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The C57BI/6J mouse strain, the genetic background of many transgenic and gene knockout models, is salt sensitive and resistant to renal injury. We tested the hypothesis that renal dopaminergic function is defective in C57B1/6J mice. On normal NaCI (0.8%, 1 wk) diet, anesthetized and conscious (telemetry) blood pressures were similar in C57B1/6J and SJL/J mice. High NaCI (6%, 1 wk) increased blood pressure (≈30%) in C57B1/6J but not in SJL/J mice and urinary dopamine to greater extent in SJL/J than in C57B1/6J mice. Absolute and fractional sodium excretions were lower in SJL/J than in C57B1/6J mice. The blood pressure-natriuresis plot was shifted to the right in C57BI/6J mice. Renal expressions of D1-like (D1R and D5R) and angiotensin II AT1 receptors were similar on normal salt, but high salt increased D5R only in C57B1/6J. GRK4 expression was lower on normal but higher on high salt in C57B116J than in SJL/J mice. Salt increased the excretion of microalbumin and 8-isoprostane (oxidative stress marker) and the degree of renal injury to a greater extent in SJL/J than in C57B1/6J mice. A D1-like receptor agonist increased sodium excretion whereas a D1-like receptor antagonist decreased sodium excretion in SJL/J but not in C57B1/6J mice. In contrast, parathyroid hormone had a similar natriuretic effect in both strains. These results show that defective D1-like receptor function is a major cause of salt sensitivity in C57B1/6J mice, decreased renal dopamine production might also contribute. The relative resistance to renal injury of C57B1/6J may be a consequence of decreased production of reactive oxygen species. [ABSTRACT FROM AUTHOR]

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. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Sustained pretreatment with angiotensin II AT1 receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT1 receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT1 receptor antagonist, 0.5 mg/kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT1 receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. In rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT1 receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT1 receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT1 receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT1 receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT1 receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions. [Copyright &y& Elsevier]

Long-term pretreatment with an angiotensin II AT1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic–pituitary–adrenal responses to isolation stress. We determined whether AT1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT1 antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT1 receptor blockade prevented the isolation-induced increase in brain AT1 receptors and decrease in AT2 binding in the locus coeruleus. AT1 receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT1 receptor antagonist completely prevented the decrease in cortical CRF1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF1 receptors and the GABAA complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT1 receptor antagonists. We propose that AT1 receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.Neuropsychopharmacology (2006) 31, 1123–1134. doi:10.1038/sj.npp.1300921; published online 5 October 2005 [ABSTRACT FROM AUTHOR]

In transgenic mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, impaired glucocorticoid feedback efficacy is accompanied by reduced hypothalamic corticotropin-releasing hormone (CRH) and vasopressin (AVP) activity and reduced peripheral sympathetic tone, indications of a shift in the balance of hypothalamic CRH and sympathetic regulation. As angiotensin II (Ang II) regulates CRH, AVP and sympathetic activity, we studied the expression of Ang II receptors in the hypothalamus and adrenal gland of GR transgenic and wild-type mice, adrenal catecholamines and mRNA for their rate-limiting enzyme, tyrosine hydroxylase (TH). We found that transgenic mice expressed significantly less numbers of Ang II AT1 receptors in the hypothalamic paraventricular nucleus and median eminence, lower numbers of AT2 receptors in supraoptic and paraventricular nuclei and lower numbers of AT2 receptors in the adrenal medulla when compared with wild-type controls. The expression of TH mRNA and the concentration of adrenomedullary epinephrine and norepinephrine were also lower in transgenic mice when compared with wild-type controls. Decreased hypothalamic and adrenal Ang II receptor stimulation as a result of decreased GR expression may explain the decreased hypothalamic CRH and AVP and decreased adrenomedullary and sympathetic activities in this model. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study examined whether serotonin transporter (SERT) de?ciency in?uences adrenal serotonin (5-HT), catecholamine and Angiotensin II (Ang II) systems, and the hormonal response to acute restraint stress. Control SERT mice (+/+) expressed high numbers of SERT binding sites in adrenal medulla. Fifteen minutes of restraint stress increased adrenal 5-HT, adrenomedullary tyrosine hydroxylase (TH) mRNA expression and plasma epinephrine (EPI), and norepinephrine levels without alterations in adrenal catecholamine content. In SERT+/+, these responses coincided with a signi?cant increase in adrenomedullary Ang II AT2 receptor expression. SERT-de?cient mice did not express SERT binding sites; their adrenal 5-HT was signi?cantly depleted and further reduced after stress. They had exaggerated stress-induced EPI release into plasma, the increase in TH transcription did not occur, adrenal catecholamine content was decreased compared with SERT+/+, and stress induced a reduction rather than increase in the number of adrenomedullary AT2 receptors. SERT-/- mice also possessed decreased pituitary 5-HT. Their pituitary ACTH was reduced after stress, but stress-induced increases in plasma ACTH and corticosterone were not different from those of SERT+/+ mice. Our results indicate that SERT function not only restrains stress-induced EPI release but also is required for the increase in adrenal catecholamine synthesis and AT2 receptor expression. [ABSTRACT FROM AUTHOR]

Examines the estrogen upregulation of renal angiotensin in mammalian kidney. Production of sodium retention with the stimulation of renal At[sub 2] receptor; Measurement on the total binding activity of compounds; Administration of supraphysiological dose of estradiol in the blood level.