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PubMed2002

Effect of lipopolysaccharide on peptide transporter 1 expression in rat small intestine and its attenuation by dexamethasone.

BACKGROUND/AIM: The peptide transporter (PepT1) activity is upregulated or preserved under certain pathological conditions. The aim of this study was to investigate the PepT1 expression during lipopolysaccharide (LPS) treatment and the effect of dexamethasone on PepT1 expression. METHODS: Rats were injected daily for 3 days with (1) LPS; (2) LPS plus dexamethasone; (3) dexamethasone, and (4) saline only. Mucosal specimens were used for Northern blot and Western blot analyses. Tissues of small intestine were taken for histological studies. In addition, tumor necrosis factor alpha and interleukin 1 beta levels were determined 3 h after single injections of the above mediators. RESULTS: Northern blot analysis revealed that LPS treatment significantly decreased the expression of mRNA for PepT1 (32-62% of controls) at different time points. In the LPS + dexamethasone group, it was 66-95% of controls. The protein level of PepT1 in the jejunum was consistent with the mRNA expression level. Immunohistochemistry also showed a reduction of PepT1 immunoreactivity in the LPS group. LPS treatment resulted in increased tumor necrosis factor alpha and interleukin 1 beta levels, but dexamethasone treatment profoundly counteracted the cytokine production. CONCLUSIONS: This is the first report that LPS treatment reduces PepT1 expression in the rat small intestine. Short-term treatment with dexamethasone attenuated the effects of LPS by decreasing the cytokine levels.

Animals↗
PubMed2004

Possible role of dexamethasone in sensitizing the beta-2-adrenergic receptor system in vivo in calves during concomitant treatment with clenbuterol.

Beta(2)-Agonists blunt the function of the beta-adrenoceptor G-protein adenylate cyclase-signalling system, whereas glucocorticoids reverse the agonist-mediated diminished beta-adrenergic responses; however, these effects have not been reported in vivo in calf lymphocytes. In this study, we first investigated the presence of the beta(2)-adrenergic receptors on calf lymphocytes, and second we tested the effects of either clenbuterol alone or in combination with dexamethasone on receptor expression and function (isoproterenol-induced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) formation) in vivo. (-)-[(125)I]-Iodocyanopindolol (ICYP) binding to intact calf lymphocytes was rapid, saturable (maximal number of binding sites 987 +/- 89 ICYP-binding sites/cell, n = 4) and of high affinity (K(D) value 17.23 +/- 2.8 pmol/l, n = 4). These binding sites were of the beta(2)-subtypes of adrenoceptors as indicated by the fact that beta-agonists inhibited ICYP binding with an order of potency: (-)-isoproterenol > (-)-adrenaline > (-)-noradrenaline. Furthermore, the selective beta(2)-adrenoceptor antagonist ICI 118.551 was about >1,500 times more potent in inhibiting ICYP binding than was the beta(1)-selective adrenoceptor antagonist CGP 20712A. Consequently, calves were treated with clenbuterol (1.0 microg/kg b.i.d., i.v.) for 9 days alone or simultaneously with dexamethasone (0.1 mg/kg, i.v., once a day for 4 days). Clenbuterol decreased the number of lymphocyte beta(2)-adrenergic receptors by about 40-50% after only 48 h of drug administration. This was accompanied by a decrement in isoproterenol-induced lymphocyte cAMP formation. Upon application of both drugs, dexamethasone restored the clenbuterol-mediated decrease in beta(2)-adrenoceptors and cAMP production. Dexamethasone elevated the number of beta(2)-adrenoceptors and cAMP almost 1.5- to 2-fold at 24 h of drug administration, an effect that persisted for up to 24 h following drug withdrawal. Neither clenbuterol nor the combination with dexamethasone had an influence on the affinity of the receptor for the ligand. The present results demonstrate that dexamethasone in vivo upregulates the number and function of calf lymphocyte beta(2)-adrenoceptors, and thus enhances the sensitivity of the beta(2)-adrenoceptor signal-transduction pathway for clenbuterol during concomitant treatment with both drugs.

Adrenergic beta-2 Receptor Agonists↗
PubMed2006

Thiamine and cyanocobalamin relieve neuropathic pain in rats: synergy with dexamethasone.

Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75-600 mg/kg), pyridoxine (75-600 mg/kg), cyanocobalamin(0.75-6 mg/kg), and dexamethasone (4-32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (approximately 58%), 600 mg/kg of pyridoxine (approximately 22%), 6 mg/kg of cyanocobalamin (approximately 73%), and 32 mg/kg of dexamethasone (approximately 68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (approximately 90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings.

Animals↗
PubMed2006

Protective effect of aspirin against dexamethasone-induced cataract in cultured rat lens.

PURPOSE: To investigate the effect of aspirin on dexamethasone-induced cataract formation in cultured rat lenses. METHODS: One hundred and forty-eight lenses were divided into 3 groups and cultured in vitro: control (DMEM), cataract (DMEM + 10 microM dexamethasone), aspirin (DMEM + 10 muM dexamethasone + 2 mM aspirin). Following incubation, the transparency of the lenses was evaluated daily using a dissecting microscope. Twelve lenses from each group were homogenized and the activities of enzymes (catalase, superoxide dismutase and lactate dehydrogenase) from supernatants were measured after 1, 3, 5 and 7 days of incubation, respectively. The ultrastructure of lenses from the control and cataract groups was observed on the completion of 7-day incubation. RESULTS: Opacity was induced by dexamethasone in the nuclear region of the rat lenses. Lenses in the control group exhibited mist-like opacity and lenses in the cataract group showed dense nuclear opacity, whereas lenses in the aspirin-treated group only had a visible demarcation between nuclear and cortical regions at day 7. The activities of catalase, superoxide dismutase and lactate dehydrogenase in the cataract group decreased in a time-dependent manner. There was no significant loss of enzyme activities in either the control or the aspirin group throughout the incubation period. An orderly arrangement of fiber cells was noted, and the cell membrane, cell junction and organelles were normal in the control group. However, in the cataract group the arrangement of fiber cells was untidy and the lenses contained abnormal-appearing cells. The group exhibited swollen mitochondria, a large number of vacuoles and expanded extracellular lacunae. CONCLUSIONS: Dexamethasone induces nuclear cataract in the organ-cultured rat lens by chemically modifying proteins, including enzymes. The enzymes, including those that normally eliminate radial oxygen species, could be especially vulnerable. Aspirin significantly inhibits dexamethasone-induced cataract formation by inhibiting inactivation of those enzymes.

Animals↗
PubMed1981

The dexamethasone suppression test as a measure of hypothalamic-pituitary feedback sensitivity and its relationship to behavioral arousal.

A nonhuman primate model was used to evaluate the value of the dexamethasone suppression test as an index of hypothalamic-pituitary-adrenal responsiveness to arousal. In 8 rhesus monkeys plasma cortisol was suppressed by dexamethasone in a dose-dependent fashion at doses between 0.75 and 33 microgram/kg. A replication study was performed 5 months later using a single dexamethasone dose (17 microgram/kg) known to produce maximal plasma cortisol suppression. This yielded highly correlated results (r = 0.91, p less than 0.005) suggesting that dexamethasone suppressibility may be a stable characteristic of individual animals. In 9 other animals whose arousal responses to a stressful procedure (nasogastric tube insertion) had been rated daily over a previous 3-month period, baseline plasma cortisol levels and the percent suppression of plasma cortisol by dexamethasone were evaluated. Baseline plasma cortisol levels did not significantly correlate with the degree of dexamethasone-suppression and the mean arousal ratings within animals. However, the postdexamethasone percent of baseline cortisol did correlate significantly (r = 0.75, p less than 0.025) with individual mean arousal ratings. These preliminary results suggest that assessment of the sensitivity of an individual's hypothalamic-pituitary glucocorticoid feedback system may be a better predictor than its baseline cortisol concentrations of its degree of behavioral arousal to stress.

Animals↗
PubMed1993

Increases in neuropeptide Y content and gene expression in the hypothalamus of rats treated with dexamethasone are prevented by insulin.

The neurotransmitter neuropeptide Y (NPY) is abundant in the hypothalamus where its actions include the potent stimulation of food intake. The peripheral metabolic and hormonal signals involved in its regulation are not clear. The aim of this study was to investigate possible actions of corticosteroids and insulin on hypothalamic NPY synthesis and content in vivo. We measured NPY content in individual hypothalamic nuclei, and hypothalamic NPY mRNA by Northern blotting in whole hypothalamus in rats treated with dexamethasone (0.4 mg/kg/day) and dexamethasone plus insulin (60 U/kg/day), compared to controls. The effect of stopping dexamethasone treatment was also studied. Dexamethasone treatment produced significant increases in NPY in the paraventricular (11.0 +/- 1.3 vs. 7.1 +/- 0.4 fmol/micrograms protein, p < 0.05) and arcuate (6.2 +/- 0.3 vs. 3.8 +/- 0.2 fmol/microgram protein, p < 0.001) nuclei of the hypothalamus, paralleled by a 38% increase in total hypothalamic NPY mRNA (p < 0.05). These changes were not seen in the group treated with dexamethasone plus insulin. In the group in whom dexamethasone was stopped, NPY mRNA was unchanged compared to controls, but peptide content remained increased in the arcuate but not the paraventricular nucleus (arcuate 7.7 +/- 0.7 vs. 5.5 +/- 0.7, PVN 4.9 +/- 1.0 vs. 4.7 +/- 0.9 fmol/microgram protein). Thus hypothalamic NPY and its mRNA were increased by corticosteroid administration, and this effect was prevented by systemic insulin treatment. This dual regulatory system for hypothalamic NPY may be important in the control of food intake by corticosteroids and insulin.

Animals↗
PubMed1996

Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat.

Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribed to 'fetal programming'. In rats fetoplacental exposure to maternally administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is unclear. Pre- and postnatal stress programmes hypothalamic-pituitary-adrenal (HPA) axis responses throughout the lifespan, an effect thought to be mediated via permanent effects on glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) gene expression in the hippocampus. Corticosteroids also have specific central effects on blood pressure control mediated by GR and MR. This study investigated corticosterone (CORT) responses to restraint stress and GR and MR gene expression in areas of the brain postulated to mediate the central effects of corticosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commissural organ, area postrema and nucleus tractus solitarius). Pregnant Wistar rats received dexamethasone (100 micrograms/kg.day-1) or vehicle on days 15-20 of gestation. This reduced birth weight by 11%. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pressure was significantly elevated in the adult offspring of dexamethasone-treated pregnancies (dexamethasone 144 +/- 2/125 +/- 2 mm Hg vs. control 133 +/- 2.7/112 +/- 2.8 mm Hg; both p < 0.01). Offspring of dexamethasone-treated pregnancies had increased basal plasma CORT (155 +/- 29 nmol/l) compared to offspring of controls (79 +/-15 nmol/l, p < 0.05), but the CORT response to stress was similar. Hippocampal neuronal GR mRNA expression was significantly lower in the offspring of dexamethasone-treated pregnancies (dentate gyrus 20% lower, CA1 15% lower; p < 0.01). Similarly, hippocampal MR gene expression was decreased in CA1 and CA2 by 24 and 25%, respectively (p < 0.05). No differences in GR or MR mRNA expression were found in the OVLT, subcommissural organ, area postrema or nucleus tractus solitarius. These findings suggest that glucocorticoid excess in the last trimester of rat pregnancy (i) is sufficient to programme offspring hypertension; (ii) also increases basal plasma CORT levels, and (iii) permanently attenuates GR and MR mRNA expression in specific hippocampal subfields. Thus, if translated into protein, may reduce sensitivity to glucocorticoid feedback and thus contribute to the CORT excess. However, hypertension in this model is unlikely to be mediated by similar changes in GR or MR gene expression in the examined areas of the brain putatively involved in the more direct central regulation of blood pressure.

Animals↗
PubMed1978

Effects of dexamethasone on the morphogenesis of two mutants of Rous sarcoma virus.

Japanese quail cells transformed by the replication-defective, Bryan high-titer strain of Rous sarcoma virus, BH RSV(-)Q, clone 3, revealed intracytoplasmic A-type particles after dexamethasone treatment. In the absence of dexamethasone, or when superinfected with a helper virus in the presence or absence of dexamethasone, no such particles were observed. Chick embryo cells (CEC) infected with a temperature-sensitive sarcoma virus mutant, LA 334, coordinately defective for transformation and viral replication, showed abnormal accumulation of viral core substances and aberrant budding at the non-permissive temperature (41 degrees). CEC infected with LA 334 and treated with dexamethasone at 41 degrees resulted in more extensive accumulation of abnormal budding without increased release of viral particles. Dexamethasone, however, did not lead to abnormal morphogenesis of virus under permissive conditions. The selective effects of dexamethasone on the morphogenesis of these two mutants of avian sarcoma virus are discussed.

Animals↗
PubMed1997

Whole body lean mass is altered by dexamethasone treatment through reductions in protein and energy utilization in piglets.

The objective of this study was to assess the effect of dexamethasone on growth, body composition and protein metabolism using the piglet as a model for rapidly growing premature infants. Seven-day-old male pigs (n = 18) were randomized to 0.5 mg/kg/day oral dexamethasone or placebo for 15 consecutive days. Weight and length gains and weight gained per energy or protein consumed were significantly lower in the dexamethasone group. Serum urea nitrogen was significantly higher in the dexamethasone group by day 15 of the study. No differences were observed between groups for urinary creatinine. The whole body percent lean mass was significantly lower and percent fat mass was significantly higher in the dexamethasone piglets, as measured by dual energy X-ray absorptiometry. In young piglets, dexamethasone, at doses similar to those in premature infants, induces protein catabolism, impairs growth and alters its composition.

Absorptiometry, Photon↗
PubMed1988

Contribution of vasopressin in dexamethasone-induced hypertension in rats.

Our previous finding that dexamethasone-induced hypertension in rats is associated with enhanced reactivity of mesenteric arteries to arginine vasopressin but not to angiotensin II (Ang II) or norepinephrine has led us to postulate that vasopressin contributes to the development or maintenance of glucocorticoid-induced hypertension. To test this view, we investigated the effects of vasopressin, Ang II, norepinephrine, and the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP on mean arterial blood pressure and heart rate with and without ganglionic blockade with hexamethonium and angiotensin I (Ang I) converting enzyme inhibition with MK 421 in pentobarbital-anesthetized rats made hypertensive by treatment with dexamethasone (1.8 mg/kg/wk for 14 days). Administration of vasopressin, Ang II, or norepinephrine (0.003-3 microgram i.v.) produced a dose-related increase in arterial blood pressure. The pressor response to vasopressin, but not to Ang II or norepinephrine, was greater in dexamethasone-treated than in vehicle-treated animals, and this difference became more pronounced in rats that received hexamethonium and MK 421. Administration of the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP significantly reduced arterial pressure in dexamethasone-treated but not in vehicle-treated animals. Hexamethonium and MK 421 reduced arterial blood pressure in dexamethasone-treated as well as in vehicle-treated rats; however, arterial blood pressure remained higher in the former. Administration of the vasopressin V1 receptor antagonist produced a greater reduction in arterial blood pressure in dexamethasone-treated than in vehicle-treated rats. These data suggest that vasopressin contributes to glucocorticoid-induced hypertension, which is probably due to enhanced vascular reactivity to the peptide.

Angiotensin II↗
PubMed1992

Potentiation of inositol trisphosphate production by dexamethasone.

One of the mechanisms of glucocorticoid-induced hypertension has been thought to be the enhancement of vascular responsiveness to vasoconstrictors. In this regard, the effects of glucocorticoids on inositol trisphosphate production in vascular smooth muscle cells were studied. Angiotensin II and arginine vasopressin transiently increased inositol trisphosphate formation in a dose-dependent manner. Pretreatment with dexamethasone for 48 hours shifted the dose-response trisphosphate curves of angiotensin II- and arginine vasopressin-induced inositol trisphosphate production to the left, that is, it significantly reduced the half-maximal effective concentrations of angiotensin II (from 25 nM to 5 nM) and arginine vasopressin (from 50 nM to 25 nM). These effects of dexamethasone required a minimum of 12 hours of incubation; maximum effect was observed after 24 hours of treatment. A glucocorticoid antagonist, RU 38486, completely blocked these effects. To elucidate the interaction with prostaglandin, we used indomethacin, a potent inhibitor of prostaglandin synthesis. Treatment with indomethacin shifted the dose-response curves of angiotensin II- and arginine vasopressin-induced inositol trisphosphate production to the left. However, this shift was less than that seen after dexamethasone treatment. Indomethacin alone did not completely reproduce dexamethasone effects, and no additive effect between indomethacin and dexamethasone was observed. These results suggest, at least in part but not entirely, that the effects of dexamethasone depended on prostaglandin synthesis inhibition. We concluded that glucocorticoids altered the responsiveness of vascular smooth muscle cells to angiotensin II and arginine vasopressin through a glucocorticoid-specific receptor. These actions strongly support the mechanism by which the glucocorticoid induced hypertension through the increased sensitivity to vasoconstrictors.

Angiotensin II↗
PubMed1990

Dexamethasone selectively attenuates prostanoid-induced vasoconstrictor responses in vitro.

Glucocorticoids bind to specific vascular receptors resulting in a variety of functional consequences that may affect vascular smooth muscle behavior. We, therefore, examined in rabbits the effect of treatment with dexamethasone (2.5 mg/kg) for 6 days on vascular responses to pressor prostanoids in aortic and carotid arterial rings and in the isolated perfused kidney. Isometric tension development to prostaglandin F2 alpha and U46619, a thromboxane/prostaglandin endoperoxide mimetic, was markedly reduced in vessels from dexamethasone-treated rabbits. The inhibitory effect of dexamethasone on vascular reactivity was manifested by an increase in the concentration of agonist for threshold tension development and a reduction in the maximal response to prostaglandin F2 alpha and U46619. In contrast, reactivity to phenylephrine, potassium, histamine, or endothelin was not affected by dexamethasone treatment. In addition, pressor responses to prostaglandin F2 alpha and U46619 in Krebs'-perfused kidneys from dexamethasone-treated rabbits were also diminished. These data suggest that dexamethasone selectively interferes with the expression of receptor-mediated contractile responses to eicosanoids.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

Experimental hyaline membrane disease in the premature monkey: effects of antenatal dexamethasone.

A blind, randomized trial of antenatal glucocorticoid treatment was conducted using the premature monkey (Macaca nemestrina) model of hyaline membrane disease (HMD). Twelve dams received dexamethasone (2 mg/dose) 72, 48, and 24 h before abdominal delivery at 135 +/- 1 days of gestation. Twelve control animals received saline. Infants of dexamethasone-treated dams had significantly lower incidence and severity of HMD than did infants of control animals (50 versus 92%, p less than 0.05). Improvement with treatment was markedly greater for males than for females. Differences in volume-pressure behavior of the excised lungs included greater distensibility in the infants from dexamethasone-treated dams (20.6 +/- 7.1 ml/g dry lung versus 14.7 +/- 6.1, p less than 0.05) and enhanced deflation stability with treatment. Accelerated production of surface active material (SAM) phospholipids in infants from dexamethasone-treated dams was indicated by increases in total lung phospholipid (84.5 +/- 8.1 mg/g dry lung versus 75.1 +/- 9.9, p less than 0.025), alveolar lavage fluid phospholipid (5.65 +/- 3.33 mg/g dry lung versus 3.01 +/- 1.84, p less than 0.05), and alveolar lavage fluid disaturated phosphatidylcholine (DPC) (2.47 +/- 1.84 mg/g dry lung versus 1.06 +/- 1.05, p less than 0.05). Incorporation of 14C-palmitate into lung lipid was not influenced by dexamethasone, but a significantly greater portion of the label appeared in the DPC fraction with treatment. Antenatal dexamethasone treatment was successful in reducing the incidence and severity of experimental HMD in this animal model; the beneficial effects of treatment were associated with accelerated maturation of fetal pulmonary functions, including, but not limited to, synthetic metabolism of SAM phospholipid.

Animals↗
PubMed1984

Dexamethasone regulation of glycosaminoglycan synthesis in cultured human skin fibroblasts. Similar effects of glucocorticoid and thyroid hormones.

The effects of dexamethasone on glycosaminoglycan accumulation were examined in confluent human skin fibroblasts in vitro. The glucocorticoid consistently inhibited the incorporation of either [3H]acetate or [3H]glucosamine into hyaluronate when added to culture medium 72 h before harvest. This effect was half-maximal at approximately 1 nM and maximal at 5-10 nM. Inhibition occurred within 5 h of hormone addition and was near maximal by 25 h. 11 alpha-hydrocortisone (10 nM), deoxycorticosterone (10 nM), and progesterone (100 nM) failed to inhibit this accumulation; however, progesterone (2 microM), a known glucocorticoid antagonist at high concentration, could attenuate the response to dexamethasone by 57%. Cultures were pulse-labeled and then chase incubated for up to 68 h. No difference in the rate of [3H]hyaluronate degradation could be demonstrated in steroid-treated cultures. Triiodothyronine (T3) can also inhibit synthesis of hyaluronate in fibroblasts (Smith, T. J., Y. Murata, A. L. Horwitz, L. Philipson, and S. Refetoff, 1982, J. Clin. Invest., 70:1066-1073). Both T3 and dexamethasone could inhibit glycosaminoglycan accumulation in a dose-dependent manner. Maximal T3 effects were achieved at 1 nM and those of dexamethasone at 10 nM. Saturating concentrations of T3 and dexamethasone added alone inhibited [3H]hyaluronate by 54 and 49%, respectively. When both hormones were added, accumulation was inhibited by 84%. Dexamethasone inhibits [3H]hyaluronate accumulation in a time, dose-dependent, and stereo-specific manner. The rate of glycosaminoglycan degradation was unaffected, and thus, the steroid inhibited the rate of macromolecular synthesis. This effect was likely mediated through glucocorticoid receptors. Hyaluronate synthesis in skin fibroblasts appears to be regulated by both glucocorticoids and T3 through different pathways.

Acetates↗
PubMed1993

Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats.

Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. After dexamethasone treatment (1 mg/kg per d for 5 d), there was no change in insulin receptor concentration in liver of rats as determined by immunoblotting with antibody to the COOH-terminus of the receptor. However, insulin stimulation of receptor autophosphorylation determined by immunoblotting with antiphosphotyrosine antibody was reduced by 46.7 +/- 9.1%. IRS-1 and PI 3-kinase protein levels increased in liver of dexamethasone-treated animals by 73 and 25%, respectively (P < 0.05). By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). In muscle, the changes were less dramatic, and often in opposite direction of those observed in liver. Thus, there was no significant change in insulin receptor level or phosphorylation after dexamethasone treatment. IRS-1 and PI 3-kinase levels were decreased to 38.6 and 65.6%, respectively (P < 0.01 and P < 0.05). IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. Thus, dexamethasone has differential effects on the proteins involved in the early steps in insulin action in liver and muscle. In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated P I3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.

Amino Acid Sequence↗
PubMed2004

Efficacy of low-dose dexamethasone for preventing postoperative nausea and vomiting following strabismus repair in children.

We studied the efficacy of a range of doses of dexamethasone for prevention of postoperative nausea and vomiting following strabismus repair in children in a hospital-based, prospective, double-blinded, randomized, placebo-controlled trial. Two hundred and ten children were randomized to receive either dexamethasone in one of four dosages: 50 microg/kg (Group 1), 100 microg/kg (Group 2), 200 microg/kg (Group 3) and 250 microg/kg (Group 4) or normal saline (Group 5) prior to corrective surgery for strabismus. Anaesthesia was standardized and included nitrous oxide, pethidine, intubation and the use of muscle relaxant and reversal with neostigmine. Postoperative nausea and vomiting were evaluated in epochs of 0-2 hours, 2-6 hours and 6-24 hours after surgery. Parent satisfaction was assessed 24 hours after surgery and the operated eye was examined for wound infection and delayed healing one week later Dexamethasone was effective in preventing nausea and vomiting after strabismus repair: 57.1% children in Group 1, 42.9% in Group 2, 52.4% in Group 3, and 59.5% in Group 4 were free from postoperative nausea and vomiting compared with 7.1% in placebo group. The lowest dose of 50 microg/kg was as efficacious as the higher dosages of dexamethasone during the 24 hours studied. Of the children who developed postoperative nausea and vomiting those who received dexamethasone had significantly fewer episodes than those in the placebo group. We conclude that dexamethasone 50 microg/kg is effective for the prevention of postoperative nausea and vomiting following strabismus repair in children.

Adolescent↗
PubMedDate not supplied

Comparison of prophylactic anti-emetic effects of ondansetron and dexamethasone in women undergoing day-case gynaecological laparoscopic surgery.

We aimed to determine the effect of ondansetron and dexamethasone on preventing post-operative nausea and vomiting (PONV). Sixty women undergoing laparoscopic gynaecological surgery were randomized to receive ondansetron 4 mg, dexamethasone 8 mg or saline. Drugs were administered 2 min before induction of anaesthesia, and anaesthesia and post-operative analgesic regimens were standardized. The incidence of PONV in the first 24 h after the operation was 35% in the ondansetron group, 55% in dexamethasone group and 85% in the control group. A significant difference between the groups was only seen in the first 3 h post-operatively. In this period, ondansetron was significantly more effective than dexamethasone and saline, but no differences were seen between dexamethasone and saline. In all treatment groups, post-operative visual analogue scale scores, sedation scores and usage of analgesics were similar. In conclusion, ondansetron, but not dexamethasone, prevented PONV in the first 3 h after gynaecological laparoscopic surgery.

Adult↗
PubMed2002

The tissue level of dexamethasone in human brain tumors is about 1000 times lower than the cytotoxic concentration in cell culture.

In glioblastoma patients dexamethasone is routinely administered as an antiedematous drug. In contrast to its empirically proven effect, the biochemical way of action remains poorly understood. In order to assess whether a direct cytotoxic effect is present in vivo we compared dexamethasone levels in brain tumor specimens with its cytotoxic concentrations in cell culture. Biopsy specimens were taken during microsurgical tumor removal, homogenized and dexamethasone levels were measured by high pressure liquid chromatography. In cell culture we tested different concentrations of dexamethasone on A172, U87, U373 cells and on eleven primary glioblastoma cell lines. Furthermore a pilocytic astrocytoma I, an astrocytoma II and an oligodendroglioma III and a meningioma were examined. Cell viability was assessed using the Alamar Blue assay and the concentrations resulting in loss of 50% of the cell population were calculated (LD50). The average brain tumor tissue concentration of dexamethasone was 225 nanogram g(-1). The mean LD50 in cell culture ranged at 222 microgram ml(-1). We conclude that a direct cytotoxic effect of dexamethasone on brain tumor cells is not present in vivo because the tissue levels of the drug are about 1000 times lower than the LD50 in cell culture.

Antineoplastic Agents, Hormonal↗