Home About us Contact
|
Home About us Contact | ||
|
|
||
Mineralocorticoid Receptor (mineralocorticoid + receptor)
Selected AbstractsMineralocorticoid Receptor Is Overexpressed in Cardiomyocytes of Patients With Congestive Heart FailureCONGESTIVE HEART FAILURE, Issue 1 2005Masahiro Yoshida MD Mineralocorticoid receptors (MRs) have been identified in the human cardiovascular tissues. We determined MR expression in the failing heart to clarify the mechanism of action of aldosterone antagonist in the treatment of congestive heart failure. MR protein and MR mRNA content were detected by immunohistochemical staining and in situ hybridization in the cardiac tissues. Immunohistochemical staining of the receptor, as well as in situ hybridization of MR mRNA, was dense in cardiomyocytes of the failing left ventricle as compared with the controls. The staining ratio of the cytoplasm to the interstitium showed that MRs were located mainly in the cytoplasm. The cytoplasm to the interstitium in the failing left ventricle was 1.53±0.13, which was significantly higher than that of the controls 1.25±0.19 (p<0.05). These findings suggest that the efficacy of aldosterone antagonists in treating congestive heart failure may be in part through blocking the MRs, which are upregulated in the failing heart. [source] PRECLINICAL STUDY: Mifepristone and spironolactone differently alter cocaine intravenous self-administration and cocaine-induced locomotion in C57BL/6J miceADDICTION BIOLOGY, Issue 1 2010Jean-François Fiancette ABSTRACT Corticosterone, the main glucorticoid hormone in rodents, facilitates behavioral responses to cocaine. Corticosterone is proposed to modulate cocaine intravenous self-administration (SA) and cocaine-induced locomotion through distinct receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), respectively. However, this remains debatable. On one hand, modulation of both responses by the GR was tested in different experimental conditions, i.e. light versus dark nycthemeral phase and naïve versus cocaine-experienced animals. On the other hand, modulation of both responses by the MR was never tested directly but only inferred based on the ability of low plasma corticosterone levels (those for which corticosterone almost exclusively binds the MR) to compensate the effects of adrenalectomy. Our goal here was to test the involvement of the GR and the MR in cocaine-induced locomotor and reinforcing effects in the same experimental conditions. C57Bl/6J mice were trained for cocaine (1 mg/kg/infusion) intravenous SA over 40 SA sessions. The animals were then administered with mifepristone (30 mg/kg i.p.), a GR antagonist, or with spironolactone (20 mg/kg/i.p.), an MR antagonist, 2 hours before either cocaine intravenous SA or cocaine-induced locomotion. In a comparable nycthemeral period and in similarly cocaine-experienced animals, a blockade of the GR decreased cocaine-induced reinforcing effects but not cocaine-induced locomotion. A blockade of the MR decreased both cocaine-induced reinforcing (but to a much lesser extent than the GR blockade) and locomotor effects. Altogether, our results comforted the hypothesis that the GR modulates cocaine-related operant conditioning, while the MR would modulate cocaine-related unconditioned effects. The present data also reveal mifepristone as an interesting tool for manipulating the impact of corticosterone on cocaine-induced reinforcing effects in mice. [source] Decreased glucocorticoid receptor mRNA and dysfunction of HPA axis in rats after removal of the cholinergic innervation to hippocampus.EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2002Jung-Soo Han Abstract Excess exposure to glucocorticoids can have deleterious effects on physiology and cognition. Glucocorticoids acting via receptors located in hippocampal neurons contribute to negative feedback after stress by terminating the further release of glucocorticoids. The current study investigated the effects of selective immunolesions of septo-hippocampal cholinergic neurons on hippocampal corticosterone receptor mRNA and on hypothalamic-pituitary-adrenal (HPA) activity. As evaluated by in situ hybridization, hippocampal glucocorticoid receptor (GR) mRNA, but not mineralocorticoid receptor (MR) mRNA, was significantly decreased in lesioned rats compared to controls. In a companion study, the peak corticosterone response to one hour of restraint stress did not differ between lesion and control groups but the post-stress decline of corticosterone was more protracted in the lesioned rats. These findings are discussed in terms of their possible relevance to ageing as age-related degeneration of the basal forebrain cholinergic system may contribute to the commonly observed dysfunction of the HPA axis in older animals. [source] ,Pseudo-aldosteronism' induced by intravenous glycyrrhizin treatment of chronic hepatitis C patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2001Tekla GJ Van Rossum Abstract Background and Aims: Treatment with intravenous glycyrrhizin reduces the progression of liver disease caused by chronic hepatitis C (HCV) infection. Glycyrrhetinic acid, a metabolite of glycyrrhizin, inhibits the renal conversion of cortisol to cortisone by inhibiting the enzyme 11,-hydroxysteroiddehydrogenase in the kidney. The resulting excess of cortisol subsequently stimulates the mineralocorticoid receptor, leading to pseudo-aldosteronism with hypertension, hypokalemia and eventually renin and aldosterone suppression. The aim of this study was to evaluate the occurrence of pseudo-aldosteronism after treatment of chronic hepatitis C (HCV) patients with increasing doses of intravenous glycyrrhizin. Methods: Forty-four HCV patients with chronic hepatitis or compensated cirrhosis were treated with intravenous glycyrrhizin 6 × 200 mg/week, 3 × 240 mg/week or 3 × 0 mg/week (placebo) for 4 weeks. In all patients, bodyweight, blood pressure and plasma concentrations of sodium, potassium, cortisol, DHEA-S (dehydroepiandrosterone sulfate), renin and aldosterone were measured before, and at 0 and 4 weeks after treatment. Results: Within the placebo group, no significant changes were observed. Within the 1200 mg group systolic blood pressure was significantly higher at the end of treatment, while aldosterone was significantly lower; at the end of the follow-up period these values had returned to baseline. The changes from baseline in systolic and diastolic blood pressure at the end of treatment were significantly higher in the 1200 mg group compared to the placebo group. The changes in aldosterone and potassium concentrations at the end of treatment increased with increasing dosage, although not significantly. Conclusion: Hepatitis C virus patients with chronic hepatitis or compensated cirrhosis show minor reversible symptoms of pseudo-aldosteronism after treatment with 1200 mg glycyrrhizin weekly for 4 weeks. [source] Chronic Prenatal Ethanol Exposure Increases Glucocorticoid-Induced Glutamate Release in the Hippocampus of the Near-Term Foetal Guinea PigJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2006U. Iqbal Exposure to high cortisol concentration can injure the developing brain, possibly via an excitotoxic mechanism involving glutamate (Glu). The present study tested the hypothesis that chronic prenatal ethanol exposure (CPEE) activates the foetal hypothalamic-pituitary-adrenal axis to produce high cortisol exposure in the foetal compartment and alters sensitivity to glucocorticoid-induced Glu release in the foetal hippocampus. Pregnant guinea pigs received daily oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding from gestational day (GD) 2 until GD 63 (term, approximately GD 68) at which time they were euthanised, 1 h after their final treatment. Adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined in foetal plasma. Basal and electrically stimulated Glu and ,-aminobutyric acid (GABA) efflux in the presence or absence of dexamethasone (DEX), a selective glucocorticoid-receptor agonist, were determined ex vivo in foetal hippocampal slices. Glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and N -methyl- d -aspartate (NMDA) receptor NR1 subunit mRNA expression were determined in situ in the hippocampus and dentate gyrus. In the near-term foetus, CPEE increased foetal plasma ACTH and cortisol concentrations. Electrically stimulated glutamate, but not GABA, release was increased in CPEE foetal hippocampal slices. Low DEX concentration (0.3 µM) decreased stimulated glutamate, but not GABA, release in both CPEE and control foetal hippocampal slices. High DEX concentration (3.0 µM) increased basal release of Glu, but not GABA, in CPEE foetal hippocampal slices. GR, but not MR, mRNA expression was elevated in the hippocampus and dentate gyrus, whereas NR1 mRNA expression was increased in the CA1 and CA3 fields of the foetal hippocampus. These data demonstrate that CPEE increases high glucocorticoid concentration-induced Glu release in the foetal hippocampus, presumably as a consequence of increased GR expression. These effects of CPEE, coupled with increased glutamate release and increased NMDA receptor expression, may predispose the near-term foetal hippocampus to GR and Glu-NMDA receptor-mediated neurodevelopmental toxicity. [source] Blunted Pituitary-Adrenocortical Stress Response in Adult Rats Following Neonatal Dexamethasone TreatmentJOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2000K. Felszeghy Abstract Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 µg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 µg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma cncentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary. [source] Aldosterone induces collagen synthesis via activation of extracellular signal-regulated kinase 1 and 2 in renal proximal tubulesNEPHROLOGY, Issue 8 2008GUOSHUANG XU SUMMARY: Aim: Aldosterone plays a crucial role in renal fibrosis by inducing mesangial cell proliferation and promoting collagen synthesis in renal fibroblasts. However, renal proximal tubule involvement in aldosterone-induced collagen synthesis has not yet been identified. The aim of this study was to examine the potential role of aldosterone in collagen expression and its possible mineralocorticoid receptor (MR)-dependent pathway, mediated by activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cultured human renal proximal tubular epithelial (HKC) cells. Methods: After HKC cells were stimulated by aldosterone with different concentrations for various time and periods, the gene expression and protein synthesis of collagen I, II, III and IV were measured by real-time polymerase chain reaction and western blot, respectively. ERK1/2 activation, ,-smooth muscle actin (,-SMA), and E-cadherin were also detected by western blot. Results: Aldosterone can increase ERK1/2 phosphorylation of human renal proximal tubular epithelial cells in a time- and dose-dependent manner. Although aldosterone had no effect on collagen I and II expression, it increased expression of ,-SMA and collagen III and IV and decreased that of E-cadherin in HKC cells after 48 h. These effects could be prevented by a ERK pathway inhibitor, U0126, or by a selective MR antagonist, spironolactone. Conclusion: The results suggest that aldosterone plays a pivotal role in tubulointerstitial fibrosis by promoting tubular epithelial,mesenchymal transition and collagen synthesis in proximal tubular cells. The process is MR-dependent, and mediated by ERK1/2 mitogen-activated protein kinase pathway. [source] Prenatal synthetic glucocorticoid exposure alters hypothalamic,pituitary,adrenal regulation and pregnancy outcomes in mature female guinea pigsTHE JOURNAL OF PHYSIOLOGY, Issue 5 2010Elizabeth Dunn Preterm delivery occurs in approximately 10% of all pregnancies. Prenatal exposure to synthetic glucocorticoids (sGCs) reduces the incidence of respiratory distress syndrome (RDS) in these babies. Therefore, administration of multiple courses of sGCs became common practice. Animal and human studies have demonstrated that multiple courses of sGCs can have long-term effects. While the majority of animal studies have been undertaken in male offspring, it is emerging that there are profound sex differences in the consequences of prenatal sGC exposure. To our knowledge, no studies have determined the effects of prenatal sGC exposure on hypothalamic,pituitary,adrenal (HPA) axis function in female offspring while accounting for reproductive cycle status, or determined if there are effects on pregnancy parameters. Pregnant guinea pigs were administered three courses of betamethasone (Beta), dexamethasone (Dex) or vehicle on gestational days 40/41, 50/51 and 60/61. In adulthood (age range: postnatal days 126,165), basal and activated HPA axis function were assessed at various stages of the reproductive cycle. The female offspring were then mated and underwent an undisturbed pregnancy. Females were killed in the luteal phase of the reproductive cycle following litter weaning, and molecular analysis undertaken. In the luteal phase, Beta-exposed females exhibited significantly lower basal salivary cortisol levels (P < 0.05). Dex-exposed females also exhibited significantly lower basal salivary cortisol levels during the luteal phase (P < 0.05), but increased basal salivary cortisol levels during the ostrous phase (P < 0.01). The Beta-exposed females exhibited increased glucocorticoid receptor (GR) mRNA expression in the CA1/2 region of the hippocampus (P < 0.05) and MC2R mRNA in the adrenal cortex (P < 0.05). The Dex-exposed animals exhibited higher hippocampal GR and mineralocorticoid receptor (MR) mRNA levels (P < 0.05). Beta-exposed females showed reduced fecundity (P < 0.05). In Dex-exposed females there was a lower male to female sex ratio. In conclusion, prenatal sGC exposure affects HPA axis activity, in a cycle-dependent manner, and long-term reproductive success. The clinical implications of the findings on endocrine function and pregnancy in females are profound and further follow-up is warranted in human cohorts. Furthermore, we have shown there are considerable difference in phenotypes between the Beta- and Dex-exposed females and the specific endocrine and maternal outcome is contingent on the specific sGCs administered during pregnancy. [source] Selection and optimization of MCF-7 cell line for screening selective inhibitors of 11,-hydroxysteroid dehydrogenase 2CELL BIOCHEMISTRY AND FUNCTION, Issue 6 2010Chi Hyun Kim Abstract An 11,-hydroxysteroid dehydrogenase type 1 (11,-HSD1) produces glucocorticoid (GC) from 11-keto metabolite, and its modulation has been suggested as a novel approach to treat metabolic diseases. In contrast, type 2 isozyme 11,-HSD2 is involved in the inactivation of glucocorticoids (GCs), protecting the non-selective mineralocorticoid receptor (MR) from GCs in kidney. Therefore, when 11,-HSD1 inhibitors are pursued to treat the metabolic syndrome, preferential selectivity of inhibitors for type 1 over type 2 isozyme is rather important than inhibitory potency. Primarily, to search for cell lines with 11,-HSD2 activity, we investigated the expression profiles of enzymes or receptors relevant to GC metabolism in breast, colon, and bone-derived cell lines. We demonstrated that MCF-7 cells had high expression for 11,-HSD2, but not for 11,-HSD1 with its cognate receptor. Next, for the determination of enzyme activity indirectly, we adopted homogeneous time resolved fluorescence (HTRF) cortisol assay. Obviously, the feasibility of HTRF to cellular 11,-HSD2 was corroborated by constructing inhibitory response to an 11b-HSD2 inhibitor glycyrrhetinic acid (GA). Taken together, MCF-7 that overexpresses type 2 but not type 1 enzyme is chosen for cellular 11,-HSD2 assay, and our results show that a nonradioactive HTRF assay is applicable for type 2 as well as type 1 isozyme. Copyright © 2010 John Wiley & Sons, Ltd. [source] Enantiomeric separation of mineralocorticoid receptor (hMR) antagonists using the Chiralcel® OJ-H HPLC column with novel polar cosolvent eluent systemsCHIRALITY, Issue 6 2006V. Scott Sharp Abstract This study demonstrates the increased versatility of the Chiralcel® OJ-H stationary phase when using various alcohol/acetonitrile mobile phases. This chiral stationary phase has traditionally been employed in the normal phase mode and more recently with neat alcohols as eluents. Selected isomeric human mineralocorticoid receptor (hMR) antagonist pharmaceutical candidates and synthetic intermediates were separated using the Chiralcel® OJ-H HPLC column with novel polar cosolvent eluent systems. The capacity factors, resolution, and selectivity of the chiral separations were assessed while varying the alcohol/acetonitrile composition and alcohol identity. The mixed polar eluents provide separations that are nearly always superior to both the traditional hexane-rich and single-alcohol "polar organic" eluents for the compounds tested in this article. Chirality, 2006. © 2006 Wiley-Liss, Inc. [source] EPLERENONE PREVENTS ADVERSE CARDIAC REMODELLING INDUCED BY PRESSURE OVERLOAD IN ATRIAL NATRIURETIC PEPTIDE-NULL MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2006Veronica Franco SUMMARY 1Atrial natriuretic peptide (ANP)-null mice (Nppa -/- ) exhibit cardiac hypertrophy at baseline and adverse cardiac remodelling in response to transverse aortic constriction (TAC)-induced pressure overload stress. Previous studies have suggested that natriuretic peptides could potentially oppose mineralocorticoid signalling at several levels, including suppression of adrenal aldosterone production, inhibition of mineralocorticoid receptor (MR) activation or suppression of MR-mediated production of pro-inflammatory factors. Thus, we hypothesized that the MR blocker eplerenone would prevent the exaggerated left ventricular (LV) remodelling/fibrosis and dysfunction after TAC in Nppa -/- . 2In the present study, Nppa -/- and wild-type Nppa+/+ mice fed eplerenone- or vehicle (oatmeal)-supplemented chow since weaning were subjected to TAC or sham operation. The daily dose of eplerenone administered was approximately 200 mg/kg. At 1 week after TAC, LV size and function were evaluated by echocardiogram and LV cross-sections were stained with picrosirius red for collagen volume measurement. Total RNA was extracted from the LV for real-time polymerase chain reaction analysis of osteopontin. 3Eplerenone had no effect on baseline hypertrophy observed in sham-operated Nppa -/- compared with Nppa+/+ mice. Eplerenone attenuated the TAC-induced increase in LV weight in both genotypes and completely prevented LV dilation, systolic dysfunction and interstitial collagen deposition seen in Nppa -/- mice after TAC. However, serum aldosterone levels were lower in Nppa -/- compared with Nppa+/+ wild types. No interaction between eplerenone and genotype in osteopontin mRNA levels was observed. 4Eplerenone prevents adverse cardiac remodelling related to pressure overload in ANP-deficient mice, mainly due to an antifibrotic effect. The mechanism whereby ANP deficiency leads to excess hypertrophy, fibrosis and early failure following TAC is increased profibrotic signals resulting from excess or unopposed MR activation, rather than increased levels of aldosterone. [source] AN ALDOSTERONE-RELATED SYSTEM IN THE VENTROLATERAL MEDULLA OBLONGATA OF SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006Natasha N Kumar SUMMARY 1The actions of aldosterone include mediation of vasoconstriction, vascular fibrosis, endothelial dysfunction and sodium retention. These actions can contribute to hypertension. Recent studies implicate an abnormal aldosterone hormonal system in the brain in hypertension. However, the study of central aldosterone actions is still in its infancy, as the exact location and abundance of its components in the brain are uncertain. 2We aimed to detect components of the aldosterone cascade in the regions of the ventrolateral medulla oblongata (VLM)-containing neurons that regulate blood pressure and to see whether there are quantitative differences in these components between the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat models. Tissues from four regions of the brainstem, namely, the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively), rostral pressor area and caudal pressor area, were examined. We measured mRNA expression of aldosterone synthase, mineralocorticoid receptor (MR1), 12-lipoxygenase (12-LO), serum- and glucocorticoid- inducible kinase and K-ras in male rats. Gene expression levels were measured using real-time reverse transcription,polymerase chain reaction. 3We detected all aldosterone components in all regions of the VLM. The K-ras levels were not significantly different in any of the regions. Expression of MR1 mRNA was lower in the RVLM of SHR (n = 5) compared with WKY rats (n = 5; t = 4.590; P = 0.002) and 12-LO mRNA levels were lower in the CVLM in SHR (n = 6) compared with WKY rats (n = 7; P = 0.04). Thus, we have shown for the first time that components of the aldosterone cascade are present in the VLM. Our results suggest that there may be a differential gene expression profile in the brainstem for genetic hypertension. [source] Individual differences in the effects of chronic prazosin hydrochloride treatment on hippocampal mineralocorticoid and glucocorticoid receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007Mohamed Kabbaj Abstract The aim of this study was to investigate the noradrenergic regulation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in high responder (HR) and low responder (LR) male rats, an animal model of individual differences in hypothalamo-pituitary-adrenal axis activity and vulnerability to drugs of abuse. The effects of a chronic treatment with the noradrenergic ,1 antagonist (1-[4-amino-6,7-dimethoxy-2-quinazolinyl]-4-[2-furanylcarbonyl] piperazine) hydrochloride (prazosin) (0.5 mg/kg, i.p., 35 days) were assessed on stress-induced corticosterone (CORT) secretion and on hippocampal MRs and GRs in adrenally intact rats. In order to ascertain whether the effects of chronic prazosin treatment on hippocampal MRs and GRs were direct or indirect, through prazosin-induced CORT secretion, we also assessed the effects of the same treatment on adrenalectomized rats with CORT substitutive therapy. When compared with LR rats, HR rats exhibited a delayed return to the basal level of CORT following acute restraint stress; this was associated with a lower binding of MRs and GRs in HR rats than in LR rats. Chronic prazosin treatment had no effect in HR animals but markedly reduced hippocampal MRs and GRs, and increased stress-induced CORT secretion in LR rats. In LR adrenalectomized rats, prazosin reduced hipppocampal MRs but did not change GRs. Our results provide evidence of a differential regulation by noradrenaline of hippocampal MRs and GRs in HR and LR rats. These data could have clinical implications in terms of individual differences in the resistance to antidepressant treatments and individual differences in drug abuse. [source] Pseudohyperaldosteronism, Liquorice, and HypertensionJOURNAL OF CLINICAL HYPERTENSION, Issue 2 2008Bruno Sontia PhD Consumption of large quantities of liquorice can cause hypokalemia and hypertension. These effects are associated with increased cortisol-mediated activation of renal mineralocorticoid receptors and hypoaldosteronism. The authors describe a patient with long-standing hypokalemia and uncontrolled hypertension related to excessive ingestion of liquorice. The case highlights the importance of obtaining a detailed dietary history, especially considering the increasing use of liquorice-containing foods, teas, and herbal products. The authors also discuss secondary causes of hypertension, focusing on pseudohyperaldosteronism. [source] Acute Activation of Hippocampal Glucocorticoid Receptors Results in Different Waves of Gene Expression Throughout TimeJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2006M. C. Morsink Abstract Several aspects of hippocampal cell function are influenced by adrenal-secreted glucocorticoids in a delayed, genomic fashion. Previously, we used Serial Analysis of Gene Expression to identify glucocorticoid receptor (GR)-induced transcriptional changes in the hippocampus at a fixed time point. However, because changes in mRNA levels are transient and most likely precede the effects on hippocampal cell function, the aim of the current study was to assess the transcriptional changes in a broader time window by generating a time curve of GR-mediated gene expression changes. Therefore, we used rat hippocampal slices obtained from adrenalectomised rats, substituted in vivo with low corticosterone pellets, predominantly occupying the hippocampal mineralocorticoid receptors. To activate GR, slices were treated in vitro with a high (100 nM) dose of corticosterone and gene expression was profiled 1, 3 and 5 h after GR-activation. Using Affymetrix GeneChips, a striking pattern with different waves of gene expression was observed, shifting from exclusively down-regulated genes 1 h after GR-activation to both up and down regulated genes 3 h after GR-activation. After 5 h, the response was almost back to baseline. Additionally, real-time quantitative polymerase chain reaction was used for validation of a selection of responsive genes including genes involved in neurotransmission and synaptic plasticity such as the corticotropin releasing hormone receptor 1, monoamine oxidase A, LIMK1 and calmodulin 2. This permitted confirmation of GR-responsiveness of 15 out of 18 selected genes. In conclusion, direct activation of GR in hippocampal slices results in transient changes in gene expression. The pattern in which gene expression was modulated suggests that the fast genomic effects of glucocorticoids may be realised via transrepression, preceding a later wave of transactivation. Furthermore, we identified a number of interesting candidate genes which may underlie the glucocorticoid-mediated effects on hippocampal cell function. [source] Central Regulation of the Hypothalamic-Pituitary-Adrenal Axis During Fetal Development in the Guinea-PigJOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2005D. Owen Abstract We have previously shown that the foetal guinea-pig hypothalamic-pituitary-adrenal (HPA) axis is activated near the time of parturition and that this is associated with changes in limbic glucocorticoid receptors (GR) and mineralocorticoid receptors. In the present study, we hypothesized that the foetal hypothalamic paraventricular nucleus (PVN) and pituitary contribute significantly to foetal HPA drive but that these areas remain sensitive to negative feedback by circulating glucocorticoids in late gestation. However, we observed decreased corticotrophin-releasing hormone mRNA expression in the PVN and decreased pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary with advanced gestational age. The reduction in POMC mRNA expression was likely the result of negative feedback via circulating glucocorticoids because GR mRNA was unchanged during development in the foetal pituitary. Furthermore, we found that maternally administered glucocorticoids significantly decreased foetal pituitary POMC mRNA expression in a dose-dependent manner at gestational day (gd) 62 with male foetuses being more sensitive to these effects. These findings show that the foetal HPA axis remains highly sensitive to glucocorticoid feedback even as plasma adrenocorticotropic hormone and cortisol levels are elevated at the end of gestation. [source] Corticosteroid Effects on Serotonin Responses in Granule Cells of the Rat Dentate GyrusJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2001Y. J. G. Karten Abstract Granule cells in the rat dentate gyrus contain mineralocorticoid and glucocorticoid receptors to which the adrenal hormone corticosterone binds with differential affinity. These cells also express various receptor-subtypes for serotonin (5-HT), including the 5-HT1A receptor which mediates a membrane hyperpolarization accompanied by a decrease in membrane resistance. Earlier studies have shown that removal of corticosterone by adrenalectomy, particularly in the dentate gyrus, results in enhanced expression of the 5-HT1A receptor mRNA and increased 5-HT1A receptor binding capacity. This was normalized by activation of mineralocorticoid receptors or concurrent activation of both receptor types. In the present, intracellular recording study in vitro, we examined if the altered levels of 5-HT1A receptor mRNA and protein are associated with changes in the response to 5-HT. We found that the hyperpolarization and resistance decrease induced in granule cells by a submaximal (10 µM) dose of 5-HT were unaltered 2,4 days after adrenalectomy, indicating a dissociation between corticosteroid actions on 5-HT1A receptor mRNA/protein levels and functional responses to 5-HT. Subsequent occupation of mineralocorticoid receptors in vitro significantly suppressed the 5-HT induced change in resistance, 1,4 h after steroid application. Compared to this, concurrent activation of glucocorticoid receptors led to large responses to 5-HT. This modulation by steroids was not observed with a higher dose of 5-HT (30 µM). The data suggest that with moderate amounts of 5-HT, corticosteroids affect the information flow through the dentate gyrus such that excitatory transmission is promoted with predominant mineralocorticoid receptor activation and attenuated with additional glucocorticoid receptor occupation. [source] Effect of Corticosteroid Treatment In Vitro on Adrenalectomy-Induced Impairment of Synaptic Transmission in the Rat Dentate GyrusJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2000Stienstra Removal of the rat adrenals results after 3 days in the appearance of apoptotic cells in the dentate gyrus. Apoptosis is accompanied by an impaired synaptic transmission in the dentate gyrus. Substitution in vivo with a low dose of corticosterone was found to prevent both the appearance of apoptotic cells and the functional impairment. In the present study we determined whether the functional normalisation after corticosterone treatment critically depends on prevention of apoptosis. To address this question, brain slices from rats showing apoptosis after adrenalectomy were treated in vitro with the mineralocorticoid aldosterone (3 nM) or with 30 nM corticosterone, which is assumed to activate both mineralo- and glucocorticoid receptors. Steroids were briefly applied either during recording (acute effects) or several hours before recording (long-term effects). While the slope of the fEPSP recorded in the outer molecular layer of the dentate gyrus in response to perforant path stimulation was not affected up to 1 h after acute administration of the steroids, fEPSP slopes recorded 2.5,3 h after corticosterone or aldosterone treatment were significantly increased, to the level of the sham-operated controls. The results indicate that delayed corticosteroid effects through in vitro activation of mineralocorticoid receptors (MRs) are sufficient to normalise synaptic transmission in the dentate gyrus of ADX rats, even in the presence of apoptotic cells. We tentatively conclude that the impaired synaptic transmission seen after ADX is probably not primarily caused by the appearance of apoptotic cells. [source] Therapeutic manipulation of glucocorticoid metabolism in cardiovascular diseaseBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009Patrick W.F. Hadoke The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11,-hydroxysteroid dehydrogenase. Selective inhibitors of 11,-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11,-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11,-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11,-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11,-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease. [source] Expanding view of aldosterone action, with an emphasis on rapid actionCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2010Gavin P. Vinson Summary 1. The actions of aldosterone beyond the ,mineralocorticoid' designation continue to attract intense interest. In recent years, two aspects have received particular attention. These are, first, the potentially damaging direct actions of aldosterone on the heart and vascular system, and the clear benefit, as illustrated by the Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival trials, of including antialdosterone therapy in the treatment of cardiovascular disease. 2. Second, the importance of non-genomic actions of aldosterone has become clear, some of which might possibly be mediated by distinct membrane receptors. Over the past 5 years, evidence has arisen to bring these two aspects together, and now emphasizes the role of rapid, nongenomic actions of aldosterone on cardiovascular events. 3. However, despite many years of study, there is still no clear view of the nature of the receptors mediating non-genomic responses. We examine the evidence, and suggest that in many cases non-genomic actions are attributable to classical mineralocorticoid receptors. [source] TRANSLATIONAL RESEARCH GOES BOTH WAYS: LESSONS FROM CLINICAL STUDIESCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008John W Funder SUMMARY 1It is currently assumed that translational research goes from benchtop to bedside; that aldosterone elevates blood pressure via its effects on salt and water homeostasis; that mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) share a common immediate ancestor; and that aldosterone plays a deleterious role in essential hypertension and heart failure. 2Meta-analysis of clinical trials in essential hypertension, in which eplerenone was dose-titrated to attain diastolic blood pressure < 90 mmHg, showed no relationship between blood pressure response and electrolyte effects, as judged by change in plasma (K). 3Reexamination of sequence data, and insights from the S810L MR mutant gene causing juvenile hypertension exacerbated by pregnancy, suggest that MR were the first to branch off the primordial ancestor for MR, GR, androgen receptors (AR) and progesterone receptors (PR). 4In clinical trials of MR blockade in heart failure and essential hypertension baseline aldosterone levels are in the low to normal range and sodium status unremarkable. Under such circumstances cortisol appears to be responsible for MR activation, thus exculpating aldosterone in these conditions. 5On the basis of these clinical studies, there is need to revisit the basic biology of aldosterone and MR as translational research very clearly goes both ways. [source] | |||||||||||||||||||||||||