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PubMed2003

Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis.

AIM: Hemorrhagic cystitis (HC) is a limiting side-effect of chemotherapy with ifosfamide (IFS). In the study presented here, we investigated the use of dexamethasone in combination with mesna for the prevention of IFS-induced HC. METHODS: Male Wistar rats (150-200 g; 6 rats per group) were treated with saline or mesna 5 min (i.p.) before and 2 and 6 h after (v.o.) administration of IFS. One, two or three doses of mesna were replaced with dexamethasone alone or with dexamethasone plus mesna. Cystitis was evaluated 24 h after its induction by the changes in bladder wet weight and by macroscopic and microscopic analysis. RESULTS: The replacement of the last dose or the last two doses of mesna with dexamethasone reduced the increase in bladder wet weight induced by IFS by 84.79% and 89.13%, respectively. In addition, it almost abolished the macroscopic and microscopic alterations induced by IFS. Moreover, the addition of dexamethasone to the last two doses of mesna was more efficient than three doses of mesna alone when evaluated microscopically. CONCLUSION: Dexamethasone in combination with mesna was efficient in blocking IFS-induced HC. However, the replacement of last two doses of mesna with saline or all of the mesna doses with dexamethasone did not prevent HC.

Animals↗
PubMed1998

Administration of dexamethasone induces proteinuria of glomerular origin in mice.

The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

The effects of dexamethasone on nucleic acid synthesis and cell numbers in rat fetuses.

Pregnant rats were treated with dexamethasone in drinking water (10 micrograms/ml) from the 15th to the 22nd day of pregnancy. Dexamethasone significantly depressed cell numbers in fetal rat adrenal glands, liver, lung, testes and pituitary from the 17th to the 22nd day of pregnancy. These data indicated that dexamethasone retarded cell multiplication in rat fetuses. Weight per cell and protein per cell were less in fetal adrenal glands, kidneys and pituitary after treatment with dexamethasone. Dexamethasone had no effect on RNA per cell in various fetal tissues. The nucleic acid synthesis in vitro from 3H-thymidine and 3H-uridine were reduced in all observed fetal tissues after dexamethasone treatment on the 22nd day of pregnancy. These results show that dexamethasone has a multisystemic effect on fetal rat development, depressing nucleic acid synthesis and depleting cell numbers and cell size in various fetal tissues.

Animals↗
PubMed2003

Perioperative dexamethasone treatment in childhood craniopharyngioma--influence on short-term and long-term weight gain.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Adolescent↗
PubMed2004

[Possibilities of the prophylaxis of arterial restenoses with dexamethasone -- an in-vitro study of human aortic smooth muscle cells].

PURPOSE: To evaluate the effect of dexamethasone on the growth of cultured human aortic smooth muscle cells in an in-vitro model depending on the dose applied. MATERIALS AND METHODS: Commercially available human aortic smooth muscle cells (haSMC) were incubated with different doses of dexamethasone (10(-6), 10(-8), 10(-10) mol/l). For 20 days, the dose-depending effects of dexamethasone on cell growth were studied by analyzing cell proliferation, clonogenic activity as well as cell cycle distribution. In addition, the migratory ability of haSMC was evaluated using a two compartment in-vitro model. RESULTS: Cell growth was reduced in a dose dependent manner. An applied dose of 10(-6) M dexamethasone effectively inhibited cell growth for the follow-up period of 20 days. Cell cycle analysis revealed a G1-phase block which was dose dependent and significant for a dose of 10(-6) M. Also a reduction of haSMC clonogenic activity could be found in the colony formation assays. Finally, dexamethasone reduced the migratory ability of the treated cells significantly for doses of 10(-6) and 10(-8) M. CONCLUSION: Depending on the dose applied, incubation with dexamethasone results in a significant growth reduction of cultured haSMC, which may be due to a drug induced G1-phase block. Dexamethasone also reduces the clonogenic activity as well as the migratory ability of cultured haSMC.

Angioplasty, Balloon↗
PubMed2006

An update on the overnight dexamethasone suppression test for the diagnosis of Cushing's syndrome: limitations in patients with mild and/or episodic hypercortisolism.

The overnight one-mg dexamethasone suppression test has been used for many years to screen for Cushing's syndrome. This test has usually been evaluated in controls versus patients with severe hypercortisolism. Under these conditions, the overnight dexamethasone suppression test has been reported to have high sensitivity and specificity. The objective of this study was to determine the sensitivity of the one mg overnight dexamethasone suppression test in patients with mild and/or periodic Cushing's syndrome. Therefore, an overnight dexamethasone suppression test was performed in 17 consecutive patients presenting to an endocrinology clinic with signs and symptoms of hypercortisolemia who were later proven to have Cushing's syndrome. The majority of patients were found to have both mild and periodic hypercortisolism. One mg of dexamethasone was given at midnight and a plasma cortisol was measured by radioimmunoassay at 08:00 the following morning. Using a cut-off for a morning cortisol following overnight dexamethasone of > 5 microg/dL, only three of 17 patients failed to suppress to a value less than this cut-off (sensitivity 18 %). A cut-off of > 2 microg/dL gave similar sensitivity. Even with a stringent cut-off point of > 1.8 microg/dL, only seven of 17 patients failed to suppress to a value less than this cut-off point (sensitivity of 41 %). These results demonstrate that the great majority of patients with mild and/or periodic Cushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/or periodic Cushing's syndrome are the patients in whom the identification of hypercortisolism is difficult, our results from this relatively small study suggest that this test should no longer be used to exclude these patients from further workup for Cushing's syndrome.

Adolescent↗
PubMed1983

The effect of dexamethasone on cerebrospinal fluid monoamine metabolites and cortisol in psychiatric patients.

The effect of 1 mg dexamethasone on CSF levels of 5-hydroxyindoleacetic acid (5 HIAA), homovanillic acid (HVA) and cortisol (CS) was investigated in 100 psychiatric inpatients: 45 subjects had their lumbar punctures 1-4 days following dexamethasone administration, and the results were compared with those from 55 other patients investigated before drug ingestion. All patients were women, and none had received psychotropic medication for at least two weeks before the study. Seven subjects consented to two LPs both before and after dexamethasone. As expected, cortisol in the CSF significantly decreased after dexamethasone: the decrease was greatest 10 hours following the drug. HVA showed a weak and transient elevation after 10 hours only. CSF 5 HIAA was found to be significantly increased in postdexamethasone samples and high levels were still found even after 82 hours. Diagnostic differences (major or minor depression, schizophrenia, alcohol abuse or dependence) did not account for the observed differences. Repeated CSF examinations in seven subjects corroborated these findings: all cortisol values were decreased and all 5 HIAA values were increased after dexamethasone while HVA values showed random changes. The data may suggest that serotonergic mechanisms may be involved in dexamethasone action in the CNS. In addition, dexamethasone administration can alter CSF 5 HIAA level, a possible factor which should be taken into consideration in CSF studies.

Adult↗
PubMed1983

The placenta as a glucocorticoid target tissue: exchange assay of (3H)-dexamethasone binding and effect of steroids on receptor content.

Binding of (3H)-dexamethasone was studied in high speed supernatant (HSS) of basal zone trophoblast and labyrinthine zone of rat placenta using an exchange assay. The system showed the following characteristics: (1) maximum binding was attained after 120 min of incubation; (2) molybdate was required in the medium to measure binding sites at 20 degrees C and equilibrium conditions; (3) exchange was near 90-100% between ligand and corticosterone added during a preincubation; (4) low capacity (190-250 fmoles/mg protein), high affinity (Kd 10(-8) M) binders were determined by saturation analysis; (5) competition with other steroids in vitro revealed that in basal zone trophoblast, only dexamethasone displaced the ligand, whereas in labyrinthine zone corticosterone, progesterone and testosterone competed to a smaller degree than dexamethasone. We have also studied the effect of in vivo treatment of pregnant rats for four days with dexamethasone, corticosterone, estradiol, progesterone or testosterone, on (3H)-dexamethasone binding. Of all tested compounds, only dexamethasone treatment (which was suspended 24 h before the experiment to prevent receptor occupancy by exogenous hormone) significantly decreased binding of the tritiated hormone in HSS of labyrinthine zone and basal zone trophoblast. These results suggest that dexamethasone regulates its own receptor in placenta. The physiological aspect of this phenomenon requires elucidation of the role of glucocorticoids on placental function in the rat.

Animals↗
PubMed1993

Hypertrophic cardiomyopathy associated with dexamethasone therapy for chronic lung disease in preterm infants.

To assess whether long-term dexamethasone therapy for chronic lung disease (CLD) in infancy is associated with any deleterious cardiac structural effects, we conducted a retrospective review of all preterm infants with CLD born between October 1, 1989, and October 1, 1990, who had serial echocardiographic data available. These infants were divided into three groups based on the length of their exposure to dexamethasone. Group 1 contained nine infants with CLD who did not receive dexamethasone. Group 2 was comprised of six infants who received dexamethasone for less than 8 days. Group 3 contained one infant who received a 26-day course, and 13 infants who received at least one 42-day course of dexamethasone for CLD. Left ventricular hypertrophy was noted in 8 of 14 (57%) infants in group 3; hypertrophy usually was noted near the end of the treatment course. Five of these eight affected infants died; the hypertrophic cardiomyopathy was considered to have contributed to mortality in three of these five infants. Regression of the hypertrophy was noted in the three surviving infants in group 3 after the dexamethasone course was completed. We speculate that prolonged dexamethasone treatment for CLD is associated with hypertrophic cardiomyopathy in a significant portion of preterm infants.

Cardiomyopathy, Hypertrophic↗
PubMed1996

Effects of prednisolone and dexamethasone in children with alkali burns of the oesophagus.

We compared the efficacies of prednisolone and dexamethasone for treatment of children with oesophageal burns due to ingestion of caustic substances. The criteria of efficacy used were a) stricture severity by 3 weeks post-ingestion, b) reduction in burn severity by 3 weeks post-ingestion and c) number of dilatations required over the first year post-ingestion. Thirty-six children (24 boys and 12 girls; mean age 23.6 +/- 7.4 months) were selected from a total of 63 patients admitted over a ten-year period to the General Hospital of Galicia with second- or third-degree oesophageal burns due to accidental ingestion of liquid alkali preparations. The patients were divided into two groups of 18, one group for treatment with prednisolone (2 mg/kg/day) and the other for treatment with dexamethasone (1 mg/kg/day). Strictures developed in 12 (66.7%) of the children in the prednisolone-treated group and only 7 (38.9%) of the children in the dexamethasone-treated group. Severe strictures developed in 10 (55.6%) of the children in the prednisolone-treated group and only 5 (27.8%) of the children in the dexamethasone treated group. However, there was no significant difference between the groups in the posttreatment distribution of stricture-severity ratings. Burn healing was significantly better in the dexamethasone-treated group. Similarly, the number of dilatations necessary during the first year of treatment was significantly lower in the dexamethasone-treated group. Our results thus indicate that, by comparison with prednisolone, dexamethasone leads to improved burn healing and reduced need for dialatations during the first year post-injury.

Anti-Inflammatory Agents↗
PubMed1984

Antiemetic efficacy of dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy.

We conducted a randomized, double-blind, crossover study comparing the antiemetic efficacy of dexamethasone and prochlorperazine in 42 patients with cancer who were receiving outpatient chemotherapy, mainly without cisplatin. Patients experienced significantly less nausea and vomiting with dexamethasone than with prochlorperazine (P less than 0.02 and less than 0.03, respectively). Twenty-five patients experienced no nausea with dexamethasone, as compared with 14 patients taking prochlorperazine (P less than 0.001). Similarly, 29 patients receiving dexamethasone did not vomit, as compared with 18 receiving prochlorperazine (P less than 0.001). Somnolence was the most frequent side effect, occurring in 60 per cent of patients receiving prochlorperazine and in 12 per cent of those receiving dexamethasone (P less than 0.001). Patients also experienced less suppression of appetite while receiving dexamethasone (P less than 0.02). We conclude that dexamethasone is an effective and safe antiemetic in patients receiving cancer chemotherapy without cisplatin.

Adult↗
PubMed2004

A randomized trial of a single dose of oral dexamethasone for mild croup.

BACKGROUND: The benefits of dexamethasone treatment for moderate-to-severe croup are well established. However, most children with croup have mild symptoms, and it is unknown whether they would derive the same degree of benefit from dexamethasone treatment as children with more severe disease. METHODS: We conducted a double-blind trial at four pediatric emergency departments in which 720 children with mild croup were randomly assigned to receive one oral dose of either dexamethasone (0.6 mg per kilogram of body weight) or placebo. The children had mild croup, as defined by a score of < or =2 on the croup scoring system of Westley et al. The primary outcome was a return to a medical care provider for croup within seven days after treatment. The secondary outcome was the presence of ongoing symptoms of croup on days 1, 2, and 3 after treatment. Other outcomes included economic costs, hours of sleep lost by the child, and stress on the part of the parent in relation to the child's illness. RESULTS: Baseline clinical characteristics were similar in the two groups. Return to medical care was significantly lower in the dexamethasone group (7.3 percent vs. 15.3 percent, P<0.001). In the dexamethasone group, there was quicker resolution of croup symptoms (P=0.003), less lost sleep (P<0.001), and less stress on the part of the parent (P<0.001). CONCLUSIONS: For children with mild croup, dexamethasone is an effective treatment that results in consistent and small but important clinical and economic benefits. Although the long-term effects of this treatment are not known, our data support the use of dexamethasone in most, if not all, children with croup.

Administration, Oral↗
PubMed2001

A prospective, randomized trial comparing the efficacy of dexamethasone and betamethasone for the treatment of antepartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome.

OBJECTIVE: This study was undertaken to determine whether dexamethasone or betamethasone is superior for the antepartum treatment of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. STUDY DESIGN: This prospective, randomized, clinical investigation compared intravenously administered dexamethasone and intramuscularly administered betamethasone in the treatment of gravid women with HELLP syndrome. Efficacy end points included laboratory values (platelet count, lactate dehydrogenase activity, aspartate aminotransferase activity) and clinical parameters (mean arterial pressure, urinary output). RESULTS: Forty patients were enrolled in the study, 19 in the dexamethasone arm and 21 in the betamethasone arm. The adjusted time-averaged changes from baseline were significant for aspartate aminotransferase activity (dexamethasone, -20.4 +/- 9.6 U/L; betamethasone, 9.9 +/- 8.9 U/L; P =.029), mean arterial pressure (dexamethasone, -15.6 +/- 1.4 mm Hg; betamethasone, -8.1 +/- 1.4 mm Hg; P <.001), and urinary output (dexamethasone, 12.9 +/- 8.6 mL/h; betamethasone, -11.9 +/- 8.2 mL/h; P =.043). CONCLUSION: Intravenously administered dexamethasone appears to be more effective than intramuscularly administered betamethasone for the antepartum treatment of mothers with HELLP syndrome.

Adult↗
PubMed2002

Effect of dexamethasone on mitochondrial maturation in the fetal rat brain.

OBJECTIVE: The objective of the present study was to explore whether prenatal dexamethasone treatment influences mitochondrial maturation in the fetal rat brain. STUDY DESIGN: Mitochondrial respiration was measured polarographically with homogenates of fetal cerebral cortical tissues on day 16 (with saline solution, n = 8; with dexamethasone, n = 8), day 18 (with saline solution, n = 8; with dexamethasone, n = 8), and day 20 (with saline solution, n = 8; with dexamethasone,n = 8) of gestation. Four doses of dexamethasone (0.1 mg small middle dot kg) or vehicle (saline solution) were given, with an interval of 12 hours, until 12 hours before each measurement. RESULTS: In the vehicle-treated animals, mitochondrial respiratory activity was increased significantly after day 18 of gestation. Dexamethasone-treated animals showed a significant increase in mitochondrial activity at day 16 of gestation compared with vehicle-treated animals. CONCLUSION: The results indicate that prenatal dexamethasone treatment contributes to the precocious maturation of mitochondrial activity in the fetal rat brain. Because acceleration in cerebral mitochondrial activities is required immediately after birth to maintain high-energy phosphate levels, the precocious maturation may be crucial for the successful outcome of the preterm infant.

Animals↗
PubMed2003

Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys.

OBJECTIVE: The purpose of this study was to determine whether treatment with the immune modulators dexamethasone or interleukin-10 prevents interleukin-1beta-induced uterine contractions in a nonhuman primate model. STUDY DESIGN: Thirteen chronically instrumented rhesus monkeys at 135 +/- 1 days of gestation (term, 167 days) received one of three interventions: (1) intra-amniotic interleukin-1beta (10 microg) infusion with maternal dexamethasone (1 mg/kg) intravenously every 6 hours for 1 day before interleukin-1beta and for 2 days thereafter (n = 4), (2) intra-amniotic interleukin-1beta infusion with maternal interleukin-10 (25 microg/kg) given intravenously and 100 microg interleukin-10 given intra-amniotically before the interleukin-1beta and continued every 8 hours for 3 days (n = 5), and (3) intra-amniotic interleukin-1beta administered alone (n = 5). Uterine activity was monitored continuously and quantified as the hourly contraction area (millimeters of mercury times seconds per hour) in all groups until delivery. Amniotic fluid was sampled for leukocyte counts and assayed for prostaglandins E(2) and F(2)alpha, cytokines interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 receptor antagonist by specific assays. Maternal and fetal blood were assayed for cortisol, dehydroepiandrosterone sulfate, and estradiol. RESULTS: Interleukin-1beta infusion in the absence of immune modulators resulted in an increase in uterine activity and amniotic fluid proinflammatory cytokines, prostaglandins, and leukocytes. Dexamethasone and interleukin-10 treatment significantly reduced interleukin-1beta-induced uterine contractility (P <.05) and amniotic fluid prostaglandins (P <.05) but not interleukin-8 or interleukin-1 receptor antagonist. Amniotic fluid interleukin-6 and maternal and fetal cortisol, dehydroepiandrosterone sulfate, and estradiol concentrations were reduced by dexamethasone (P <.05), whereas tumor necrosis factor-alpha levels and leukocyte counts were attenuated by interleukin-10 treatment (P <.05). An inverse relationship was noted between amniotic fluid interleukin-10 concentrations and interleukin-1beta-induced uterine activity (r = -0.74, P <.05). CONCLUSION: Dexamethasone and interleukin-10 exert similar inhibitory effects on interleukin-1beta-induced uterine activity, which appears to be mediated by a decrease in prostaglandin production. Reduced estrogen biosynthesis or suppression of tumor necrosis factor-alpha and leukocyte migration may contribute to the tocolytic actions of dexamethasone and interleukin-10, respectively. Dexamethasone and interleukin-10 are likely to be useful adjuncts in the treatment of preterm labor that is associated with inflammation or infection.

Amniotic Fluid↗
PubMed2002

Efficacy of oral dexamethasone in outpatients with acute bronchiolitis.

OBJECTIVE: To examine the efficacy of oral dexamethasone in acute bronchiolitis. STUDY DESIGN: A double-blind randomized, placebo-controlled trial involving 70 children < 24 months old in the emergency department with Respiratory Disease Assessment Instrument > or = 6. Each patient received either 1 dose of 1 mg/kg of oral dexamethasone or placebo and was assessed hourly for a 4-hour period. Repeated measures regression analysis evaluated a change in the Respiratory Assessment Change Score (RACS). RESULTS: The 2 groups had similar baseline characteristics with Respiratory Disease Assessment Inventory of 9.4 +/- 2.3 in the dexamethasone group (n = 36) and 10.0 +/- 2.7 in the placebo group (n = 34). The RACS was -5.0 +/- 3.1 in the dexamethasone group and -3.2 +/- 3.7 in the placebo group (P =.029). Poor RACS occurred in 41% and 17% of the placebo and dexamethasone groups, respectively (P =.034). Of the children treated with dexamethasone, 19% were hospitalized compared with 44% in the placebo group (P =.039). There was no difference in RACS between the groups on day 7 (P =.75). CONCLUSION: Outpatients with moderate-to-severe acute bronchiolitis derive significant clinical and hospitalization benefit from oral dexamethasone treatment in the initial 4 hours of therapy.

Acute Disease↗
PubMed1997

Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells.

The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. The increase in p85alpha protein was associated with a coordinate increase in p85alpha mRNA. Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates.

Animals↗
PubMed1997

Dexamethasone induces neuropeptide Y (NPY) expression and impairs insulin release in the insulin-producing cell line RINm5F. Release of NPY and insulin through different pathways.

Neuropeptide Y (NPY) occurs in adrenergic as well as in non-adrenergic nerves innervating the islets of Langerhans and inhibits glucose-stimulated insulin secretion. Recently we demonstrated that NPY is expressed within islet beta cells of the rat pancreas following treatment with dexamethasone in vivo. In this study we examined the cellular expression of NPY following dexamethasone treatment of the insulin-producing cell line RINm5F, which under control conditions does not express or release NPY. The cells were cultured with or without dexamethasone (100 nM) for 5 days. Over the 5-day culture period, dexamethasone time dependently induced an increased release of NPY with a concomitant decrease in the release of insulin. Northern blot and in situ hybridization revealed a corresponding time-dependent increase in the amount of NPY transcripts and in the number of cells labeled for NPY mRNA, whereas immunocytochemistry for NPY revealed only a few immunoreactive cells, indicating a rapid release of the formed peptide. Following 5 days of culture with dexamethasone, acute stimulation with D-glyceraldehyde (10 mM) or KCl (20 mM) Ca2+ dependently stimulated the release of insulin. In contrast neither stimulation with D-glyceraldehyde or KCl nor removal of extracellular Ca2+ affected the release of NPY. Furthermore the D-glyceraldehyde- and KCl-induced increase in cytosolic Ca2+, evident in control RINm5F cells, was impaired after dexamethasone treatment. We conclude that RINm5F cells show steroid-sensitive plasticity and express NPY after dexamethasone treatment concomitantly with a decreased insulin secretion and impaired increase in cytosolic Ca2+ upon depolarization with KCl or stimulation with D-glyceraldehyde. We also conclude that NPY and insulin secretion are regulated differently and suggest that the inability of the removal of extracellular Ca2+ to inhibit NPY secretion and the failure of D-glyceraldehyde and KCl to stimulate NPY secretion reflect a constitutive release of this peptide from the cells in contrast to the regulated release of insulin.

Animals↗