphetamine challenge injection and the animals received an AT1 blocker, losartan, or saline 5min before the amphetamine challenge. An increase of AT1 receptor density induced by amphetamine was found in both studied areas and a decrease in angiotensinogen mRNA and protein only in CPu at 21 days after treatment; meanwhile, no changes were established in NAcc. Finally, the increased locomotor activity induced by amphetamine challenge was blunted by losartan administration in CPu. No differences were detected in the behavioral sensitization when the AT1 blocker was injected in NAcc. Our results support the hypothesis of a key role of brain RAS in the neuroadaptative changes induced by amphetamine.
- [Show abstract] [Hide abstract] ABSTRACT: Central nucleus of the amygdala (CeA) is one of the most important regulatory centres for the emotional processes. Among the different neurotransmitter systems present in this nucleus, AT1 receptors have been also found, but their role in the generation and modulation of emotions is not fully understood. The present work evaluated the effect of intra-amygdalar injection of losartan (AT1 receptor antagonist) and angiotensin II (Ang II) in the anxiety state induced by fear-potentiated plus maze in male Wistar rats. Fear in the elevated plus maze can be potentiated by prior inescapable footshock stress. The decrease in the time spent in the open arms induced by the inescapable footshock was totally prevented by losartan (4 pmol) administration in CeA. It was also found that Ang II (48 fmol) administration decreased the time spent in the open arms in animals with or without previous footshock exposure. The locomotor activity and grooming behaviour were also evaluated. The results obtained from the different parameters analyzed allowed us to conclude that the Ang II AT1 receptors in CeA are involved in the anxiety state induced by stress in the fear-potentiated plus-maze behaviour.
- [Show abstract] [Hide abstract] ABSTRACT: Background: The effect of the agonism on γ-aminobutyric acid (GABA) receptors was studied within medial prefrontal cortex (mPFC), amygdala (AMY) and ventral hipocampus (VH) in the plus-maze test in male rats bilaterally cannulated. These structures send glutamatergic projections to the nucleus accumbens septi (NAS), in which interaction and integration between these afferent pathways has been described. In a previous study of our group, blockade of glutamatergic transmission within NAS induced an anxiolytic like effect. Methods: Three rat groups received either saline or dipotassium chlorazepate (1 or 2 μg/1 μl solution) 15 min before testing. Time spent in the open arms (TSOA), time per entry (TPE), extreme arrivals (EA), open and closed arms entries (OAE, CAE) and relationship between open- and closed-arms quotient (OCAQ) were recorded. Results: In the AMY injected group TSOA, OAE and EA were increased by the higher doses of dipotassium chlorazepate (p < 0.01). In the mPFC, TPE was decreased by both doses (p < 0.05). Injection within ventral hippocampus (VH) decreased TSOA, OAE and OCAQ with lower doses (p < 0.05). When the three studied saline groups were compared, TSOA, OAE, EA and OCAQ were enhanced in the VH group when compared to mPFC and AMY (p < 0.001). Insertion of inner canula (p < 0.001, p < 0.01, p < 0.01) and saline injection showed an increasing significant difference (p < 0.001 in all cases) with the action of guide cannula alone within VH in TSOA, OAE and EA. Conclusion: We conclude that the injection of dipotassium chlorazepate has a differential effect depending of the brain area, leading to facilitatory and inhibitory effects on anxiety processing.
- [Show abstract] [Hide abstract] ABSTRACT: It has been recognized that the stress-related peptides are involved in anxiety states. Angiotensin II receptor blockade by systemic administration of the AT(1) receptor antagonists has been proposed as a new treatment possibility for anxiety disorders. For better understanding of the related mechanisms, in this study we evaluated effects of bilateral intraamygdaloid injections of 2 (LOS 2) and 4 (LOS 4) μg of losartan (LOS), a selective AT(1) receptor antagonist, on the behavior of the not stressed and acutely stressed rats in an elevated "plus" maze. Under non-stress conditions, LOS 4 increased time spent in the open arms (p < 0.01), number of extreme open arm arrivals (p < 0.05), time per entry (p < 0.01), and the number of total arm entries (p < 0.05) showing thus considerable anxiolytic activity. The open arm extreme arrivals were increased by LOS 4 in both not stressed (p < 0.05) and stressed (p < 0.05) rats. When no stressed and stressed LOS 4 animals were compared, time per entry and the number of closed arm entries (p < 0.05, both) were decreased in the latter group. Moreover, the LOS 4 stressed rats had significantly increased open/closed arm quotient (p < 0.05) as compared to the both control and LOS 4 non-stress group (p < 0.05, both). These findings suggest that the AT(1) receptor blockade in amygdala is important for the anxiolytic action of LOS (and probably other AT(1) receptor blockers) under both non-stress and stress conditions.
- [Show abstract] [Hide abstract] ABSTRACT: Angiotensin II (Ang II) is known as a peripheral hormone involved in the control of blood pressure and fluid homeostasis. The study and characterization of Ang II and its receptors in the brain has opened a new vision of its physiological role and also offers a variety of research fields. Ang II is involved in the response to stress, which stimulates the brain and the peripheral (hormonal) Ang II systems. Activation of brain angiotensin II AT1 receptors is required for stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of central sympathetic activity. The blockade of peripheral but also brain AT1 receptors prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers, through ischemia and inflammation. The AT1 receptor antagonists prevent inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-α) in the gastric mucosa and partially inhibit sympathoadrenal stimulation, without affecting the protective effect of glucocorticoid release during stress. The coordination of behavioral and autonomic responses to stress is partially under the control of extrahypothalamic, including cortical, CRF neurons expressing CRF1 receptors. AT1 receptor activation is thus also involved in the cortical decrease of CRF1 binding induced by stress. A large number of studies have been conducted on the effect of drugs of abuse on hypothalamic and extrahypothalamic CRF systems in the brain and on the role of CRF in mediating the behavioral and physiological effects of drugs of abuse. It is also known that dopaminergic neurotransmission in the nucleus accumbens and caudate-putamen plays a critical role in the locomotor and stereotypic effects of psychostimulant drugs. Ang II receptors are found on the soma and terminals of dopaminergic neurons and it has been shown that Ang II, acting through its AT1 receptors, facilitates the release of dopamine in the rat striatum in vitro and in vivo. Repeated exposure to amphetamine, as with most addictive drugs, results in progressive and lasting enhancement of their psychomotor and positive reinforcing effects. Neuroadaptive changes in mesotelencephalic dopaminergic projections play a key role in the induction and expression of amphetamine sensitization. Recently, we found evidence showing that brain AT1 receptor activation is involved in the neuroadaptive changes induced by amphetamine. The results of studies on the physiological role of brain Ang II offer new pharmacological tools for the treatment of some stress-related disorders such as drug abuse.
- [Show abstract] [Hide abstract] ABSTRACT: The amygdaloid complex is involved in anxiety or fear responses to stressful stimuli. In this study the effect of neuropeptide-EI on anxiety-like behavior and its influence on adrenocortical function was tested in male Wistar rats that were injected bilaterally in the basolateral amygdala with neuropeptide-EI (1 μg/1 μl) or artificial cerebrospinal fluid and placed on the plus maze. The plasma corticosterone levels were analyzed in controls and plus-maze exposed animals. Neuropeptide-EI in the basolateral amygdala significantly decreased the time spent in open arms but had no effect on locomotor activity, showing an anxiogenic effect. However, neuropeptide administration did not change serum corticosterone levels compared with vehicle controls. Our results suggest that the anxiogenic effect of neuropeptide-EI could be independent of the hypothalamic-pituitary-adrenocortical system response.
- [Show abstract] [Hide abstract] ABSTRACT: We studied the effect of ovariectomy and estrogen replacement on expression of adrenal angiotensin II AT1 and AT2 receptors, aldosterone content, catecholamine synthesis, and the transcription factor Fos-related antigen 2 (Fra-2). Ovariectomy increased AT1 receptor expression in the adrenal zona glomerulosa and medulla, and decreased adrenomedullary catecholamine content and Fra-2 expression when compared to intact female rats. In the zona glomerulosa, estrogen replacement normalized AT1 receptor expression, decreased AT1B receptor mRNA, and increased AT2 receptor expression and mRNA. Estrogen treatment decreased adrenal aldosterone content. In the adrenal medulla, the effects of estrogen replacement were: normalized AT1 receptor expression, increased AT2 receptor expression, AT2 receptor mRNA, and tyrosine hydroxylase mRNA, and normalized Fra-2 expression and catecholamine content. We demonstrate that the constitutive adrenal expression of AT1 receptors, catecholamine synthesis and Fra-2 expression are partially under the control of reproductive hormones. Our results suggest that estrogen treatment decreases aldosterone production through AT1 receptor downregulation and AT2 receptor upregulation. AT2 receptor upregulation and modulation of Fra-2 expression may participate in the estrogen-dependent normalization of adrenomedullary catecholamine synthesis in ovariectomized rats. The AT2 receptor upregulation and the decrease in AT1 receptor function and in the production of the fluid-retentive, pro-inflammatory hormone aldosterone partially explain the protective effects of estrogen therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Excessive grooming behaviour is induced by intracerebroventricular injections of the neuropeptide glutamic acid isoleucine amide (neuropeptide-EI), via the activation of A-10 dopaminergic neurons and the noradrenergic system. Our object was to study the latter system involved in these behaviours, using male Wistar rats weighing 250-300 g with i.c.v. implants. The results show that all the adrenoceptor antagonists "per se" do not affect excessive grooming behaviour or motor activity. Intracerebroventricular administration of propranolol, a general beta-adrenoceptor antagonist, before neuropeptide-EI, inhibited the induced excessive grooming behaviour in a dose dependent manner. Metoprolol, a beta(1)-adrenoceptor antagonist, also blocked this behaviour. However, intracerebroventricular injections of phentolamine, an alpha-adrenoceptor antagonist, and ((+/-)-1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), a beta(2)-adrenoceptor antagonist, had no effect on the behaviour induced by neuropeptide-EI induced behaviour for any of the doses tested. On the other hand, isoproterenol, a general beta-adrenoceptor agonist and dobutamine, a beta(1)-adrenoceptor agonist, both elicited similar behaviours as those induced by neuropeptide-EI. These results support the hypothesis that a relationship exists between neuropeptide-EI and beta-adrenoceptors, more specifically the beta(1)-adrenoceptor, as found with other similar endogenous peptides such as neurotensin, cholecystin, substance P and alpha-melanocyte stimulating hormone. Hence, neuropeptide-EI could probably be exerting a neuromodulating effect on the central nervous system.
- [Show abstract] [Hide abstract] ABSTRACT: Effects of blocking N-methyl-D-aspartic acid (NMDA) and non-NMDA glutamatergic receptors on performance in the hole board test was studied in male rats bilaterally cannulated into the nucleus accumbens (Acc). Rats, divided into 5 groups, received either 1 microl injections of saline, (+/-) 2-amino-7-phosphonoheptanoic acid (AP-7) (0.5 or 1 microg) or 2,3-dioxo-6-nitro-1,2,3,4,tetrahydrobenzo-(f)quinoxaline-7-sulphonamide disodium (NBQX, 0.5 or 1 microg) 10 min before testing. An increase by AP-7 was observed in ambulatory movements (0.5 microg; p < 0.05), non-ambulatory movements and number of movements (1 microg; p < 0.05); sniffing and total exploration (1 microg; p < 0.01). When holes were considered in order from the first to the fifth by the number of explorations, the most visited holes (first and second) of the AP-7 group were significantly higher than the corresponding holes of saline group (p < 0.05 for 0.5 microg and p < 0.001 for 1 microg). When the second hole was compared with the first of his group, a difference was only observed in the AP-7 1 microg group (p < 0.001). Increasing differences between the other holes and the first were observed by drug treatment. At molecular level, it was observed that AP-7 induced an increase of the coat protein AP-2 expression in Acc, but not AP-180 neither the synaptic protein synaptophysin. The increase of AP-2 was also observed in the medial prefrontal cortex by the action of AP-7 but not NBQX. We conclude that NMDA glutamatergic blockade might induce an activation of the endocytic machinery into the Acc, leading to stereotypies and perseverations, lacking cortical intentional direction.
- [Show abstract] [Hide abstract] ABSTRACT: 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 stress-induced 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-alpha) 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.
- [Show abstract] [Hide abstract] ABSTRACT: We studied renal AT1 and AT2 receptors in male, female, ovariectomized and ovariectomized-estrogen-treated Wistar-Hanover and Wistar-Kyoto rats. AT1 receptors and AT1A receptor mRNA predominated, with no significant differences between males and females. AT2 receptor expression was restricted in female rats to the capsule, the transition zone between outer and inner medulla, the endothelium lining the papilla, and arcuate arteries and veins. There were no AT2 receptors in male rats, while male mice express substantial numbers of estrogen-dependent AT2 receptors. Arcuate arteries and veins expressed AT1B mRNA in males and females, and AT2 mRNA in females only. AT1 receptor and AT2 receptor expression were estrogen-dependent, with increases in AT1 and AT2 receptor expression after estrogen treatment in ovariectomized rats. Estrogen treatment increased prostaglandin E2 (PGE2) and cGMP concentrations in the renal medulla, and eNOS expression in cortical arteries. In rodents, expression of renal Angiotensin II receptor types is estrogen-dependent, with significant species, strain and area differences. Our results support an important role for AT2 receptors in the regulation of renal function and in the protective effects of estrogen in the kidney.
- [Show abstract] [Hide abstract] 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.
- [Show abstract] [Hide abstract] ABSTRACT: The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin-angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT(1) receptors to regulate thirst and fluid metabolism. Some AT(1) receptors are located outside the blood-brain barrier and are sensitive to brain and circulating Ang II. Other AT(1) receptors, located inside the blood-brain barrier, respond to stimulation by Ang II of brain origin. AT(1) receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT(1) receptors in the PVN are under glucocorticoid control and regulate corticotrophin-releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT(1) receptor mRNA expression. The expression of paraventricular AT(1) receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic-pituitary-adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT(1) receptor antagonist blocks peripheral and brain AT(1) receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold-restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT(1) receptor blockade has a place in the prevention and treatment of stress-related disorders.