The role of endogenous steroid hormones in the generation of T helper 2-mediated autoimmunity in mercuric chloride-treated Brown-Norway rats.
(41/1561)
Injection of Brown-Norway rats with mercuric chloride (HgCl2) activates a T helper type 2 (Th2) autoimmune response, with production of a number of autoantibodies and vasculitis primarily affecting the gut. Glucocorticoids have been shown to suppress Th1 and to promote the development of Th2-type responses. Conversely dehydroepiandrosterone (DHEA) promotes Th1 responses with suppression of Th2 responses. This study set out to define the role of these hormones in this animal model. Rats were adrenalectomized (Adx) with no steroid replacement (n = 11), Adx with basal steroid replacement given by a 25 mg corticosterone pellet inserted subcutaneously (n = 13), or sham-Adx (n = 14) prior to administration of HgCl2. In both groups of Adx animals there was a delay in the production of immunoglobulin E (IgE) and serum concentrations on day 9 were marginally lower (P = 0.035, repeated measures ANOVA). All of the animals Adx with no steroid replacement and two Adx animals with steroid replacement died between 10 and 14 days after HgCl2 challenge. There was no difference in the severity of caecal vasculitis between the groups. A significant increase in adrenal size was noted following administration of HgCl2. Administration of subcutaneous DHEA implants (100 mg and 200 mg) had no significant effect on IgE concentrations or severity of vasculitis. These observations do not support the hypothesis that corticosterone and DHEA play a central role in setting the Th1/Th2 balance in this experimental Th2-mediated autoimmune disease; in contrast with the Th1-mediated autoimmune disease experimental allergic encephalomyelitis where corticosterone plays a key role in immunoregulation. (+info)
Water-retention effect of suberogorgin was due to secretion of antidiuretic hormone in rat.
(42/1561)
AIM: To study the mechanism of antidiuretic effect of suberogorgin (Sub). METHODS: Conscious rat was given i.g. Sub 3.16 mg.kg-1 20 min after water-loaded treatment and then urine was collected in metabolic cage. Ion excretion was determined in atomic emission spectrometry. Urinary prostaglandin E (PGE), plasma PGE, antidiuretic hormone (ADH), and aldosterone were measured with RIA. Sub vs pituitrin or DOCA effects were carried out in hypophysectomized or adrenalectomized rats. RESULTS: The urine volume and the excretions of urinary sodium and potassium were decreased, maximally by 91%, 76%, and 86%, during the 24-h period after Sub. This antidiuretic effect possessed a progressive weakening with time. The concentrations of urinary PGE, plasma PGE, and ADH were increased by 25%, 212%, and 538%, respectively, but plasma aldosterone was not significantly influenced, 2 h after Sub dosing. The response of urine-excretion of rat to Sub was almost resisted by hypophysectomy but not by adrenalectomy. CONCLUSION: Sub decreased the urine excretion by, at least in part, accelerating the secretion of ADH but neither by PGE nor by aldosterone. (+info)
Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney.
(43/1561)
Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role. (+info)
Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis.
(44/1561)
OBJECTIVE: To explore the regulation of macrophage migration inhibitory factor (MIF) by endogenous glucocorticoids in adjuvant-induced arthritis (AIA). METHODS: Adrenalectomy or sham operation was performed 2 days prior to adjuvant arthritis induction. Synovial explant supernatant levels of MIF and tumor necrosis factor alpha (TNFalpha) were measured by enzyme-linked immunosorbent assay (ELISA). Synovial MIF immunostaining was detected by 3-layer immunohistochemistry. Serum MIF levels were measured by Western blotting. Pituitary MIF release was measured by ELISA. Anti-MIF monoclonal antibody (mAb) or isotype-matched control antibody was administered to adrenalectomized (ADX) animals throughout AIA development. RESULTS: Compared with sham operation, adrenalectomy was associated with significant exacerbation of clinical disease parameters (P < 0.05). Adrenalectomy was associated with significantly reduced levels of synovial MIF, but not TNFalpha. In contrast, adrenalectomy was associated with increased serum MIF levels. Concomitant increased pituitary MIF levels were observed in ADX rats, consistent with the pituitary being the principal source of this increase. The administration of specific anti-MIF mAb conferred 100% protection from lethality during arthritis development and decreased arthritis disease expression. CONCLUSION: These findings provide the first in vivo confirmation of the observation that endogenous glucocorticoids are involved in the regulation of MIF in a site of inflammation, and that local and systemic MIF production are differentially regulated in this setting. The reversal of disease in ADX rats by anti-MIF mAb suggests that balance between glucocorticoids and MIF may influence the expression of inflammatory disease. (+info)
The surgical approach to the adrenal gland: a comparison of the retroperitoneal and the transabdominal routes in 326 operations on 284 patients.
(45/1561)
BACKGROUND: To compare the results of adrenalectomy using a retroperitoneal and a transabdominal approach, especially for adrenal carcinoma and pheochromocytoma. METHODS: A retrospective study was carried out at the Leiden University Medical Center. Charts of 284 patients who had undergone 326 adrenal operations between 1947 and 1995, including 44 patients with adrenal cancer and 60 patients with pheochromocytoma, were reviewed. The main outcome measures were operation time, blood loss, hospital stay and intra- and post-operative complications. RESULTS: In patients who underwent adrenalectomy (ADX) using a retroperitoneal (RP) approach, duration of operation, intra-operative blood loss, hospital stay and post-operative morbidity compared favourably with those undergoing a transabdominal approach (TA-ADX). However, most of these differences could be explained by the more frequently benign nature and smaller size of the lesions in patients undergoing RP-ADX. However, blood loss remained lower after correction for confounding in all patients undergoing RP-ADX. In patients with larger adrenal lesions, adrenal cancer and pheochromocytoma, that would nowadays be held unsuitable for laparoscopic adrenalectomy, RP-ADX was associated with shorter operation time, less blood loss and less intra-operative complications. CONCLUSION: Although laparoscopic adrenalectomy is the treatment of choice for small and benign adrenal lesions, larger lesions and/or adrenal malignancy require open adrenalectomy. In these cases the retroperitoneal approach is the preferred route. (+info)
Role of citrate synthase in aldosterone-mediated sodium reabsorption.
(46/1561)
Aldosterone and other mineralocorticoids increase citrate synthase activity in the kidney and enhance renal sodium reabsorption, but it is unclear whether the increased citrate synthase activity is involved in renal sodium transport. We used the Wistar-Furth rat, an inbred strain found to be deficient in renal citrate synthase activity, as an experimental model to investigate this issue. We confirmed that renal citrate synthase activity from adrenalectomized Wistar-Furth rats was decreased compared with that from control Wistar rats (by 28%). Similarly, urinary citrate excretion was 23% lower in Wistar-Furth rats. Subnormal citrate formation in Wistar-Furth rats could not be accounted for by differences in systemic pH or circulating potassium levels. Because renal citrate synthase activity was reduced in Wistar-Furth rats, we hypothesized that renal sodium excretory responses to mineralocorticoids would be reduced as well. Four-hour sodium excretion after intraperitoneal injection of 5 microg of aldosterone was reduced by 56% in adrenalectomized Wistar rats and by 52% in adrenalectomized Wistar-Furth rats (both P<0.01 compared with vehicle injection). Similarly, the pattern of urinary sodium excretion in response to subcutaneous injections of deoxycorticosterone acetate over a 2-week period was similar in adrenalectomized Wistar and Wistar-Furth rats. In summary, acute and chronic antinatriuretic responses to mineralocorticoids are maintained in Wistar-Furth rats at the level of Wistar rats, despite the marked reduction in citrate synthase activity. These findings are not consistent with an important role for citrate synthase activity in mineralocorticoid-mediated renal sodium transport. (+info)
Plasma membrane calcium pump isoform 1 gene expression is repressed by corticosterone and stress in rat hippocampus.
(47/1561)
Glucocorticoids (GCs) are critical to learning and memory, in large part because of their actions in the hippocampus. Chronic high levels of GCs have profound effects on hippocampal structure and function and can even result in irreversible neurodegeneration. Hippocampal GC actions are mediated by intracellular receptors that modulate the transcription of specific target genes. In a screen for genes repressed by GCs in rat hippocampus, we identified plasma membrane calcium pump isoform 1 (PMCA1), a plasma membrane calcium ATPase. In Northern blots, PMCA1 was repressed approximately 33% after a high, but not a low dose of the GC, corticosterone (B), suggesting glucocorticoid (but not mineralocorticoid) receptor-mediated repression. Furthermore, in situ hybridization demonstrated that B significantly downregulated PMCA1 mRNA in all brain regions examined. Repression of PMCA1 was also observed in cultured hippocampal neurons, but only when the cells were in the differentiated state. Stress also repressed PMCA1 expression in hippocampus of adrenal-intact animals, and a clear inverse correlation between B level and PMCA1 mRNA could be discerned. However, other non-B-dependent factors appeared to be involved in the response of PMCA1 to stress because, unlike exogenous B, cold stress did not repress PMCA1 in brain regions other than hippocampus. Moreover, in the presence of constant B (B-replaced, adrenalectomized animals), cold stress led to increased hippocampal PMCA1 expression. These observations suggest that repression of PMCA1 represents one molecular mechanism by which corticosteroids regulate Ca(2+) homeostasis and hence influence neuronal activity. Moreover, other stress-related neurohumoral factors appear to counter the repressive effects of B. Defects in the balance between GC-mediated and non-GC-mediated effects on PMCA1 expression may have adverse effects on neuronal function and ultimately result in irreversible neuronal damage. (+info)
Effect of adrenalectomy and exposure to corticosterone on alcohol intake in alcohol-preferring and alcohol-avoiding rat lines.
(48/1561)
The daily fluid intake of male rats of the alcohol-preferring (AA) and alcohol-avoiding (ANA) lines with simultaneous access to 10% (v/v) ethanol and water was determined during a baseline period (2 weeks), following adrenalectomy (1 week), and for 2 weeks following corticosterone treatment. The results showed that adrenalectomized AA rats decreased their ethanol intake compared to the sham-operated AA controls and that treatment with corticosterone restored the intake of ethanol to that observed during the baseline period. In contrast to the AA rats, there were no alterations in ethanol intake after adrenalectomy and following corticosterone replacement in the ANA rats. These results suggest that corticosterone stimulates ethanol intake in animals with pronounced high preference for ethanol. (+info)