Peripheral Administration of an Angiotensin II AT 1 Receptor Antagonist Decreases the Hypothalamic-Pituitary-Adrenal Response to Isolation Stress (original) (raw)
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Journal of Neuroendocrinology, 1995
Double staining in situ hybridization studies have shown that angiotensin II (All) type 1 receptors (AT1) in the hypothalamic paraventricular nucleus (PVN) are located primarily in corticotropin releasing hormone (CRH) neurons of the parvicellular subdivision. The purpose of these studies was to investigate the role of All regulating the hypothalamic-pituitary adrenal (HPA) axis, by correlating AT, receptor expression levels in the PVN with the known changes in activity of the HPA axis under different stress paradigms, and manipulation of circulating glucocorticoids. AT, receptor mRNA was measured by in situ hybridization using 35S-labelled cRNA probes and All binding by autoradiography using '"I[Sar',lle8]All in slide mounted hypothalamic sections. AT, receptor mRNA levels and All binding in the PVN were reduced by about 20% 18 h after adrenalectomy remaining at these levels up to 6 days after. This effect was prevented by corticosterone administration in the drinking water, or dexamethasone injection (1 00 mg, s.c., daily). Conversely, dexamethasone injection in intact rats caused a 20% increase in AT, receptor mRNA in the PVN. AT, receptor mRNA and binding in the PVN increased 4 h after exposure to stress paradigms associated with activation of the HPA axis (immobilization for 1 h, or i.p. injection of 1.5 M NaCI), and remained elevated after repeated daily stress for 14 days. Unexpectedly, two osmotic stress models associated with inhibition of the HPA axis (60 h water deprivation or 12 days of 2% saline intake) also resulted in increased AT, receptor mRNA levels and All binding in the parvicellular PVN. In intact rats, the stimulatory effect of acute stress on AT, receptor mRNA in the PVN was significantly enhanced by dexamethasone administration (100 pg, s.c., 14 h and 1 h prior to stress), while in adrenalectomized rats, with or without glucocorticoid replacement, stress reduced rather than increased, AT, receptor mRNA. Dexamethasone, 100 pg, injected sc within 1 min the beginning of immobilization in adrenalectomized rats, increased AT, receptor mRNA in the PVN to levels significantly higher than those after dexamethasone alone, indicating that the stress induced glucocorticoid surge is required for the stimulatory effect of stress on AT, receptor mRNA. The data suggest that AT, receptor expression in the PVN is under dual control during stress: stress-activated inhibitory pathways and the stimulatory effect of glucocorticoids. The lack of specificity of the changes in AT, receptor expression in the PVN following stressors with opposite effects on ACTH secretion (osmotic and physical-psychological stress) does not support a role for All as a major determinant of the response of the HPA axis during stress.
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.
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.
Stress: The International Journal on the Biology of Stress, 2008
Spontaneously hypertensive rats, a stress-sensitive strain, were pretreated orally for 14 days with the AT 1 receptor antagonist candesartan before submission to 2 h of cold-restraint stress. In non-treated rats, stress decreased AT 1 receptor binding in the median eminence and basolateral amygdala, increased AT 2 receptor binding in the medial subnucleus of the inferior olive, decreased AT 2 binding in the ventrolateral thalamic nucleus and increased tyrosine hydroxylase mRNA level in the locus coeruleus. In non-stressed rats, AT 1 receptor blockade reduced AT 1 receptor binding in all areas studied and enhanced AT 2 receptor binding in the medial subnucleus of the inferior olive. Candesartan pretreatment produced a similar decrease in brain AT 1 binding after stress, and prevented the stress-induced AT 2 receptor binding decrease in the ventrolateral thalamic nucleus. In the locus coeruleus and adrenal medulla, AT 1 blockade abolished the stress-induced increase in tyrosine hydroxylase mRNA level. Our results demonstrate that oral administration of candesartan effectively blocked brain AT 1 receptors, selectively increased central AT 2 receptor expression and prevented the stress-induced central stimulation of tyrosine hydroxylase transcription. The present results support a role of brain AT 1 and AT 2 receptors in the regulation of the stress response, and the hypothesis that AT 1 receptor antagonists may be considered as potential therapeutic compounds in stress related disorders in addition to their anti-hypertensive properties.
Journal of Endocrinology, 2012
While the renin-angiotensin system is important for adrenomedullary responses to stress, the involvement of specific angiotensin II (Ang II) receptor subtypes is unclear. We examined gene expression changes of angiotensin II type 1A (AT 1A) and type 2 (AT 2) receptors in rat adrenal medulla in response to immobilization stress (IMO). AT 2 receptor mRNA levels decreased immediately after a single 2-h IMO. Repeated IMO also decreased AT 2 receptor mRNA levels, but the decline was more transient. AT 1A receptor mRNA levels were unaltered with either single or repeated IMO, although binding was increased following repeated IMO. These effects of stress on Ang II receptor expression may alter catecholamine biosynthesis, as tyrosine hydroxylase and dopamine b-hydroxylase mRNA levels in PC12 cells are decreased with Ang II treatment in the presence of ZD7155 (AT 1 receptor antagonist) or with CGP42112 (AT 2 receptor agonist) treatment. Involvement of stress-triggered activation of the hypothalamic-pituitaryadrenocortical or sympathoadrenal axis in AT 2 receptor downregulation was examined. Cultured cells treated with the synthetic glucocorticoid dexamethasone displayed a transcriptionally mediated decrease in AT 2 receptor mRNA levels. However, glucocorticoids are not required for the immediate stress-triggered decrease in AT 2 receptor gene expression, as demonstrated in corticotropin-releasing hormone knockout (Crh KO) mice and hypophysectomized rats, although they can regulate basal gene expression. cAMP and pituitary adenylate cyclase-activating polypeptide also reduced AT 2 receptor gene expression and may mediate this response. Overall, the effects of stress on adrenomedullary AT 1A and AT 2 receptor expression may contribute to allostatic changes, such as regulation of catecholamine biosynthesis.
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
Journal of Endocrinology, 2008
Exposure to chronic restraint (CR) modifies the hypothalamicpituitary-adrenal (HPA) axis response to subsequent acute stressors with adaptation of the response to a homotypic and sensitization of the response to a heterotypic stressor. Since vasopressin (AVP) activity has been reported to change during chronic stress, we investigated whether this was an important factor in HPA facilitation. We therefore tested whether vasopressin 1b receptor (AVPR1B) blockade altered the ACTH and corticosterone response to heterotypic stressors following CR stress. Adult male rats were exposed to CR, single restraint, or were left undisturbed in the home cage. Twentyfour hours after the last restraint, rats were injected with either a AVPR1B antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in saline, 0 . 2/kg, s.c.) and then exposed to either restraint, lipopolysaccharide (LPS) or white noise. CR resulted in the adaptation of the ACTH and corticosterone response to restraint and this effect was not prevented by pretreatment with Org. Although we found no effect of CR on LPS-induced ACTH and corticosterone secretion, both repeated and single episodes of restraint induced the sensitization of the ACTH, but not corticosterone response to acute noise. Pretreatment with Org reduced the exaggerated ACTH response to noise after both single and repeated exposure to restraint.