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Modulation of intracellular calcium signaling and mitochondrial function in cultured osteoblastic cells by dexamethasone and celecoxib during mechanical stimulation.

OBJECTIVE: Evaluation of potentially therapeutically relevant effects of dexamethasone and celecoxib on crucial parameters of bone physiology during and following mechanical stimulation in cultured osteoblasts. METHODS: An in vitro mechanical stimulation model based on the rat osteogenic cell line UMR-106 was developed to investigate glucocorticoid (dexamethasone) and selective COX-2 inhibitor (celecoxib) induced changes in the intracellular calcium concentration ([Ca2+]i) and mitochondrial membrane potential (deltapsi(m)). Microfluorometric techniques were applied to monitor [Ca2+]i (Fura-2 AM) and deltapsi(m) (rhodamine 123) online as the main parameters of the actual cellular metabolism. RESULTS: Basal [Ca2+] was found to be 92.2 +/- 3.7 nM and increased tip to 711 +/- 27 nM during mechanical stimulation under controlled conditions. Addition of 100 nM dexamethasone or 10 microM celecoxib for 24 h suppressed the increase in [Ca2+]i significantly to 530 +/- 33 nM and 546 +/- 39 nM, respectively. Dexamethasone significantly reduced, but celecoxib significantly increased the spread velocity of the mechanically induced intracellular calcium wave. Furthermore, the effects induced by dexamethasone were amplified during the inhibition of gap junction coupling and diminished following enlarged gap junction coupling. In contrast, the modulation of gap junction coupling exerted only a minor influence on the celecoxib-induced effects. Short-term application of dexamethasone (5 min) caused significantly reduced mechanically induced depolarization of the mitochondrial membrane, but long-term application (24 h) did not. In contrast, only the long-term application (24 h) of celecoxib caused such depolarization. CONCLUSION: The observed effects of dexamethasone and celecoxib on mechanically induced changes in [Ca2+] and deltapsi(m) are suggested to result from short-term changes in membrane characteristics and long-term changes in protein synthesis. This indicates an influence of these drugs on cell-to-cell communication and metabolism that may be therapeutically relevant.

Animals↗
PubMed1992

Inhibition of fibrinolytic activity in-vivo by dexamethasone is counterbalanced by an inhibition of platelet aggregation.

Dexamethasone decreases the fibrinolytic activity in cultured medium of several cell types by an induction of PAI-1 synthesis. As a result of this enhanced PAI-1 synthesis a prothrombotic state is expected in patients treated with dexamethasone. However, such a prothrombotic state is not reported as a major adverse effect. We have studied the effects of dexamethasone (dose range: 0.1-3.0 mg/kg) on the fibrinolytic system of rats after a 5 day pretreatment period. It appeared that dexamethasone dose dependently decreased the fibrinolytic activity (a dose of 1 mg/kg showed a reduction of about 40%). This reduced fibrinolytic activity could be functionally translated into an increased thrombus size as measured with a venous thrombosis model: thrombus size was increased by 50% with 1 mg/kg dexamethasone. No effects could be measured on the coagulation system, but it appeared that ex-vivo measured platelet aggregation was dose dependently inhibited by dexamethasone treatment. This effect resulted in-vivo in prolonged obstruction times as measured with a modified aorta-loop model. These results indicate that the expected prothrombotic state due to a diminished fibrinolytic activity caused by dexamethasone is counterbalanced by an inhibition of platelet aggregation.

Animals↗
PubMed1992

Effects of dexamethasone on late radiation injury following partial-body and local organ exposures.

Dexamethasone was evaluated as a treatment for radiation-induced lung, kidney, liver, and spinal cord injuries in rats. One experimental group was partial-body-irradiated (22.5 Gy) with the head, femur, and exteriorized intestine shielded to prevent acute mortality. Other animals received local irradiation to the kidney (20 Gy), liver (25 Gy), or a 1-cm segment of cervical spinal cord (18 to 40 Gy). Following irradiation half of the animals in each radiation group were given drinking water containing 188 micrograms/liter of dexamethasone. Tests were done to assess kidney function (hematocrit, plasma urea nitrogen, ethylenediaminetetraacetic acid clearance), liver function (rose bengal clearance, plasma glutamic oxaloacetic acid transaminase), or spinal cord injury (paralysis). The effectiveness of dexamethasone in preventing radiation injury was tissue specific. Dexamethasone eliminated lethal pleural fluid accumulation after partial-body irradiation and delayed development of kidney dysfunction after local kidney irradiation. As a result, dexamethasone increased the median survival time from 63 to 150 days after partial-body irradiation and from 126 to 175 days after local kidney irradiation. After whole-liver irradiation, development of hepatic functional injury was retarded by dexamethasone treatment but without significantly changing survival time. Dexamethasone had no effect on spinal cord tolerance but significantly shortened the latent period between radiation and paralysis.

Animals↗
PubMed2005

[Effects of dexamethasone on the expression of muscarinic receptor mRNA in asthmatic guinea pig airway smooth muscle and eosinophil infiltration in bronchoalveolar lavage fluid].

OBJECTIVE: To investigate the effect of dexamethasone on the expression of muscarinic receptor (MR) mRNA in smooth muscle and infiltration of eosinophils (Eos) in the airway of asthmatic guinea pigs. METHODS: Thirty healthy guinea pigs were randomized into 3 equal groups, the control group, asthmatic group and dexamethasone therapy group. Asthma was induced in the latter 2 groups with the asthma-inducing agents and received treatments as indicated. Bronchial alveolar lavage fluid(BALF) were collected subsequently from the guinea pigs for examining the total cell number and cell classification, and histopathologic examination of the lung tissue was performed. Semi-quantitative analysis with reverse transcriptional- polymerase chain reaction (RT-PCR) was performed for M(2) and M(3) receptor mRNA in airway smooth muscle. RESULTS: Compared with the control and the asthmatic group, the number of Eos in the BALF of dexamethasone therapy group was significantly lower (P<0.01). In spite of the presence of hyperemia and edema in the lung tissues of the dexamethasone therapy group, Eos infiltration was less severe than that in the asthmatic group. As found by RT-PCR, the quantity of M(2) receptor mRNA in the airway smooth muscle of the dexamethasone therapy group was significantly higher than those in both the control and asthmatic groups (P<0.01), and the quantity of M(3) receptor mRNA in the airway smooth muscle of dexamethasone therapy group was significantly higher than that in the asthmatic group, but did not significantly differ from that in the control group. The quantities of M(2) and M(3) receptor mRNAs in the control group were both significantly higher than that in asthmatic group (P<0.01). CONCLUSION: The expression of M(2) receptor is increased in antigen- challenged guinea pigs, and that of M(3) receptor decreased. Dexamethasone can treat asthma by inhibiting inflammatory action involving Eos infiltration, regulating the expressions of M(2) and M(3) receptors and restoring the function of M(2) receptor.

Animals↗
PubMed1991

Dexamethasone markedly induces Na,K-ATPase mRNA beta 1 in a rat liver cell line.

Exposure of Clone 9 cells, a "nontransformed" rat liver cell line, to 10(-8) M dexamethasone resulted at 3 h in 1.8 +/- 0.2- and 40 +/- 5-fold increases in mRNA alpha 1 and mRNA beta 1 content, respectively, an effect that was not mimicked by 10(-8) M aldosterone. The increments in mRNA alpha 1 and mRNA beta 1 abundances in total cell RNA were half-maximal at 5 x 10(-9) M dexamethasone and persisted for more than 24 h. Na,K-ATPase activity, however, increased only slightly (by 9%) at 24 h. The induction of mRNA beta 1 by dexamethasone was not prevented by the presence of cycloheximide. mRNA beta 1 abundance increased earlier in the nuclear RNA pool (becoming apparent within 45 min) than in the cytoplasmic RNA pool, consistent with a precursor-product relationship. Moreover, putative pre-mRNA beta 1 bands of approximately 4,600 and approximately 12,000 nucleotides accumulated in the nRNA pool after 1 h of exposure to dexamethasone. Incubation in the presence of dexamethasone for 3 h enhanced the incorporation of [3H]uridine into total cell mRNA alpha 1 and mRNA beta 1 by 1.3- and 12-fold, respectively. In nuclear run-on assays, however, transcription of mRNA alpha 1 and mRNA beta 1 was not altered after 30 min of exposure to 10(-8) M dexamethasone. The abundance of mRNA beta 1 in rat liver also increased markedly (greater than 30-fold) in rats treated with the hormone for 6 h. We conclude that dexamethasone causes an induction of Na,K-ATPase subunit mRNAs, an effect that is markedly greater for mRNA beta 1 than for mRNA alpha 1. The increases in subunit mRNA content, however, are associated with, at most, a small increase in Na,K-ATPase activity, suggesting that the increments in mRNA abundances, especially that of mRNA beta 1, do not play a determining role in the regulation of Na,K-ATPase activity in these cells.

Animals↗
PubMed2006

[Effect of dexamethasone on degradation of cultured myotube protein and its mechanism].

OBJECTIVE: To study the effect of dexamethasone on degradation of long-lived protein in myotubes and to elucidate its possible mechanism. METHODS: After isolating skeletal muscles of rat's hind limb under sterile condition, the myoblasts were proliferated in tissue-block culture. After being passaged and purified, the myoblasts fused into myotubes. The protein in myotubes was radiolabelled with L-[3,5-(3)H]-tyrosine, and then the myotubes were divided into two groups. In group A, the myotubes were cultured in Dubbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 2 mmol/L tyrosine without dexamethasone (control group), with dexamethasone 10 nmol/L (group A1), dexamethasone 100 nmol/L (group A2), and dexamethasone 1,000 nmol/L (group A3), respectively. The amounts of L-[3,5-(3)H]-tyrosine in culture medium and cells were determined and the degradation rates of long-lived protein were calculated at 12, 24, 36, 48 hours of culture. In group B, the myotubes were cultured in DMEM containing 10% FBS and 2 mmol/L tyrosine with 50 micromol/L proteasome inhibitor MG132 (group B1), or 50 micromol/L MG132 and 100 nmol/L dexamethasone (group B2). Proteolytic rates of protein were calculated with the same way as group A at 24 hours. RESULTS: The proteolytic rate of long-lived protein in group A1, group A2 and group A3 was all increased significantly compared with that in control group (all P<0.01), and that in group A2 and A3 rose markedly compared with that in group A1 (both P<0.01), respectively. There was no statistically significant difference between group A2 and group A3 (P>0.05). Proteolytic rate of long-lived protein in group B1 was significantly lower than that in control group (P<0.01). The degradation rate of long-lived protein in group B2 was markedly lower than that in group A2 (P<0.01). CONCLUSION: The results suggest that the ubiquitin-proteasome system is one of the important pathways of degradation of long-lived protein in cultured myotubes, and dexamethasone could enhance the degradation of long-lived protein in cultured myotubes by activating ubiquitin proteasome pathway in dose-dependent manner.

Animals↗
PubMed2006

[Protective effects of dexamethasone on myocardium in rats with sepsis].

OBJECTIVE: To investigate the changes in heart function and myocardial mechanics in murine sepsis model, and the mechanism of the protective effect of dexamethasone on heart. METHODS: Wistar rats were randomly divided into control group, lipopolysaccharide (LPS) group (4 mg/kg LPS intravenously), LPS+dexamethasone group (4 mg/kg LPS+2 mg/kg dexamethasone intravenously), with 32 rats in each group. A catheter was passed through right common carotid artery to the left cardiac ventricle. Function of the left ventricle was monitored, and blood was drawn at 0, 2, 4, 6 hours to detect concentrations of tumor necrosis factor-alpha (TNF-alpha), troponin T (TnT), with 8 rats for each time point. RESULTS: In sepsis rats, TnT increased significantly and could be lowered by dexamethasone [at 6 hours after the treatment (1.76+/-0.57) microg/L vs. (0.70+/-0.36) microg/L, P<0.01]. There were changes in left ventricular peak systolic pressure (LVPP) and maximum rate of intraventricular pressure rise/down (+/-dp/dt max) to certain extent, and increase in left ventricular end-diastolic pressure (LVEDP), but these changes could be ameliorated by using dexamethasone. TNF-alpha increased significantly in sepsis rats, but dexamethasone could lower its level [at 2 hours after the treatment (11.22+/-2.38) pmol/L vs. (7.62+/-3.21) pmol/L, P<0.01]. CONCLUSION: Myocardium is remarkably damaged in rats with sepsis. TNF-alpha could be regarded as one of the factors which could produce injury to myocardium. Dexamethasone could alleviate cardiac damage produced by endotoxin in sepsis model.

Animals↗
PubMed1990

Inhibition by dexamethasone of histamine production in allergic inflammation in rats.

In an allergic inflammation model of air pouch type in rats, histamine level in the pouch fluid and histidine decarboxylase activity of pouch wall tissues in the postanaphylaxis phase were increased. Although treatment with dexamethasone failed to inhibit histamine release from mast cells in the anaphylaxis phase, histamine production in the postanaphylaxis phase was inhibited dose dependently. Histamine production-increasing activity in the pouch fluid collected 8 h after the Ag challenge, which was estimated by an activity to stimulate histamine production by bone marrow cells, was decreased by the administration of dexamethasone at the time of the Ag challenge. The addition of steroidal antiinflammatory drugs, dexamethasone, prednisolone, or hydrocortisone, into the incubation medium inhibited the pouch fluid-induced histamine production by bone marrow cells. Hydrocortisone mesylate antagonized the inhibitory effect of dexamethasone on histamine production by bone marrow cells. However, hydrocortisone mesylate failed to recover the decrease in histamine production-increasing activity of the pouch fluid collected from dexamethasone-treated rats. In addition, the dialyzed sample of pouch fluid obtained from dexamethasone-treated nonsensitized rats did not reduce the stimulated histamine production by the pouch fluid sample obtained from the sensitized rats. However, increase in histamine production of bone marrow cells stimulated by the pouch fluid was not inhibited by cyclosporin A that inhibited histamine production induced by Con A. This observation indicates that the pouch fluid has no effect to induce production of the histamine production-increasing factor by bone marrow cells. Consequently, it is suggested that dexamethasone inhibits not only the production of histamine production-increasing factor but also the response of histamine-producing cells to this factor.

Animals↗
PubMed1990

Dexamethasone increases heparan sulfate proteoglycan core protein content of glomerular epithelial cells.

Heparan sulfate proteoglycan (HSPG) has been identified as an important determinant of glomerular permselectivity. We have previously reported that glomerular epithelial cells in culture synthesize HSPG, suggesting that in vivo these cells contribute to the HSPG present in the glomerular basement membrane. In this study we examined the effects of dexamethasone on the metabolism of HSPG core protein in cultured glomerular epithelial cells. Dexamethasone caused a dose-dependent and time-dependent increase in the HSPG core protein content of the cells. This effect was not seen with an equimolar concentration of aldosterone, indicating it was selective for dexamethasone. Dexamethasone caused a significant inhibition in 3H-leucine incorporation into de novo synthesized proteins at concentrations that caused maximum increment in the HSPG core protein content. These findings support the interpretation that HSPG core protein is a selective target for dexamethasone. Actinomycin-D completely abrogated the dexamethasone effect on HSPG core protein content, implying that enhanced transcription may be the major mechanism underlying the dexamethasone-induced increment in HSPG core protein content. Our findings suggest that glucocorticoids have important effects on the metabolism of the core protein moiety of heparan sulfate proteoglycan. Furthermore, these data imply that the glucocorticoid-induced amelioration of proteinuria could involve metabolic effects on the local determinants of glomerular permselectivity (e.g., HSPG) in addition to their well-known systemic anti-inflammatory effects.

Aldosterone↗
PubMed1990

Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects.

High concentrations of tumor necrosis factor (TNF) alpha have been detected in the plasma of patients undergoing immunotherapy with interleukin 2 (IL-2), suggesting that this cytokine may play a role in the fever and shocklike state induced by the administration of high-dose IL-2. Dexamethasone has been shown to inhibit the synthesis of TNF by monocytes activated in vitro by endotoxin. To determine if dexamethasone can exert a similar suppressive effect on IL-2-induced TNF synthesis in vivo, the concentration of TNF alpha was measured in plasma samples serially obtained (a) from cancer patients participating in a phase I dose escalation clinical trial with high-dose IL-2 administered in conjunction with dexamethasone (IL-2/Dex) and (b) from patients participating in concurrent studies with IL-2 alone. In contrast to the high plasma levels of TNF alpha detected in patients receiving IL-2 alone, TNF levels in most of the IL-2/Dex patients remained below the threshold of detectability of our TNF radioimmunoassay. The concurrent administration of dexamethasone also prevented the IL-2-induced increase in serum levels of C-reactive protein, a hepatic acute phase reactant whose synthesis is regulated by proinflammatory cytokines such as TNF. The steroid-treated patients also failed to develop the neutrophil chemotactic defect characteristic of IL-2 recipients. The concomitant administration of dexamethasone increased the maximum tolerated dose of IL-2 approximately threefold and markedly reduced the hypotension and organ dysfunction ordinarily observed in these patients. These results demonstrate that dexamethasone inhibits the release of TNF into the circulation of patients undergoing immunotherapy with IL-2. They further suggest that the altered spectrum and reduced severity of IL-2 side effects observed in patients receiving dexamethasone may be attributable in part to the suppressive effect of steroids on IL-2-induced TNF synthesis.

C-Reactive Protein↗
PubMed1989

Transcriptional regulation of alpha-fetoprotein expression by dexamethasone in human hepatoma cells.

The level of alpha-fetoprotein (AFP) mRNA in HuH-7 human hepatoma cells is elevated by the addition of dexamethasone to the culture medium. To locate the DNA region involved in hormonal regulation of the AFP gene, we constructed recombinant plasmids in which various lengths of the 5'-flanking sequence of the human AFP gene were fused to the CAT gene. Various cell lines were transfected with the recombinant plasmids, incubated with or without 3 x 10(-6) M dexamethasone, and then assayed for chloramphenicol acetyltransferase expression. In hepatoma cells that produce AFP, the dexamethasone treatment resulted in the stimulated chloramphenicol acetyltransferase expression when the transfected plasmids contained 169 base pairs (bp) or longer AFP 5'-flanking sequence. No dexamethasone effect was observed when the 5'-flanking sequence was less than 98 bp long. The dexamethasone stimulation was effectively suppressed by the glucocorticoid antagonist RU486, indicating that this effect is mediated by glucocorticoid receptors. The 71-bp region between positions -169 and -98 contains a nucleotide stretch which is similar to the consensus sequence of the glucocorticoid responsive element (GRE). Partial alterations of this sequence resulted in decreased dexamethasone response. The GRE-containing region stimulated heterologous (SV40) promoter activity in response to dexamethasone treatment in an orientation- and position-independent manner. The GRE and the upstream AFP enhancer function independently from each other.

Base Sequence↗
PubMed1989

[Effect of dexamethasone on osteoblastic cells derived from mouse calvaria].

In the present study, the effect of dexamethasone on MC3T3-E1 cells, a strain of osteoblasts derived from mouse cranial bone, was determined. The following results were obtained. 1) Dexamethasone showed dose-dependent suppression of the growth of MC3T3-E1 cells at concentration of 1 microgram/ml or more. 2) The alkaline phosphatase activity was increased 12, 24, and 48 hours after treatment with dexamethasone at 1, 10 or 30 micrograms/ml. The activity was highest at 48 hours, the level being 311% of the control value at a dose of 10 micrograms/ml. When dexamethasone at a dose of 60 micrograms/ml or more was used, the activity was increased at 12 hours, but was lower than the control at 48 hours. 3) Synthesis of collagenous protein was facilitated after 24-hour treatment with dexamethasone at 1, 10 or 30 micrograms/ml. In particular, the level of synthesis was highest, 232% of the control value, at 10 micrograms/ml. Such synthesis, however, was suppressed at a dose of 60 micrograms/ml or more. 4) Synthesis of collagenous protein was facilitated by 48-hour treatment with dexamethasone at a dose of 1 or 10 micrograms/ml and suppressed at a dose of 30 micrograms/ml or more. 5) Microscopic observation of stained preparations revealed that dexamethasone caused vacuolar degeneration, deep staining of the nucleus, and pyknosis at 60, 150, and 200 micrograms/ml, respectively.

Alkaline Phosphatase↗
PubMed1989

Potentiation of 3-methylcholanthrene induction of rat hepatic cytochrome P450IA1 by dexamethasone in vivo.

The potentiation of the expression of polycyclic aromatic hydrocarbon-inducible cytochromes P450IA1 and P450IA2, and phenobarbital-inducible cytochrome P450IIB1 and NADPH-cytochrome P-450 reductase by dexamethasone in vivo was investigated using adrenalectomized and sham-operated rats. Hepatic cytochrome P450IA1 activity (determined by ethoxyresorufin O-deethylase activity) was induced maximally (30-fold) in both sham-operated and adrenalectomized rats 24 hr after a single injection of 3-methylcholanthrene (10 mg/kg). Dexamethasone (10 mg/kg) increased hepatic tyrosine aminotransferase activity 3- to 4-fold, but had little or no effect on ethoxyresorufin O-deethylase activity. However, dexamethasone potentiated the 3-methylcholanthrene-dependent induction of hepatic P450IA1 activity 2- to 3-fold in adrenalectomized rats and 1.5- to 2-fold in sham-operated rats when administered concomitantly with 3-methylcholanthrene (P less than .05). The dose of dexamethasone required to potentiate 3-methylcholanthrene induction of P450IA1 activity (greater than 1 mg/kg) correlated well with the dose required to induce hepatic tyrosine aminotransferase activity; a marker of glucocorticoid action. Potentiation of 3-methylcholanthrene induction of P450IA1 activity in the rat appears to be tissue specific in that dexamethasone was found not to potentiate 3-methylcholanthrene induction of P450IA1 activity of rat lung or kidney. Cytochrome P450IA1 content induced by 3-methylcholanthrene in the liver was also potentiated 2- to 3-fold by dexamethasone. In contrast, potentiation of 3-methylcholanthrene induction of cytochrome P450IA2 content was not observed. Western blot analyses indicate that the increase in monooxygenase activity induced by 3-methylcholanthrene or 3-methylcholanthrene plus dexamethasone corresponds well only with the induction of cytochrome P450IA1 protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1987

Dexamethasone causes translocation of glucose transporters from the plasma membrane to an intracellular site in human fibroblasts.

To investigate the mechanism by which glucocorticoids inhibit glucose transport in peripheral tissues, we have used a monoclonal antibody directed against the human glucose transporter to measure the relative amounts of glucose transporter polypeptide in various cell fractions of human foreskin fibroblasts after treatment with and without dexamethasone. In cells treated for 4 h with 100 nM dexamethasone, a decrease of 48% in glucose transport was accompanied by a decrease of 40% in the amount of glucose transporter polypeptide in a plasma membrane fraction enriched 10-fold in 5'-nucleotidase activity and a 78% increase in the amount of transporter polypeptide in a fraction of putative intracellular membranes, designated P2. There was no significant change in the amount of transporter polypeptide in whole cell lysates. Insulin (200 nM) stimulated glucose transport in basal fibroblasts by only 9%. However, addition of insulin for 30 min to cells that had been treated for 4 h with dexamethasone completely reversed the dexamethasone-induced decrease in glucose transport and also reversed the dexamethasone-induced changes in glucose transporter polypeptide content of the plasma membrane and P2 fractions. From these observations we conclude that dexamethasone decreases glucose transport by causing translocation of glucose transporters from the plasma membrane to an internal location and that insulin reverses the dexamethasone effect by reversing the translocation.

5'-Nucleotidase↗
PubMed1986

The regulation of somatostatin production in human medullary thyroid carcinoma cells by dexamethasone.

There have been few studies of physiological importance on the regulation of somatostatin by hormones. We have studied the effect of the synthetic glucocorticoid dexamethasone on somatostatin production in the human medullary thyroid carcinoma TT cell line, a model for somatostatin production by the parafollicular cell. Dexamethasone inhibited somatostatin production in a dose-related manner with a maximal effect at a concentration of 10(-6) M. TT cells treated with dexamethasone (10(-6) M) showed an almost complete inhibition of somatostatin peptide production by 48 h of treatment. Molecular sizing chromatography demonstrated a decrease in both the probable somatostatin precursor (13,000 dalton) and the fully processed peptide. Analysis of mRNA content by hybridization revealed that dexamethasone also caused a decrease in detectable somatostatin mRNA. The hybridizable somatostatin mRNA decreased to approximately 50% of basal levels within 12 h of treatment. Northern blot hybridization showed a decrease in a single RNA species representing mature somatostatin mRNA. Dose-response experiments revealed inhibition of both peptide and mRNA at concentrations from 1 X 10(-8) to 1 X 10(-5) M dexamethasone. Four days after withdrawal from dexamethasone treatment, peptide and mRNA levels were higher than dexamethasone-treated controls. The sex steroid estradiol had no inhibitory effect on somatostatin production. These results suggest a potential regulator of somatostatin production and provide a system for the study of somatostatin gene regulation.

Cell Line↗
PubMed1985

The effect of dexamethasone on the cytotoxic and enzymatic response of cultured endothelial cells to radiation.

Experiments were conducted to determine (1) whether glucocorticoids directly protected endothelial cells (EC) from radiation and (2) if angiotensin converting enzyme (ACE) activity, known to be increased by glucocorticoid, played a role in the EC response to radiation. Confluent monolayers of EC cultured from bovine aorta EC were treated with dexamethasone (10(-6) M); after irradiation (5.0 Gy, 60Co gamma), ACE and lactate dehydrogenase (LDH) activities, DNA and protein contents, and nuclei number were measured. Twenty-four hours after 5 Gy, there was increased cell loss (-40%, P less than 0.001), greater LDH release (greater than 100%, P less than 0.001), more LDH activity per cell (+40%, P less than 0.001), and unchanged ACE activity compared to sham-irradiated control EC. However, 48 hr after 5 Gy, ACE activity per cell was decreased (-24%, P less than 0.005). A 48-hr exposure to dexamethasone alone was accompanied by a slight cell loss (-10%, P less than 0.001) and increased cellular ACE activity (+40-140%, P less than 0.001), but a 24-hr dexamethasone exposure was not cytotoxic and did not change ACE activity. Dexamethasone exposure for 48 hr before and after irradiation did not attenuate cell loss or LDH release. However, combined dexamethasone treatment and radiation increased cellular ACE activity at a time when neither agent alone had an effect (24-hr dexamethasone exposure before 5 Gy and assayed 24 hr after 5 Gy). This interaction between radiation and dexamethasone treatment suggests that the glucocorticoid modifies the cell's response to injury. Although this interaction does not ameliorate radiation cytotoxicity, maintenance of ACE levels in injured vessels by hormones may have physiological significance in the hemodynamics of irradiated tissues.

Animals↗
PubMed1988

Anovulation and plasma hormone concentrations after administration of dexamethasone during the middle of the luteal phase in sows undergoing estrous cycles.

The effect of glucocorticoids on early follicular growth in sows undergoing normal estrous cycles was evaluated by administration of dexamethasone during the middle of the luteal phase. Plasma specimens were obtained for measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and estradiol-17 beta concentrations. Fifteen sows were used. Control sows (n = 5) were given physiologic saline solution twice daily from day 9 to day 14 of the estrous cycle. Sows of the second group (n = 5) were given dexamethasone (30 micrograms/kg of body weight, IM) similarly, and those of the third group (n = 5) were given dexamethasone plus gonadotropin-releasing hormone (GnRH; 50 micrograms at 6-hour intervals, IV). Plasma specimens, obtained twice daily from day 8 through day 26, indicated that progesterone production and luteal regression were not inhibited by any of the 3 treatment regimens. Although preovulatory plasma estradiol concentration increased in control sows, such was not observed in the sows treated with dexamethasone or dexamethasone plus GnRH (P less than 0.01). Ovulation, with formation of corpora lutea, occurred in gilts given saline solution. Dexamethasone administration resulted in persistence of 19 to 41 follicles/ovary (2 to 4 mm in diameter), and dexamethasone-plus-GnRH treatment resulted in 6 to 18 follicles/ovary (5 to 6 mm in diameter). Plasma was obtained at 15-minute intervals for 12 hours to compare the effect of treatment on hormone concentrations on day 12 of the estrous cycle with the values on day 8.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Dexamethasone alters glucose, lactate, and insulin dyshomeostasis during endotoxicosis in the rat.

This study examined the effects of dexamethasone on the glucose, lactate, and insulin dyshomeostasis of endotoxicosis in the rat. To assess the effects of dexamethasone on carbohydrate dyshomeostasis, sequential measurements of plasma glucose and lactate were made in vivo. The effects of dexamethasone on endotoxin-induced portal and systemic hyperinsulinemia also were evaluated in vivo. The ability of dexamethasone to alter the insulin hypersecretory state of the endotoxic pancreas was evaluated by using the in vitro perfused rat pancreas. Endotoxicosis caused severe hypoglycemia and hyperlactacidemia in the pentobarbital-anesthetized rat. Dexamethasone prevented the hypoglycemia, significantly reduced the hyperlactacidemia, and prevented endotoxin-induced hyperinsulinemia in vivo. Dexamethasone reduced endotoxin-induced pancreatic hypersecretion of insulin when administered as a pretreatment 1 h prior to endotoxin treatment; however, when administered as a cotreatment with endotoxin, no significant reduction of insulin hypersecretion occurred. The results of this study suggest that the ameliorating effects of dexamethasone on glucose and lactate dyshomeostasis occur not only at the peripheral tissue level, but also through effects on insulin secretion.

Animals↗