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PubMed2005

Dexamethasone and prognostic factors in adults with bacterial meningitis.

OBJECTIVE: To determine the effect of dexamethasone on prognostic factors in adults with bacterial meningitis. DESIGN AND SETTING: A post hoc multivariate analysis of the European Dexamethasone Study. PATIENTS AND PARTICIPANTS: Dexamethasone-treated patients in the European Dexamethasone Study. As internal validation we performed an identical analysis on patients in the placebo group. MEASUREMENTS AND RESULTS: Only focal cerebral abnormalities on admission were predictive for unfavourable outcome in patients treated with early adjunctive dexamethasone (Odds ratio 3.22; 95% confidence interval 1.11-9.35; P=0.03). Other potential prognostic factors failed to achieve statistical significance. An analysis on patients in the placebo group showed prognostic factors comparable with those found in the literature without routine use of dexamethasone. CONCLUSIONS: Routine use of dexamethasone therapy may lead towards new risk stratification in adults with bacterial meningitis.

Adult↗

PubMed1998

Effect of 0.1% dexamethasone on epithelial healing in experimental corneal alkali wounds: morphological changes during the repair process.

BACKGROUND: The effect of 0.1% dexamethasone on epithelial healing was evaluated in corneal alkali wounds. METHODS: Epithelial wounds were induced by a 60-s application of a round filter paper (5.5 mm) soaked in 1 N NaOH onto the central cornea of the rabbit. Animals were treated with 0.1% dexamethasone 4 times each day for 8 weeks in one subgroup and only for the 1st week in the other subgroup. The control eyes were treated with a balanced salt solution. The repair processes of epithelium and its basement membrane were evaluated morphologically and morphometrically. RESULTS: Treatment with 0.1% dexamethasone was found to retard the repair process of epithelial healing compared with the control eyes. Morphologically, the basement membrane in the control cornea was damaged focally at 2 days, maximally disrupted at 4 weeks, and regained the normal integrity at 8 weeks after the initial alkali damage. In 0.1% dexamethasone-treated corneas, regardless of the application period, the basement membrane structure was visible up to 4 weeks but disappeared at 8 weeks after the initial alkali wounds. The eyes treated with 0.1% dexamethasone for 8 weeks showed an intense infiltration of inflammatory cells in the superficial stroma 4 weeks after treatment. CONCLUSION: A topical application of 0.1% dexamethasone retarded the corneal epithelial healing. The cornea treated with 0.1% dexamethasone only for the 1st week maintained a well-preserved basement membrane for as long as 4 weeks after initial damage without enhancement of the inflammatory cell infiltration. However, further study is needed to prevent late disintegration of the basement membrane.

Animals↗

PubMed1999

Lack of effectiveness of dexamethasone in neonatal bacterial meningitis.

UNLABELLED: A clinical trial was conducted to determine whether dexamethasone as adjunctive therapy alters the outcome of bacterial meningitis in neonates. Fifty-two full-term neonates with bacterial meningitis were enrolled in a prospective study. Infants were alternately assigned to receive either dexamethasone or not. Twenty-seven received dexamethasone in addition to standard antibiotic treatment and 25 received antibiotics alone. Dexamethasone therapy was started 10-15 min before the first dose of antibiotics in a dose of 0.15 mg/kg per 6 h for 4 days. Baseline characteristics, clinical and laboratory features in the two groups were virtually similar. Both groups showed a similar clinical response and similar frequency of mortality and sequelae. Six (22%) babies in the treatment group died compared to 7 (28%) in the control group (P = 0.87). At follow up examinations up to the age of 2 years, 6 (30%) of dexamethasone recipients and 7 (39%) of the control group had mild or moderate/severe neurological sequelae. Audiological sequelae were seen in two neonates in the dexamethasone group compared to one in the control group. CONCLUSION: Adjunctive dexamethasone therapy does not improve the outcome of neonatal bacterial meningitis.

Anti-Bacterial Agents↗

PubMed2000

A double-blind, randomised, parallel study comparing intravenous dolasetron plus dexamethasone and intravenous dolasetron alone for the management of fractionated cisplatin-related nausea and vomiting.

Fractionated cisplatin-containing regimens are routinely used for chemotherapy in certain types of cancer. Dolasetron has been shown to be effective in preventing acute emesis related to high-dose cisplatin chemotherapy over 24 h; its effectiveness has not been evaluated in fractionated cisplatin-containing chemotherapy. This trial was designed to assess the efficacy of dolasetron alone or dolasetron plus dexamethasone in preventing nausea and vomiting related to fractionated cisplatin chemotherapy. The patients were 210 cancer in-patients, who were randomised to receive 100 mg dolasetron i.v. or 100 mg dolasetron i.v. plus 20 mg dexamethasone before chemotherapy primarily with cisplatin (15-50 mg/m2) infused over < or =4 h for at least 2 but not more than 5 consecutive days. Dolasetron was administered to all patients 30 min before cisplatin. Dexamethasone was administered in double-blind fashion 5 min before cisplatin. Efficacy was measured at hour 24 of each study day using complete response (no vomiting and no rescue medication) and maximum severity of nausea, self-assessed by patients using a 100mm visual analogue scale. Most (198) of the patients completed the study and were evaluable. Overall complete response rates were significantly higher in the dolasetron plus dexamethasone group than in the dolasetron only group (72.9% vs. 40.8%, respectively; P<0.0001). Complete response rates on each study day were also significantly higher with dolasetron plus dexamethasone than with dolasetron alone (P<0.029), with an attenuated efficacy in the delayed phase in both groups. Chi-square test and logistic regression applied to daily response rates indicated a significant influence of treatment (day 1: P = 0.0002, day 2: P<0.0001, day 3: P = 0.0007, day 4: P = 0.0007, day 5: P = 0.029). Treatment and duration of chemotherapy exerted the only statistically significant subgroup effects on complete response (P<0.0001). Both treatments were administered safely. As seen with other 5-HT3 receptor antagonist antiemetics, the addition of dexamethasone to dolasetron significantly increases effectiveness in preventing nausea and vomiting related to fractionated cisplatin chemotherapy. Both dolasetron and dolasetron plus dexamethasone were well tolerated.

Adult↗

PubMed2007

Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1.

We previously reported that inhibition of both COX-1 and COX-2 is required for the gastrointestinal ulcerogenic properties of nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-1 up-regulates COX-2 expression, and the prostaglandins (PGs) produced by COX-2 help to maintain the mucosal integrity during inhibition of COX-1. In the present study we investigated whether dexamethasone damages rat gastrointestinal mucosa during inhibition of COX-1 and further developed the idea that COX-2 expression is a key event in the ulcerogenic actions of NSAIDs. Dexamethasone was given p.o. in the absence or presence of SC-560 (a selective COX-1 inhibitor), and the stomach or intestine was examined 8 or 24 hr later, respectively. Neither dexamethasone nor SC-560 alone damaged the gastrointestinal mucosa. In the presence of SC-560, however, dexamethasone damaged the stomach but not small intestine. SC-560 decreased PGE(2) levels in both tissues, with a gradual recovery accompanying the up-regulation of COX-2 expression, and both the recovery of PGE(2) levels and the expression of COX-2 were inhibited by dexamethasone. In the animals treated with SC-560, iNOS expression was up-regulated in the intestinal but not the gastric mucosa, and this response was also inhibited by dexamethasone. These results suggest a risk from steroid therapy in the stomach when COX-2 expression is up-regulated. Dexamethasone does not provoke damage in the intestine, despite inhibiting the up-regulation of COX-2 expression under conditions of PG deficiency; at least one of the reasons is that this agent prevents the expression of iNOS, a major factor in the pathogenesis of intestinal lesions.

Animals↗

PubMed2005

Changes in the glycolipid composition and characteristic activation of GM3 synthase in the thymus of mouse after administration of dexamethasone.

Glycolipids in the thymus of mice after administration of dexamethasone were compared with those in control mice. In parallel with a decrease in the tissue weight due to the disappearance of immature thymocytes in the cortex, the amounts of GlcCer, Gg4Cer and GM1 decreased from 18 h after intraperitoneal administration of dexamethasone, but those of Gb4Cer and Forssman glycolipid did not change, indicating the differential distribution of ganglio- and globo-series glycolipids in the thymus, GlcCer, Gg4Cer and GM1 being on dexamethasone-sensitive cortical thymocytes, and Gb4Cer and Forssman glycolipid on dexamethasone-resistant cells including thymic stromal cells, respectively. At the same time, a characteristic increase in GM3, whose amount per thymus and concentration per mg of thymus were increased 4-fold and 13-fold compared to those in the control mice, respectively, was observed at the onset of the decrease in tissue weight and was due to the increased activity of LacCer sialyltransferase with the enhanced expression of its gene and the concomitant decrease in cytosolic sialidase activity. One can suggest that endogenous accumulation of GM3 is involved in the dexamethasone-induced apoptosis of cortical thymocytes. On radiolabeling of the thymus with CMP-[14C]-NeuAc, the incorporation of radioactivity into GM3 was preferentially observed in the thymuses of dexamethasone-administered mice, but not in those of control mice, suggesting the possible involvement of plasma membrane-associated sialytransferase in GM3 synthesis in the thymuses of dexamethasone-administered mice.

Animals↗

PubMed2003

Effect of dexamethasone on growth inhibition and chondrogenic maturation of human chondrosarcoma.

The effect of dexamethasone, a synthetic glucocorticoid, on in vitro and in vivo growth and differentiation of the human chondrosarcoma cell line (OUMS-27) was studied. Cells were treated with various doses of dexamethasone, and increasing doses produced an inhibitory effect on OUMS-27 tumor cell proliferation and induced maturation. Cell counts for OUMS-27 on day 9 ranged from 59% of the control at 10(-8) M to 45% of the control at 10(-5) M dexamethasone. Northern blot analysis revealed that the type II collagen mRNA level in cells given dexamethasone was lower than that in the controls, and the type X collagen mRNA level was higher than that in the controls. Phase-contrast microscopy revealed that cells grown in control medium formed monolayers consisting of small, polygonal cells, whereas dexamethasone-treated cells became larger and more irregular in shape. In the in vivo study the growth rate of masses in nude mice induced by inoculating OUMS-27 cells was also reduced in a dose-dependent manner with dexamethasone administration. These results suggest that dexamethasone caused growth inhibition and induced chondrogenic maturation of human chondrosarcoma cells.

Animals↗

PubMed1982

Hypothalamic-pituitary-adrenocortical function during long-term low-dose dexamethasone therapy in hyperandrogenized women.

Hypothalamic-pituitary-adrenocortical (H-P-A) function was tested in 14 hyperandrogenized women, aged 17 to 32 years, who had been continuously treated with nightly single-dose oral dexamethasone, 0.25 to 1.00 mg, for 3.7 to 16.5 months. Daily AM serum cortisol concentrations were measured in nine subjects after discontinuation of dexamethasone. Basal cortisol concentrations returned to normal (greater than or equal to 6.0 micrograms/dl) within 36 hours in 67%, within 60 hours in 89%, and within 84 hours in 100%. Median time to return to normal was between 12 and 36 hours. Rate of return correlated with both the dose-adjusted duration of dexamethasone therapy (p less than 0.01) and the degree of adrenocortical suppression during treatment (p less than 0.01). The H-P-A response to insulin-induced hypoglycemia and the adrenal response to an acute intravenous adrenocorticotropic hormone (ACTH) challenge were evaluated in eight subjects 12 to 36 hours after the final dexamethasone dose. Thirty-eight percent demonstrated normal cortisol increments to hypoglycemia, 25% had blunted or absent cortisol responses to hypoglycemia but normal cortisol increments to exogenous ACTH, and 38% had blunted or absent responses to both hypoglycemia and exogenous ACTH. The responsiveness of the H-P-A axis correlated with the degree of adrenocortical suppression (p less than 0.05) but not with dose of dexamethasone or duration of treatment. Small doses of dexamethasone are not necessarily "physiologic", but dexamethasone therapy with maintenance of serum cortisol levels greater than or equal to 2.0 micrograms/dl was associated with rapid return to normal basal cortisol concentration and a normal cortisol response to insulin-induced hypoglycemia.

Adolescent↗

PubMed1984

Hormonal regulation of key gluconeogenic enzymes and glucose release in cultured hepatocytes: effects of dexamethasone and gastrointestinal hormones on glucagon action.

Hormonal regulation of key gluconeogenic enzymes and glucose release by glucagon, dexamethasone, secretin and somatostatin was evaluated in maintenance cultured rat hepatocytes. (i) Phosphoenolpyruvate (PEP)-carboxykinase activity declined rapidly during the first 24 h in serum- and hormone-free culture with a further slight decay during the following 2 days. Dexamethasone and glucagon independently increased PEP-carboxykinase and acted synergistically when added in combination. Glucose-6-phosphatase activity declining linearly during hormone-free culture was stimulated by glucagon. Dexamethasone itself was without significant effects but completely abolished glucagon action. Fructose-1,6-diphosphatase was maintained at its initial level during the first day under control conditions and declined thereafter. Neither glucagon nor dexamethasone affected total activity or substrate (fructose-1,6-diphosphate) affinity of this enzyme. In short-term experiments on cells cultured under control conditions, protein synthesis-dependent stimulation of PEP-carboxykinase by glucagon and the permissive action of dexamethasone was demonstrated. Glucose-6-phosphatase and fructose-1,6-diphosphatase were not altered by hormones within this period. (ii) Stimulation by glucagon of gluconeogenesis was independent of its action on PEP-carboxykinase. Dexamethasone inhibited glycogenolysis but maintained glucose release at control levels probably by stimulation of gluconeogenesis. When added in combination, the glycogen-preserving action of dexamethasone acutely reduced the glucose release in response to glucagon. Glucagon sensitivity remained unchanged. (iii) The gastrointestinal hormones secretin and somatostatin were ineffective in modulating basal or glucagon-stimulated glucose release and gluconeogenic key enzymes. They are therefore unlikely to play a physiological role in hepatic glucose metabolism.

Animals↗

PubMed1992

Dexamethasone up-regulates mannose receptor activity by increasing mRNA levels.

The macrophage mannose receptor is highly susceptible to modulation by a variety of inflammatory and anti-inflammatory agents. Previous studies have demonstrated that mannose receptor activity is dramatically enhanced in rat bone marrow macrophages following treatment with dexamethasone. In the present study we have investigated potential mechanisms that might be involved in this up-regulation. Uptake of ligands by the mannose receptor was increased 2.5-fold in a dose- and time-dependent manner. Maximal stimulation was seen following treatment of macrophages with 0.1-1.0 microgram/ml of dexamethasone for 24-48 h. Dexamethasone treatment increased both the number of cell surface binding sites and total cellular binding activity to 250% of control levels. In addition, total receptor protein as measured by immunoprecipitation was increased 2.5-fold. Neither the maturation rate nor the turnover rate of the protein was altered by dexamethasone treatment. Using an oligonucleotide probe derived from sequence data from the cloned human receptor cDNA, we investigated the effect of dexamethasone on the expression of mannose receptor mRNA. Following incubation with dexamethasone for 12-24 h, the level of mRNA was significantly increased. These results demonstrate that dexamethasone treatment of rat bone marrow macrophages induces synthesis of new receptor protein through an increase in the level of mannose receptor mRNA.

Animals↗

PubMed1988

Altered plasma dexamethasone and cortisol suppressibility in patients with panic disorders.

Some abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis in patients with panic disorders were recently reported. The possibility that the disposition of dexamethasone, which has been reported to influence the Dexamethasone Suppression Test (DST), might be altered in this subgroup of patients has not, as yet, been reported. We report that 4:00 PM dexamethasone plasma concentrations following a 1-mg oral DST were significantly (p less than 0.01) lower in 23 patients with panic disorders (0.49 +/- 0.44 ng/ml) compared to 52 normal control subjects (1.09 +/- 0.64 ng/ml). This is in addition to the significantly higher (p less than 0.05) 4:00 PM postdexamethasone cortisol values per nanogram per milliliter of dexamethasone in the panic disorder patients compared to normal controls (17.7 +/- 29.6 versus 5.0 +/- 11.2 micrograms/dl). The mean percent suppression of cortisol from baseline in panic disorder was normal despite one-half the dexamethasone concentrations in these subjects. The cortisol suppression versus dexamethasone concentration curve was also shifted lower (greater fraction of cortisol suppression) and to the left (toward lower dexamethasone concentrations). These results further suggest that the HPA system is indeed altered in panic disorders, but in a manner that is not readily apparent from the DST alone.

Adult↗

PubMed1990

Prediction of the DST results in depressives by means of urinary-free cortisol excretion, dexamethasone levels, and age.

This study investigates the relationships between cortisol escape from suppression by dexamethasone during a depressive episode, and the baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, circulating dexamethasone levels, and age. To this end, we measured urinary-free cortisol (UFC) excretion in 24-hr urine samples and the 8 AM cortisol and dexamethasone levels after administration of 1 mg dexamethasone in 50 depressive patients. We found that up to 54% of the variance in the postdexamethasone cortisol values could be explained by the multiple regression on UFC, age, and dexamethasone levels. By utilizing these three parameters, the dexamethasone suppression test (DST) nonsuppressor/suppressor state was correctly identified in 92% of the subjects. It was shown that an important part of the variance in postdexamethasone cortisol is actually background variance, irrelevant to depression and produced by the cumulative effects of the three aforementioned parameters. Only a small part (less than 20%) of the variance in postdexamethasone cortisol is determined by the actual depressive state. It was concluded that (1) baseline hypersecretion of cortisol, (2) decrements in the bioavailability of the test substance, (3) increasing age, and (4) the depressive state per se--all of which are cumulative--contribute independently to cortisol escape from suppression by 1 mg dexamethasone.

Adult↗

PubMed1992

Dexamethasone ameliorates retinal photic injury in albino rats.

The effect of dexamethasone in two regimens on retinal photic injury was studied in Lewis albino rats that were exposed to 24 hr of continuous green fluorescent light. Under regimen 1, dexamethasone was given at a daily dosage of 1 mg kg-1 for 8 days, starting 6 days before light exposure. Under regimen 2, dexamethasone was given at the same daily dosage for 3 days, started 1 day before light exposure. Pathologic study of the light-exposed retina, morphometric evaluation of the photoreceptor cell loss, cell counts of the macrophages in the subretinal space, and measurements of rhodopsin levels were undertaken in the dexamethasone-treated and control retinas at various times. The administration of dexamethasone in both regimens did not produce pathologic changes in the retina before light exposure, but rhodopsin levels were significantly lowered in both treated groups when compared to corresponding vehicle treated control animals. Under regimen 1, at 6 hr after light exposure, both the treated and the control groups showed comparable loss of photoreceptor cells, degeneration of the photoreceptor elements and retinal pigment epithelium, but a significantly lowered level of rhodopsin in the treated group was noted. At 6 days after exposure, the outer nuclear layer thickness, and the outer and inner segments showed significant preservation in the treated group. Also in the treated group, the number of macrophages was significantly reduced and the retinal pigment epithelial (RPE) vacuolation was markedly less. However, there was no difference in rhodopsin levels. At 14 days after exposure, the outer nuclear layer thickness and rhodopsin levels of the treated rats had significantly higher values than the controls. Under regimen 2, however, at 6 days after exposure, an ameliorative effect in the RPE was observed but there were no differences of rhodopsin levels, the outer nuclear thickness and number of macrophages between the treated and control groups. Regimen 1 was associated with a significantly higher retinal level of dexamethasone when compared with regimen 2. The ameliorative effect of dexamethasone on rat retinal photic injury may be through inhibition of lipid peroxidation, in which a high retinal level of the steroid is required.

Animals↗

PubMed1993

The growth-supportive effect of thrombospondin (TSP1) and the expression of TSP1 by human MG-63 osteoblastic cells are both inhibited by dexamethasone.

Thrombospondin (TSP) is a 450-kDa extracellular matrix glycoprotein which supports the growth of human MG-63 osteoblastic cells [Abbadia et al., FEBS Lett., 329 (1993) 341-346]. In this study, we describe the effect of the glucocorticoid, dexamethasone, on cell proliferation and TSP expression by MG-63 cells. Using a serum-free mitogenesis assay, dexamethasone (25 to 500 nM) caused a dose-dependent decrease in [3H]thymidine incorporation by MG-63 cells in culture, reaching 40% inhibition of cell proliferation at a concentration of 250 nM. Similarly, the stimulatory effect of TSP (500 ng/ml) on proliferation of MG-63 cells was totally abolished in the presence of dexamethasone (250 nM). In situ hybridization indicated that TSP mRNA level in dexamethasone-treated MG-63 cells decreased compared to quiescent cells. As judged by fluorescence-activated cell sorting analysis, dexamethasone treatment of MG-63 cells resulted in a 50 to 70% decrease in TSP cell surface expression compared to quiescent cells. Secretion of TSP in the culture fluid of dexamethasone-treated MG-63 cells also decreased by 40% while, under similar experimental conditions, a 180% increase in alkaline phosphatase activity was observed in dexamethasone-treated cells. Because glucocorticoids induce osteoporosis in vivo and reduce proliferation of osteoblasts in vitro, our results argue for an important role of TSP during bone formation.

Alkaline Phosphatase↗

PubMed1987

Effect of dexamethasone and ACTH on oocyte growth and recruitment in the frog Rana cyanophlyctis during the prebreeding vitellogenic phase.

The effects of 5, 25, 50 and 75 micrograms of dexamethasone and 0.1 or 0.5 IU ACTH on oocyte growth and recruitment were studied in Rana cyanophlyctis during prebreeding vitellogenic phase (May). Injections (ip) were given 6 days a week for 31 days and frogs were killed on the 32nd day. Treatment with 5 micrograms dexamethasone had no effect on gonadosomatic index (GSI) or on the number and percentage of different oocytes. Administration of 25 micrograms dexamethasone caused a significant (P less than 0.05) increase in both number and percentage of medium second growth phase (MSGP) oocytes and atretic follicles (AF), and a numerical reduction in number and percentage of large second growth phase (LSGP) oocytes. Frogs which received 50 or 75 micrograms dexamethasone exhibited a significant (P less than 0.05) decrease in GSI, ovarian weight, and number and percentage of LSGP oocytes, while those of MSGP oocytes and AF increased. There was no effect of dexamethasone on first growth phase (FGP) oocytes. The administration of 0.1 IU ACTH had no effect on GSI, percentage of different oocytes, or MSGP and LSGP number. There was a numerical increase in number of FGP oocytes. Treatment with 0.5 IU ACTH caused a significant (P less than 0.05) decrease in GSI, ovary weight, and number and percentage of LSGP oocytes, while those of AF increased. The above findings suggest that lower doses of dexamethasone (5 or 25 micrograms) and of ACTH (0.1 IU) have no effect on oocyte recruitment and growth, but that higher doses (50 or 75 micrograms dexamethasone and 0.5 IU ACTH) impair vitellogenic growth of oocytes and increase follicular atresia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1985

A correlative study of the binding of dexamethasone in hypothalamic blocks in vitro with its ability to inhibit the release of bioactive corticotrophin-releasing factor.

Rat hypothalamic blocks incubated in vitro were used to study the characteristics of binding of [3H]dexamethasone and other steroids to cytosolic binding sites. Cytosols prepared following incubation of the tissue with [3H]dexamethasone for 2 h contained specifically bound steroid in amounts that depended upon the concentration of potassium (but not sodium) ions in the extracting buffer. There was an increase in bound [3H]dexamethasone extracted as the potassium ion concentration increased up to 0.1 M, but not beyond. Dexamethasone, when added to hypothalami in vitro caused a biphasic inhibition of bioactive corticotrophin-releasing factor (CRF) release, and the extent of the second phase of inhibition was dose-related. 11-Epicortisol, when added in a 100-fold molar excess over dexamethasone was able to prevent the second phase of inhibition caused by the latter steroid, as in the binding studies it was able to cause a 50% reduction in the binding of [3H]dexamethasone. In the functional studies it was shown that 11-epicortisol was able to "rescue" the tissue from dexamethasone-mediated delayed inhibition of CRF secretion if added to the blocks 30 min (but not later) after the agonistic steroid.

Animals↗

PubMed1986

The effect of dithiothreitol on the kinetics of dissociation of dexamethasone from the non-transformed mammary cytosolic glucocorticoid receptor.

Sulfhydryl reducing agents such as dithiothreitol are required for maximum binding of dexamethasone to the mammary cytosolic glucocorticoid receptor, but little is known concerning the effects of dithiothreitol on the kinetics of the binding reaction. In this report we have examined the influence of dithiothreitol on the dissociation kinetics of dexamethasone from the non-transformed glucocorticoid-receptor complex at 0-4 degrees C under various experimental conditions. Without dithiothreitol, the rate of dissociation of dexamethasone remains essentially the same (t1/2 approximately 17 h) regardless of the method chosen to monitor dissociation. With dithiothreitol, however, there is a marked acceleration in the rate of dissociation of receptor-bound dexamethasone when an excess of unlabeled dexamethasone is used to study dissociation (t1/2 approximately 5 h) but not when dissociation is investigated by removal of free labeled dexamethasone by charcoal adsorption (t1/2 approximately 21 h); dithiothreitol also accelerates the observed rate of dissociation when a combination of these methods is used. An acceleration in the rate of receptor-bound dexamethasone is also observed when an excess of the synthetic progestin, R5020, is used in the dissociation assay. The possible reasons and importance underlying these findings have been discussed.

Animals↗

PubMed1987

The mechanism of [3H]dexamethasone uptake into prolactin producing rat pituitary cells (GH3 cells) in culture.

Glucocorticosteroids stimulate growth hormone (GH) synthesis and inhibit prolactin (PRL) synthesis and cell growth in cultured GH3 cells, a clonal cell strain derived from a rat pituitary tumour. This model system was used to study the mechanism by which glucocorticosteroids enter target cells. The cellular uptake of [3H]dexamethasone was temperature dependent and was further inhibited by addition of an excess amount of cold dexamethasone. Half maximal uptake was obtained after about 5 min at 37 degrees C. The initial rates of [3H]dexamethasone uptake were a linear function of the extracellular hormone concentration. The uptake of [3H]dexamethasone in intact cells studied at different temperatures resulted in linear Arrhenius plots, with a calculated energy of activation of 91.0 kJ x mole-1 x degree-1. Scatchard analysis of specifically cell bound [3H]dexamethasone at equilibrium (0 degrees C) showed a straight line with a calculated dissociation constant (Kd) of 1.6 x 10(-9) M and a maximal uptake of 180 x 10(-15) mole/mg cell protein. Specific binding of [3H]dexamethasone to cytosol proteins could only be demonstrated at 0 degrees C. These results indicate that [3H]dexamethasone diffuses passively into the cell, and binds to specific receptors in an energy dependent way.

Animals↗