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PubMed2006

PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma.

PURPOSE: We have shown previously that the 88 kDa glycoprotein PC cell-derived growth factor (PCDGF/GP88) is expressed and acts as an autocrine growth factor in human multiple myeloma cells. The present study investigates whether PCDGF/GP88 expression in multiple myeloma cells leads to the development of resistance to dexamethasone, a conventional drug for multiple myeloma patients. EXPERIMENTAL DESIGN: PCDGF functions and signaling pathways in dexamethasone-induced apoptosis were studied using a representative dexamethasone-sensitive multiple myeloma cell line ARP-1. The effect of PCDGF/GP88 was further confirmed in PCDGF/GP88-overexpressed ARP-1 cells. RESULTS: Dexamethasone inhibits cell growth and induces apoptosis in a time- and dose-dependent fashion. Exogenous addition of PCDGF/GP88 to the ARP-1 cells prevented dexamethasone-induced apoptosis as examined by flow cytometry analysis and poly(ADP-ribose)polymerase cleavage assay. Signaling studies showed that mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and nuclear factor-kappaB were involved in the antiapoptotic effect of PCDGF/GP88. Overexpression of PCDGF/GP88 in ARP-1 cells rendered the cells refractory to dexamethasone-mediated apoptosis, enhanced their ability to form colonies in soft agar, and to form tumors in vivo without any change in glucocorticoid receptor expression and function. CONCLUSION: These data suggest that expression of PCDGF/GP88 confers resistance to dexamethasone and increase tumorigenesis of multiple myeloma cells in mouse xenografts. Our data here also raises the possibility of PCDGF/GP88 as a potential therapeutic target for dexamethasone-resistant multiple myeloma.

Antineoplastic Agents↗
PubMed1998

Paper chromatography prior to cortisol RIA allows for accurate use of the dexamethasone suppression test in chronic renal failure.

The assessment of the hypothalamic-pituitary-adrenal axis in patients with chronic renal failure (CRF) on hemodialysis is often hampered by abnormal responses to the standard 1-mg dexamethasone suppression test. Various mechanisms have been proposed to explain this lack of suppressibility. The present study was designed to look into the mechanisms possible for these findings in patients with CRF. We studied 6 patients with CRF on hemodialysis and 5 healthy subjects utilizing the 1-mg dexamethasone suppression test as well as the 50-mg hydrocortisone suppression test. Samples were assayed for dexamethasone, adrenocorticotropic hormone, corticosterone, and cortisol by both direct radioimmunoassay (RIA) and RIA after paper chromatography. Utilizing the direct cortisol RIA, 4 of 6 patients with CRF exhibited blunted dexamethasone suppression, while all 6 patients showed normal suppressibility after dexamethasone when cortisol was measured after paper chromatography. In contrast, all controls showed normal suppressibility regardless of the cortisol assay procedure used. The hydrocortisone suppression test was unreliable in the setting of CRF. Mean dexamethasone levels were similar in both groups. Plasma adrenocorticotropic hormone levels were significantly higher in the CRF patients, possibly indicative of an underlying hypothalamic-pituitary-adrenal axis abnormality. Abnormalities in dexamethasone suppression testing in patients with CRF may be explained by the overestimation of cortisol levels by direct RIA rather than by alteration of dexamethasone absorption or metabolism. Measurement of cortisol after paper chromatography is superior to direct RIA of cortisol in patients with CRF.

Adrenocorticotropic Hormone↗
PubMed2004

Effects of postnatal dexamethasone on oxygen toxicity in neonatal rats.

We investigated the effect of timing of early postnatal dexamethasone on survival of hyperoxia-exposed neonatal rats. Pups <24 h old were treated with a tapering course of dexamethasone or saline beginning either prior to exposure (day 0), or after 2, 4, or 6 days of > or =98% O2 (n=11-14) or air (n=8-11). Exposures were continued for 14 days. By day 14, day 0 pups had poor survival regardless of the exposure (14% in O2, 13% in air). Survival of pups treated with dexamethasone after 2, 4 and 6 days of O2 exposure was significantly higher at 14 days (50, 86 and 79%, respectively) compared to saline O2 controls (9%, p < 0.001 for each). Pulmonary biochemical analyses were conducted after exposure for 7 days in rat pups treated with dexamethasone or saline beginning after 4 days of exposure to air or O2 (n=11-12 for each group). While pups treated with dexamethasone showed greatly improved survival compared to O2 controls, there was no decrease in neutrophil influx into the lung as measured by lung myeloperoxidase and neutrophil counts in histologic specimens and lavage fluid. Catalase, glutathione peroxidase, total and manganese superoxide dismutase activities as well as manganese superoxide dismutase (MnSOD) mRNA expression were elevated in both O2 groups after 7 days compared to the air groups (p < 0.05) and MnSOD mRNA expression was elevated in the O2/dexamethasone group, but there were no differences between dexamethasone and saline groups in O2. Thus, this study indicates that the timing of dexamethasone administration is crucial. Mechanisms other than increases in antioxidant enzymes or decreases in lung neutrophils underlie the ability of dexamethasone to improve survival of these neonatal rats.

Animals↗
PubMed2006

Dexamethasone pharmacokinetics in Guinea pig inner ear perilymph.

AIM: To study the dexamethasone pharmacokinetics in the inner ear perilymph of guinea pigs using high-pressure liquid chromatography. METHODS: Sixty-five guinea pigs were divided into three groups. In the first group, the drug application protocol used an intra-abdominal dose of 0.5% dexamethasone 4 mg x kg(-1). In the second group, an intratympanic application dose of 0.5% dexamethasone 150 microl was used. The third group was the control group. The concentrations of dexamethasone in inner ear perilymph were determined by high-pressure liquid chromatography. RESULTS: The perilymph concentration-time curves of dexamethasone conformed to a one-compartment open model after an intra-abdominal application. The Cmax was 0.927 +/- 0.008 mg x l(-1), the Tmax 1.47 +/- 0.04 h, the T(1/2K) 2.92 +/- 0.056 h, the AUC 5.533 +/- 0.05 mg x h x l(-1), the T(1/2Ka) 0.47 +/- 0.024 h. After an intratympanic application, the perilymph concentration-time curves of dexamethasone also conformed to a one-compartment open model. The Cmax was 0.201 +/- 0.006 mg x l(-1), the Tmax 0.117 +/- 0.06 h, the AUC 0.868 +/- 0.004 mg x h x l(-1), the T(1/2K) 2.918 +/- 0.089 h, the T(1/2Ka) 0.161 +/- 0.009 h. Compared to the intra-abdominal application, the intratympanic application resulted in similar levels of inner ear perilymph drug concentrations in 30 min. CONCLUSION: Dexamethasone can penetrate the blood-labyrinthine barrier after intra-abdominal application. Dexamethasone can enter into perilymph after intratympanic application. Under the condition of the study, the intratympanic application resulted in a similar level of inner ear perilymph drug concentrations compared to the intra-abdominal application in 30 min.

Animals↗
PubMed1987

Effects of dexamethasone on central and peripheral ACTH systems in the rat.

To investigate the simultaneous effects of dexamethasone on peripheral and central adrenocorticotropic hormone (ACTH) systems, rats were treated with dexamethasone or saline for 4 days. Pituitary, plasma, hypothalamus and cerebrospinal fluid (CSF) were then collected and analyzed for ACTH immunoreactivity. Additionally, hypothalamic tissue extracts were analyzed for corticotropin-releasing hormone (CRH) immunoreactivity. Dexamethasone significantly lowered peripheral levels of ACTH as measured in pituitary and plasma. Hypothalamic ACTH content significantly increased while CSF ACTH significantly decreased with dexamethasone treatment. Hypothalamic CRH concentrations showed a small but statistically insignificant decrease. These results suggest that prolonged exposure to dexamethasone affects central as well as peripheral ACTH activity, corroborate our previous findings in rhesus monkeys of decreased CSF ACTH in response to prolonged dexamethasone treatment, suggest that dexamethasone may inhibit the release of ACTH from hypothalamic neurons into the CSF, and provide evidence that the effect of dexamethasone on pituitary ACTH content is of greater magnitude than its effect on hypothalamic CRH.

Adrenocorticotropic Hormone↗
PubMed1990

Effect of vasopressin and naloxone alone and in combination on cortisol secretion after dexamethasone pretreatment.

In order to further examine the possible role of endogenous opioid peptides and vasopressin in the phenomenon of dexamethasone nonsuppression, we studied the effect of naloxone, vasopressin, and vasopressin-naloxone combination on cortisol secretion following dexamethasone pretreatment. Nine healthy males were given 1 mg dexamethasone at 23.00 h. The following day starting at 12.30 h and at 90-min intervals they received intravenously naloxone (0.2 mg/kg), arginine vasopressin 3 units, or the two drugs combined. The order of drug administration was counterbalanced using a Latin square design. Blood samples were drawn at 15-min intervals, and plasma aliquots were assayed for cortisol and dexamethasone. Naloxone failed to induce an escape from dexamethasone suppression. Four of the 9 subjects responded with an escape from dexamethasone suppression in response to vasopressin alone. The observed variability in response to vasopressin was unrelated to dexamethasone plasma levels but was associated with a decrease in systolic blood pressure. Peak cortisol levels were lowest in response to naloxone and highest in response to vasopressin. There was no evidence of an increased cortisol response to the coadministration of naloxone with vasopressin compared to vasopressin alone. These results fail to implicate an opioidergic mechanism in the pathophysiology of dexamethasone nonsuppression.

Adult↗
PubMed1990

Effects of mifepristone on rabbit intraocular pressure in the presence and absence of dexamethasone.

Topical dexamethasone was used to elevate rabbit intraocular pressure in order to study the interaction with a steroid antagonist, mifepristone. Dexamethasone did not cause a consistently significant increase in intraocular pressure. Animals treated with mifepristone followed by dexamethasone showed no apparent increase in intraocular pressure after dexamethasone, indeed mifepristone caused a lower intraocular pressure than seen in other groups whether in the presence or absence of dexamethasone. Reductions of intraocular pressure when mifepristone was given after 14 days of dexamethasone administration were not found. No conclusion can be reached regarding any dexamethasone antagonism by mifepristone, except that intraocular pressure tended to be lower even in the presence of dexamethasone.

Administration, Topical↗
PubMed1995

Effects of dexamethasone on the synthesis, degradation, and secretion of apolipoprotein B in cultured rat hepatocytes.

Oversecretion of apoB and decreased removal of apoB-containing lipoproteins by the liver results in hyperapobetalipoproteinemia, which is a risk factor for atherosclerosis. We investigated how dexamethasone, a synthetic glucocorticoid, affects the synthesis, degradation, and secretion of apoB-100 and apoB-48. Primary rat hepatocytes were incubated with dexamethasone for 16 hours. Incorporation of [35S]methionine into apoB-48 and apoB-100 was increased by 36% and 50%, respectively, with 10 nmol/L dexamethasone, despite a 28% decrease of incorporation into total cell proteins. However, Northern blot analysis revealed that dexamethasone (1 to 1000 nmol/L) did not significantly alter the steady-state concentrations of apoB mRNA, suggesting that the net increase in apoB synthesis may involve increased translational efficiency. The intracellular retention and the rate and efficiency of apoB secretion were determined by pulse-chase experiments in which the hepatocytes were labeled with [35S]methionine for 10 minutes or 1 hour, and the disappearance of labeled apoB from the cells and its accumulation in the medium were monitored. Degradation of labeled apoB-100 after a 3-hour chase in both protocols was decreased from about 50% to 30%, whereas degradation of apoB-48 was decreased from 30% to 10% to 20% by treatment with 10 or 100 nmol/L dexamethasone. Additionally, the half-life of decay (time required for 50% of labeled cell apoB-100 to disappear from the peak of radioactivity following a 10-minute pulse) was increased by treatment with 10 nmol/L dexamethasone from 77 to 112 minutes, and the value for apoB-48 increased from 145 to 250 minutes. Treatment with 100 nmol/L dexamethasone also stimulated secretion of 35S-labeled apoB-100 and apoB-48 by twofold and 1.5-fold, respectively. The increased secretion of apoB-100 and apoB-48 after dexamethasone treatment was confirmed by immunoblot analysis for apoB mass, and the effect was relatively specific since albumin secretion was not significantly changed. We conclude that glucocorticoids promote the secretion of hepatic apoB-containing lipoproteins by increasing the net synthesis of apoB-100 and apoB-48 and by decreasing the intracellular degradation of newly synthesized apoB. An increased action of glucocorticoids coupled with a decreased ability of insulin to suppress these effects in insulin resistance can lead to hyperapobetalipoproteinemia and an increased risk of atherosclerosis.

Animals↗
PubMed2003

Prenatal dexamethasone programs hypertension and renal injury in the rat.

Dexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number compared with control at 6 to 9 months of age (22 527+/-509 versus 28 050+/-561, P<0.05), which was comparable to the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380+/-587) compared with control rats (P<0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats. This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis, and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a reduction in glomerular number is not the sole cause for the development of hypertension.

Animals↗
PubMed1996

Regulation of angiotensin II receptor subtypes by dexamethasone in rat mesangial cells.

The objective of this study was to examine the role of dexamethasone on the expression of angiotensin II (Ang II) receptors in cultured rat mesangial cells. Dexamethasone caused concentration- and time-dependent decreases in 125I-[Sar1,Ala8]Ang II binding that were prevented by glucocorticoid receptor inhibition with mifepristone. A lag time of 24 hours and a dexamethasone concentration of at least 10 nmol/L were necessary for this effect to occur. Dexamethasone-induced reduction of 125I-[Sar1,Ala8]Ang II binding resulted from decreased Ang II type 1 (AT1) receptor density. No change in the apparent dissociation constant was observed. Dexamethasone also markedly inhibited Ang II-dependent inositol phosphate accumulation. Both reverse transcription-polymerase chain reaction and Northern blot analysis using specific short probes from the 3' noncoding region of the cDNA demonstrated the presence of AT1A and AT1B receptor mRNAs in rat mesangial cells, with a slight predominance of AT1B. Therefore, we studied the effect of dexamethasone on the expression of these two subtypes in rat mesangial cells. Dexamethasone produced a time-dependent decrease of AT1B receptor mRNA that was apparent after 6 hours of incubation, whereas AT1A receptor mRNA did not change. Mifepristone also suppressed the dexamethasone-induced decrease in AT1B receptor mRNA. In conclusion, glucocorticoids diminish Ang II receptor density at the mesangial cell surface through a mechanism that implies successive interaction with the glucocorticoid receptor and specific reduction in AT1B receptor mRNA expression. This differential regulation of both AT1 receptor subtypes might allow glucocorticoids to exert adjusted effects in their various target tissues.

Angiotensin II↗
PubMed1993

Dexamethasone prevents cerebral infarction without affecting cerebral blood flow in neonatal rats.

BACKGROUND AND PURPOSE: We recently demonstrated that pretreatment with the synthetic glucocorticoid dexamethasone prevents hypoxic-ischemic brain damage in neonatal rats. Presently, we examine whether this protective effect of dexamethasone is due to an improvement in local cerebral blood flow. METHODS: Neonatal rats were treated with either vehicle or 0.1 mg/kg i.p. dexamethasone 24 hours before hypoxia-ischemia (right carotid artery occlusion +3 hours of 8% O2). Cerebral blood flow was measured with [14C]iodoantipyrine autoradiography after either 2 (n = 17) or 3 (n = 15) hours of hypoxia-ischemia. Additional animals (n = 20) were perfusion-fixed 3 days after hypoxia-ischemia. The area of cerebral pathological changes was measured from hematoxylin and eosin-stained coronal sections taken at three different levels. RESULTS: Pathological outcome differed between groups. In vehicle-treated rats, sections from anterior, mid, and posterior portions of the cerebrum all had extensive infarction or cellular necrosis ipsilateral to the occlusion (mean areas of damage were 62.6 +/- 10%, 70.2 +/- 9%, and 54.2 +/- 8%, respectively). However, in dexamethasone-treated animals, brain damage in sections at corresponding levels was minimal (0%, 1.6 +/- 2%, and 1.5 +/- 1%, respectively; p < 0.0002). In contrast to the pathological results, cerebral blood flow was equivalent in the dexamethasone- and vehicle-treated groups. After either 2 or 3 hours of hypoxia, cerebral blood flow was reduced 60-80% ipsilateral to the carotid artery occlusion in animals treated with either vehicle or dexamethasone. CONCLUSIONS: Despite ischemic levels of cerebral blood flow, pretreatment with dexamethasone prevents cerebral damage in neonatal rats. Instead of improving local cerebral perfusion, dexamethasone presumably acts via peripheral or central glucocorticoid receptors to produce some alteration in the brain that decreases its susceptibility to hypoxia-ischemia.

Animals↗
PubMed1988

Dexamethasone inhibits respiratory glycoconjugate secretion from feline airways in vitro by the induction of lipocortin (lipomodulin) synthesis.

The effect of glucocorticoids on respiratory glycoconjugate (RGC) secretion was studied in a cat tracheal organ culture system. Dexamethasone (10(-5) to 10(-9) M) added to culture medium for 24 h caused a dose-related reversible inhibition of RCG of as much as 40% with a peak effect at 24 to 60 h after initiation of dexamethasone treatment. A monoclonal antilipocortin antibody added to the cultures blocked the inhibitory effect of dexamethasone on RGC secretion and accelerated the reversal of the dexamethasone effect after discontinuation of dexamethasone treatment. A control antibody without antilipocortin activity had no effect on RGC secretion or dexamethasone-induced inhibition of RGC secretion. Measurement of the concentration of lipocortin in airways revealed a 220% increase after treatment with dexamethasone for 24 h. We conclude that dexamethasone inhibits RGC secretion through the induction of lipocortin synthesis.

Animals↗
PubMed1967

Comparison of effects of deoxycorticosterone and dexamethasone on cardiovascular responses to norepinephrine.

Cardiovascular responses to graded iv infusions of norepinephrine were observed in 24 dogs that had been treated for 1 week with either placebo, dexamethasone, or deoxycorticosterone. Eight dogs served as control and received daily iv injections of placebo; eight dogs received the mineralocorticoid, deoxycorticosterone; and eight received the glucocorticoid, dexamethasone. The three groups did not differ with respect to base-line hemodynamic variables either before administration of norepinephrine or after autonomic reflexes had been inhibited by ganglionic blockade. Comparisons of the three groups' hemodynamic responses to norepinephrine were made both before and after ganglionic blockade with the parallel line bioassay as a statistical test. Dogs given deoxycorticosterone had much greater increases in mean arterial pressure and peripheral resistance with norepinephrine than did dogs given dexamethasone or placebo. Dogs given dexamethasone had slightly greater increases in mean arterial pressure than did dogs given placebo; changes in peripheral resistance were similar in the two groups. The augmented response of mean arterial pressure was apparent only after ganglionic blockade in the dexamethasone group. The vascular effects of norepinephrine, therefore, were markedly augmented by treatment with doxycorticosterone and only slightly augmented by treatment with dexamethasone. The effect of norepinephrine on mean right atrial pressure was augmented in both groups treated with steroid before hexamethonium but only in the group treated with dexamethasone after hexamethonium. The results indicate that deoxycorticosterone and dexamethasone have different qualitative and quantitative effects on circulatory responses to norepinephrine.

Animals↗
PubMed1984

Effect of dexamethasone on in vivo prostanoid production in the rabbit.

To investigate the effects of antiinflammatory steroids on in vivo prostaglandin production, urinary excretion rates of six different cyclo-oxygenase products were determined before, during, and after the administration of dexamethasone (1 mg/kg per d). Urine was collected in metabolism cages and was analyzed for prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) by radioimmunoassay after open-column chromatography; 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) were determined by radioimmunoassay after organic solvent extraction and reversed-phase high performance liquid chromatography; 7 alpha-hydroxy-5,11-di-keto-tetranorprostane-1,16-dioic acid (PGE-M) and 5 alpha,7 alpha-dihydroxy-11-keto-tetranorprostane-1,16-dioic-acid (PGF-M), the major urinary metabolites of prostaglandins E and F, were determined by gas chromatography-mass spectrometry and by radioimmunoassay, respectively. Dexamethasone failed to cause a statistically significant change in the excretion rate of PGE2 (control, 250.4 +/- 40.8; dexamethasone, 297.6 +/- 78.7 ng/kg per d). In contrast, PGF2 alpha excretion decreased during administration of dexamethasone (from 1,036 +/- 228 to 449 +/- 158 ng/kg per d; P less than 0.05). The urinary excretion rates of 6-keto-PGF1 alpha, TxB2, PGE-M, and PGF-M were not significantly altered by dexamethasone. (Control and dexamethasone values were, respectively, 63.6 +/- 7.9 and 103.5 +/- 17.9 ng/kg per d for 6-keto-PGF1 alpha; 13.0 +/- 3.0 and 14.8 +/- 2.1 ng/kg per d for TxB2; 1,251 +/- 217 and 1,905 +/- 573 ng/kg per d for PGE-M; and 4,131 +/- 611 and 4,793 +/- 600 ng/kg per d for PGF-M). Urine flow was significantly higher during dexamethasone administration (control, 159 +/- 24; dexamethasone, 305 +/- 29 ml/24 h; P less than 0.01). However, no correlation could be detected between changes in urine flow and changes in the excretion rate of any of the prostanoids investigated. It is concluded that the administration of pharmacological doses of glucocorticoids does not affect the basal rate of total body prostanoid synthesis.

Animals↗
PubMed1996

Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor.

Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS- and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.

Animals↗
PubMed1997

Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets.

The direct effects of glucocorticoids on pancreatic beta cell function were studied with normal mouse islets. Dexamethasone inhibited insulin secretion from cultured islets in a concentration-dependent manner: maximum of approximately 75% at 250 nM and IC50 at approximately 20 nM dexamethasone. This inhibition was of slow onset (0, 20, and 40% after 1, 2, and 3 h) and only slowly reversible. It was prevented by a blocker of nuclear glucocorticoid receptors, by pertussis toxin, by a phorbol ester, and by dibutyryl cAMP, but was unaffected by an increase in the fuel content of the culture medium. Dexamethasone treatment did not affect islet cAMP levels but slightly reduced inositol phosphate formation. After 18 h of culture with or without 1 microM dexamethasone, the islets were perifused and stimulated by a rise in the glucose concentration from 3 to 15 mM. Both phases of insulin secretion were similarly decreased in dexamethasone-treated islets as compared with control islets. This inhibition could not be ascribed to a lowering of insulin stores (higher in dexamethasone-treated islets), to an alteration of glucose metabolism (glucose oxidation and NAD(P)H changes were unaffected), or to a lesser rise of cytoplasmic Ca2+ in beta cells (only the frequency of the oscillations was modified). Dexamethasone also inhibited insulin secretion induced by arginine, tolbutamide, or high K+. In this case also the inhibition was observed despite a normal rise of cytoplasmic Ca2+. In conclusion, dexamethasone inhibits insulin secretion through a genomic action in beta cells that leads to a decrease in the efficacy of cytoplasmic Ca2+ on the exocytotic process.

Animals↗
PubMedDate not supplied

Dexamethasone -induced apoptosis of human monocytes exposed to immune complexes. Intervention of CD95- and XIAP-dependent pathways.

Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone.

Acridine Orange↗
PubMed1990

Characterization of dexamethasone binding in normal and uremic human serum.

The purpose of this study was to examine the extent and linearity of dexamethasone binding over a wide concentration range in normal and uremic serum. Tritiated dexamethasone was added to both untreated and charcoal-treated pooled normal serum and to pooled uremic serum to produce concentrations similar to those attained therapeutically (10-1000 ng/mL). Protein binding was determined by equilibrium dialysis at 37 degrees C. Dexamethasone serum binding was linear over the entire range of concentrations for each set of pooled serum. The mean (+/- SD) percent bound (mean +/- SD) for dexamethasone was similar for untreated (75.1 +/- 3.6 percent) and charcoal-treated (77.3 +/- 3.5 percent) normal serum. Dexamethasone binding (69.2 +/- 1.8 percent, p less than 0.05) and serum albumin concentrations (39.9 vs. 55.1 mmol/L) were significantly less in uremic vs. normal serum, respectively. These results suggest that (1) the binding of dexamethasone is linear and occurs primarily to albumin, with little or no binding to corticosteroid-binding globulin; (2) endogenous cortisol does not compete with dexamethasone for protein binding sites; and (3) steroid pharmacokinetics may be altered in uremic patients due to the 24 percent higher free fraction of dexamethasone in this population.

Adult↗