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PubMed1984

Plasma concentrations, renal excretion, and tissue release of prostaglandins in the rat with dexamethasone-induced hypertension.

This study was designed to investigate whether the hypertension produced by dexamethasone in the rat is associated with a deficit in circulating and renal prostaglandin E2 (PGE2) and PGI2, PGs that are presumed to contribute to antihypertensive mechanisms. The administration of dexamethasone (2.5 mg kg-1 week-1, sc) increased systolic blood pressure by 41 +/- 6 mm Hg (P less than 0.05) after 14 days of treatment, associated with elevations of urine volume and fluid intake and loss of body weight. The glucocorticoid, however, had no effect on the plasma concentration, urinary excretion, or vascular and renal tissue release of immunoreactive 6-keto-PGF1 alpha, a PGI2 metabolite. In contrast, dexamethasone increased (P less than 0.05) the plasma PGE2 concentration by 157% and PGE2 urinary excretion by 134% after 14 days of treatment. However, the basal release of immunoreactive PGE2 as well as the angiotension II-induced release of radiolabeled arachidonic acid and PGs from renal medulla slices incubated in Krebs solution were diminished in rats receiving dexamethasone. The steroid also reduced to about 60% (P less than 0.05) of the control value the activity in renal homogenates of 15-hydroxyprostaglandin dehydrogenase (PGDH), a major PG-catabolizing enzyme, without affecting the activity of the enzyme in the lung. Hence, the increased plasma concentration and renal excretion of PGE2 caused by dexamethasone in the face of reduced renomedullary production of the PG is presumably related to diminished degradation in the kidney and perhaps in other extrapulmonary tissues. Altogether, this study demonstrates that the hypertension induced by dexamethasone in the rat is not associated with a deficit in circulating and renal PGE2 and PGI2.

Angiotensin II↗
PubMed1984

The effect of dexamethasone on parathyroid hormone stimulation of adenylate cyclase in ROS 17/2.8 cells.

Treatment of ROS 17/2.8 osteosarcoma-derived cells with dexamethasone potentiates the PTH stimulation of adenylate cyclase in these cells, yielding a detectable response to as little as 10 pM PTH. Isoproterenol stimulation was also enhanced. The dexamethasone effect is first apparent at 12 h and increases with time of treatment. The apparent EC50 for dexamethasone is 3 nM. Hydrocortisone and corticosterone act similarly to dexamethasone, but require 30-fold higher concentrations. Dexamethasone treatment produces no change in high affinity phosphodiesterase activity. Glucocorticoid-potentiating effects are much more pronounced in whole cells than in broken cells and do not influence forskolin stimulation. Particulate fractions of dexamethasone-treated cells have higher adenylate cyclase specific activity, but are stimulated by guanyl-5'-yl imidodiphosphate to the same extent as control cells. These findings suggest that the glucocorticoids potentiate hormone responsiveness through promotion of hormone receptor-adenylate cyclase coupling by a mechanism dependent on cellular integrity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Combined effects of dexamethasone and 1,25-dihydroxyvitamin D3 on parathyroid hormone secretion in cultured bovine parathyroid cells.

The present studies investigate the effects of glucocorticoids on the function of the parathyroid glands using primary cultures of bovine parathyroid cells. Treatment of parathyroid cell cultures with dexamethasone for 48 h caused a dose-dependent stimulation of PTH secretion. The minimal concentration of dexamethasone required for a significant stimulation of PTH secretion was 0.1 nM. The stimulatory effect of dexamethasone on the secretion of PTH was found within 12 h of treatment with 100 nM dexamethasone. The steroids deoxycorticosterone and cortexolone, which do not have glucocorticoid activity were without effect of PTH secretion. Since glucocorticoids may modulate the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in other tissues, additional studies were performed to evaluate the interactions of glucocorticoids and 1,25-(OH)2D3. Addition of 1,25-(OH)2D3 to parathyroid cell cultures for 48 h significantly suppressed PTH secretion. In the presence of dexamethasone, however, 1,25-(OH)2D3 also significantly decreased PTH secretion, although it did not reduce PTH secretion to control levels. The treatment of parathyroid cell cultures with 100 nM dexamethasone did not affect the parathyroid cell content of 1,25-(OH)2D3 receptors. In summary, these studies indicate that glucocorticoids significantly increase the secretion of PTH in vitro. This stimulatory effect can be inhibited by 1,25-(OH)2D3. The parathyroid gland is an additional site of physiological antagonism of glucocorticoids and 1,25-(OH)2D3.

Animals↗
PubMed1990

Dexamethasone inhibits insulin biosynthesis by destabilizing insulin messenger ribonucleic acid in hamster insulinoma cells.

Glucocorticoid effects on insulin biosynthesis and secretion have been controversial. To define whether glucocorticoids affect insulin biosynthesis in vitro, the actions of dexamethasone on insulin gene expression were examined using the HIT cell line, a transformed clonal line of hamster beta-cells. Dexamethasone induced a dose-dependent decrease in steady-state insulin messenger RNA (mRNA) levels, which was prevented by adding an excess of RU 486, a competitive inhibitor for the binding to the glucocorticoid receptor. Inhibition was not observed before 6 h of dexamethasone treatment and was maximal at 24 h. To further assess the molecular mechanisms of the dexamethasone-induced decreases in insulin mRNA levels, we investigated whether transcription of the insulin gene was affected. Run-on assays revealed that transcription rates were not changed by glucocorticoids. Inhibition of RNA and protein synthesis by actinomycin D and cycloheximide, respectively, completely abolished the dexamethasone effects, whereas actinomycin D added 9 h after dexamethasone had no effect on insulin mRNA levels. The present results demonstrate that glucocorticoids can acutely inhibit insulin biosynthesis by destabilizing insulin mRNA; this effect requires the transcriptional activation of a gene encoding a protein responsible for the accelerated disappearance of insulin mRNA.

Adenoma, Islet Cell↗
PubMed1994

Dexamethasone increases growth hormone receptor messenger ribonucleic acid levels in liver and growth plate.

Glucocorticoid inhibits linear growth and renders target tissues, particularly liver and growth plate, insensitive to GH. We hypothesized that glucocorticoid-induced GH insensitivity is due to decreased gene expression of the GH receptor at the messenger RNA (mRNA) level. To test this hypothesis, we treated 4.5-wk-old male rabbits (n = 6-9 per group) with ip dexamethasone or vehicle and measured GH receptor mRNA levels (by RNase protection assay) and serum GH-binding protein levels (by radioimmunoprecipitation assay). Contrary to our hypothesis, dexamethasone administered in growth-suppressing doses did not decrease GH receptor mRNA levels in liver or growth plate. Instead a tissue-specific stimulation of GH receptor mRNA levels was observed. The dose-response relationship of this effect was biphasic, since the lower growth-suppressing dose of dexamethasone (0.1 mg/kg.day) caused the greater increase in GH receptor mRNA levels, whereas the higher growth-suppressing dose (4 mg/kg.day) had less effect. The dexamethasone-induced increase in GH receptor mRNA was observed in growth plate and liver, target tissues important for linear growth, but not in kidney. Serum GH-binding protein levels also showed a stimulatory response to dexamethasone treatment, with a biphasic dose-response relationship. These data suggest that glucocorticoid-induced GH insensitivity cannot be explained by decreased GH receptor mRNA levels. To the contrary, dexamethasone causes a tissue-specific stimulation in GH receptor mRNA levels with a biphasic dose-response relationship.

Animals↗
PubMed2003

Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent adrenal Cushing's syndrome (CS), which is often associated with Carney complex (CNC). We have recently described a paradoxical increase in cortisol excretion after dexamethasone administration in most patients with PPNAD. In the present study we investigated the hypothesis that this phenomenon is due to a primary abnormality of the tissues affected by PPNAD, rather than a defect of the patients' hypothalamic-pituitary-adrenal axis; as such it should be replicated in vitro by adrenal slices exposed directly to dexamethasone. We were able to study adrenal tissues from eight patients with CS caused by PPNAD; two patients were also studied in vivo according to a protocol first described in ACTH-independent macronodular adrenal hyperplasia (AIMAH) for the clinical detection of aberrant hormone receptor expression. Their DNA has been previously screened for inactivating mutations of the PRKAR1A gene, the most frequent molecular defect leading to PPNAD and/or CNC. We also investigated whether glucocorticoid receptor (GR) expression underlies paradoxical dexamethasone responses in PPNAD by immunohistochemistry and semiquantitative PCR, and we correlated GR expression with that of other markers for PPNAD (e.g. synaptophysin). Indeed, we demonstrated that dexamethasone induced cortisol secretion in vitro in five of these tumors; no such increase was seen in adenomatous or AIMAH tissues that were treated in the same manner. GR mRNA was expressed, and GR immunoreactivity was detected in PPNAD nodular cells. Staining for GR was not seen in surrounding cortical cells, and hence, it correlated with synaptophysin, which also stains PPNAD in a similar manner. In normal adrenal tissue, GR was detected mostly in medullary areas, whereas GR immunoreactivity was weak in adenomatous and AIMAH tissues. We conclude that 1) dexamethasone produces an increase in glucocorticoid synthesis by PPNAD adrenal slices in vitro, suggesting a direct effect on adrenocortical tissue, and 2) this phenomenon is accompanied by increased expression of the GR in PPNAD nodules. PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena.

Actins↗
PubMed1985

Aging alters somatomedin-C-dexamethasone synergism in the stimulation of deoxyribonucleic acid synthesis and replication of cultured human fibroblasts.

The effects of dexamethasone on somatomedin-C (SM-C) stimulation of [3H]thymidine incorporation and cell replication were studied in early passage fibroblasts from normal donors, aged 7-24 yr (young) and 85-96 yr (old), and one patient with progeria. Preincubation of cells from young donors with dexamethasone dramatically enhanced SM-C stimulation of [3H]thymidine incorporation [e.g. 19- vs. 3-fold in serum-free medium; 66- vs. 14-fold in 0.25% human hypopituitary serum (HHS)], with no alteration in the timing of peak thymidine incorporation. In contrast, preincubation of cells from old and progeric donors with dexamethasone resulted in a 6- to 12-hr lengthening of the prereplicative period and, generally, little or no synergism with SM-C. Cells from old and progeric donors had a normal replicative response to SM-C with or without 0.25% HHS. In cells from young donors, dexamethasone enhanced the SM-C-stimulated increase in cell number 32-49% in serum-free medium and 70-189% in 0.25% HHS. In comparison, dexamethasone had no potentiating effect on SM-C stimulation of multiplication of cells from old and progeric donors. These data indicate that dexamethasone and SM-C are synergistic in stimulating DNA synthesis and replication of fibroblasts from young donors, but that this synergism is impaired in cells from aged and progeric donors.

Adolescent↗
PubMed1994

Mechanisms of dexamethasone-induced insulin resistance in healthy humans.

Insulin resistance may result from decreased muscle blood flow, impaired cellular glucose transport, or intracellular deficits of glucose metabolism. The mechanisms responsible for dexamethasone-induced insulin resistance were investigated in healthy human subjects. During a 2-h hyperinsulinemic clamp, dexamethasone decreased glucose uptake, oxidation, and nonoxidative glucose disposal during the first hour. During the second hour, glucose uptake was normalized by means of hyperglycemia; glucose oxidation, however, remained suppressed by dexamethasone. Dexamethasone also abolished the insulin-mediated increase in calf blood flow. When acipimox was administered during the clamps to correct glucocorticoid-induced inhibition of glucose oxidation, dexamethasone decreased whole body glucose uptake and nonoxidative glucose disposal in the same proportion as when no acipimox was administered. However, glucose oxidation and insulin-mediated calf blood flow were normalized after acipimox. During the second hour, exogenous glucose infusion was matched to that used in the control clamp and normalized whole body glucose uptake. However, hyperglycemia developed, indicating insulin resistance. It is concluded that dexamethasone 1) decreases glucose oxidation independently of glucose transport; this inhibition is reversed by acipimox; and 2) decreases whole body glucose uptake independently of increased lipolysis, decreased glucose oxidation, or an altered muscle blood flow.

Adult↗
PubMed1998

Synergistic effects of feeding and dexamethasone on serum leptin levels.

The objectives of this study were to determine the time course of the stimulatory effect of dexamethasone on serum leptin and whether it depends on food intake. Dexamethasone (4mg) was administered I.V. over 1 minute to healthy human volunteers (n=8) under fasting and feeding conditions (2000 kcal given at three meals over 7 hours). At 10 hours, serum leptin levels were increased only in the fed subjects (delta leptin 10.6+/-1.6 vs -2.4+/-1.9 ng/ml, p=0.01, n=8). To assess the interactive effect of food and dexamethasone on serum leptin, a subgroup (n=4) was studied under 4 conditions: 1) dexamethasone/fast; 2) dexamethasone/food; 3) saline/fast; 4) saline/food. Serum leptin declined from baseline under the fasting conditions, with or without dexamethasone. Feeding prevented the drop in serum leptin. In the dexamethasone/food condition, leptin levels rose from baseline after 7 hours and doubled after 10 hours (p<0.05). The rise in serum leptin was significantly greater in the food/dexamethasone condition compared to all other conditions (p<0.05). In summary, dexamethasone has no independent effect on serum leptin in the absence of food intake. Rather, dexamethasone appears to potentiate the food-induced increase in serum leptin. This synergism may be mediated by insulin and/or other factors associated with food ingestion.

Adult↗
PubMed2000

Interleukin-1 receptor antagonist ribonucleic acid and protein expression by cultured Graves' and normal orbital fibroblasts is differentially modulated by dexamethasone and irradiation.

Recent data have indicated that orbital fibroblasts (OF) can be stimulated to produce marked quantities of interleukin-1 receptor antagonist (IL-1RA), a powerful inhibitor of the proinflammatory activities of interleukin-1 in the orbital tissues in Graves' ophthalmopathy (GO). We examined whether the beneficial effects of dexamethasone or irradiation, the two main therapeutic modalities applied in patients with active GO, may be related to their capacity to alter IL-1RA ribonucleic acid (RNA) and protein expression in OF. Early passages of cultured OF were obtained from orbital connective tissue and extraocular muscle of patients with severe active GO and five control subjects. Modulation of the two variants of IL-1RA, intracellular IL-1RA (icIL-1RA) and soluble IL-1RA (sIL-1RA), was studied after exposure of OF to increasing concentrations of dexamethasone (10(-10)-(10(-6) mol/L)), the glucocorticoid receptor antagonist RU 38486 (10(-3) mol/L), or combinations thereof. Alternatively, cell monolayers were exposed to increasing doses of UV irradiation (0.1-1 J/cm2) or ionizing irradiation (0.2-2 Gy). The IL-1RA gene and protein variants were analyzed by RT-PCR, immunocytochemistry, immunoblotting, and enzyme-linked immunosorbent assay. Dexamethasone inhibited IL-1RA RNA steady state levels in GO OF and control OF in a dose-dependent manner. Combined exposure of OF to dexamethasone and RU 38486 completely restored baseline levels of IL-1RA RNA. By contrast, low doses of UV and ionizing irradiation dose dependently up-regulated IL-1RA-specific transcripts in GO OF and control OF, whereas higher doses were less effective. Immunoblotting and enzyme-linked immunosorbent assay revealed suppression of IL-1RA immunoreactivity after treatment with dexamethasone and enhanced expression of IL-1RA by GO OF and normal OF after low doses of UV and ionizing irradiation. Our results indicate that, in contrast to dexamethasone, low doses of irradiation stimulate expression of the IL-1RA gene and protein variants in OF. Induction by irradiation of IL-1RA expression in target cells of the orbital immune process represents an as yet unrecognized mechanism by which orbital radiotherapy may exert some of its beneficial therapeutic effects in patients with active GO.

Cells, Cultured↗
PubMed2001

Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 gene.

Glucocorticoid-remediable aldosteronism is an inherited disorder caused by a chimeric gene duplication between the CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes. The disorder is characterized by hyperaldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol, which are under ACTH control. The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene. The aim of this work was to evaluate whether other genetic alterations exist in CYP11B genes (gene conversion in the coding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic cause of glucocorticoid-remediable aldosteronism. We also evaluated the role of 18-hydroxycortisol as a specific biochemical marker of glucocorticoid-remediable aldosteronism. We studied eight patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric gene. In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter. We also measured the levels of 18-hydroxycortisol, and we compared the results with those found in four subjects with the chimeric gene. None of eight cases showed abnormalities in exons 3-9 of CYP11B1, disproving a gene conversion phenomenon. In all patients a fragment of 393 bp corresponding to a specific region of the promoter of CYP11B2 gene was amplified. The sequence of the fragment did not differ from that of the wild-type promoter of the CYP11B2 gene. The 18-hydroxycortisol levels in the eight idiopathic hyperaldosteronism patients and four controls with chimeric gene were 3.9 +/- 2.3 and 21.9 +/- 3.5 nmol/liter, respectively (P < 0.01). In summary, we did not find other genetic alterations or high levels of 18-hydroxycortisol that could explain a positive dexamethasone suppression test in idiopathic hyperaldosteronism. We suggest that the dexamethasone suppression test could lead to an incorrect diagnosis of glucocorticoid-remediable aldosteronism.

Adult↗
PubMed1990

Dexamethasone stimulates transcription of the insulin-like growth factor-binding protein-1 gene in H4-II-E rat hepatoma cells.

Binding proteins for the insulin-like growth factors (IGFBP) are important modulators of the biological actions of IGF-I and IGF-II. Concentrations of one of these proteins, IGFBP-1, in human plasma and IGFBP-1 mRNA in rat liver are markedly altered in diabetes and fasting. We now examine the regulation of IGFBP-1 and IGFBP-I mRNA in H4-II-E cells, a rat cell line derived from the minimal deviation H35 Reuber hepatoma previously reported to synthesize IGFBP-1 as its predominant IGF-binding protein. Confluent H4-II-E cells in serum-free medium were incubated with different hormones for 48 h, and the conditioned medium was analyzed by ligand blotting. Dexamethasone (10(-6) M) increased levels of 30-kDa IGFBP-1 approximately 10-fold; stimulation was half-maximal at 6 x 10(-9) M dexamethasone. No stimulation was seen with progesterone, testosterone, IGF-I, or rat GH, whereas insulin gave a small inhibition. Immunoblot analysis using a monoclonal antibody to human IGFBP-1 confirmed that the 30-kDa IGFBP induced by dexamethasone was IGFBP-1. IGFBP-1 mRNA was increased to a similar extent (7-fold), as determined by Northern blot hybridization using human or rat IGFBP-1 cDNA probes. The stimulation of IGFBP-1 mRNA was observed within 3 h after the addition of dexamethasone; IGFBP-1 in the medium increased more slowly. After withdrawal of dexamethasone from stimulated cells, IGFBP-1 mRNA decreased by 80% after 48 h; IGFBP-1 decreased more slowly. The increased abundance of IGFBP-1 mRNA in dexamethasone-treated cells primarily reflected increased transcription rather than increased mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

The effect of dexamethasone on side effects after coronary revascularization procedures.

UNLABELLED: Corticosteroids decrease side effects after noncardiac elective surgery. We designed this randomized, double-blinded, placebo-controlled study to test the hypothesis that standard doses of dexamethasone (4 mg x2) would reduce postoperative nausea, vomiting, and pain, decrease the incidence of atrial fibrillation (AF), and improve appetite after cardiac surgery, thereby facilitating the recovery process. A total of 300 patients undergoing coronary revascularization surgery were enrolled in this clinical study. The anesthetic management was standardized in all patients. Dexamethasone (4 mg/mL) or saline (1 mL) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery. The incidence of AF was determined by analyzing the first 72 h of continuously recorded electrocardiogram records after cardiac surgery. The patients were assessed at 24- and 48-h intervals after surgery, as well as at the time of hospital discharge, to determine the incidence and severity of postoperative side effects (e.g., nausea, vomiting, pain) and patient satisfaction scores. Dexamethasone significantly reduced the need for antiemetic rescue medication on the first postoperative day (30% versus 42%), and the incidences of nausea (15% versus 26%) and vomiting (5% versus 16%) on the second postoperative day (P < 0.05). In addition, dexamethasone significantly reduced the percentage of patients with a depressed appetite on the second postoperative day. However, the corticosteroid failed to decrease the incidence of AF (27% versus 32%) or the total dosage of opioid analgesic medication administered in the postoperative period. We conclude that dexamethasone (8 mg in divided doses) was beneficial in reducing emetic symptoms and improving appetite after cardiac surgery. However, this dose of the corticosteroid does not seem to have antiarrhythmic or analgesic-sparing properties. IMPLICATIONS: Dexamethasone (8 mg IV) was beneficial in reducing emetic symptoms and increasing appetite after cardiac surgery. However, this dose of the corticosteroid failed to decrease postoperative pain or the incidence of new-onset atrial fibrillation.

Aged↗
PubMed2003

Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps.

Depending on dose, dexamethasone has been shown to inhibit or stimulate growth of rat 9L gliosarcoma and decrease the expression of vascular endothelial growth factor (VEGF), an important mediator of tumor-associated angiogenesis. We demonstrate, by constructing relative cerebral blood volume (rCBV) maps with MRI, that dexamethasone also decreases total blood volume while increasing microvascular blood volume in Fischer rats bearing intracranial 9L gliosarcoma. Animals were inoculated with 1 x 10(5) 9L gliosarcoma tumor cells. On days 10-14 after tumor cell inoculation, animals were intra-peritoneally injected with dexamethasone (3 mg/kg) over 5 days. MRI-derived gradient echo (GE) and spin-echo (SE) rCBV maps were created to demonstrate total vasculature (GE) and microvasculature (SE). After MRI studies were performed, the rat's vasculature was perfused with a latex compound. Total vessel volume and diameters were assessed by microscopy. Dexamethasone decreased the tumor-enhancing area of postcontrast T1-weighted images (P < 0.0001) and total tumor volume(P = 0.0085). In addition, there was a greater than 50% decrease in GE rCBV (total vasculature) (P = 0.007) as well as a significant decrease in total fractional blood volume, as validated by histology (P = 0.0007). Conversely, there was an increase in SE rCBV signal (microvasculature) in animals treated with dexamethasone (P = 0.05), which was consistent with microscopy (P < 0.0001). These data demonstrate that (1) dexamethasone selectively treats tumor vasculature, suggesting a vessel-size selective effect and (2) MRI-derived rCBV is a noninvasive technique that can be used to evaluate changes in blood volume and vascular morphology.

Angiogenesis Inhibitors↗
PubMed1993

Determination of the lethal dose of dexamethasone for early passage in vitro human glioblastoma cell cultures.

Previous investigators have supported the idea that glucocorticoids may be oncolytic. In this study, the percentage of cell death in two human glioblastoma cell cultures was related to the concentration of dexamethasone that was administered. It was determined that for Cell line 1, the median lethal dose was approximately 500-800 micrograms/ml and the completely lethal dose was about 900-1000 micrograms/ml; the 3H-thymidine uptake to approximate the mitotic rate was 16,607 cpm, and the dexamethasone receptor activity was 228 fmol/mg protein. The median lethal dose and completely lethal dose for Cell line 2 was approximately 500-600 micrograms/ml and 700-1000 micrograms/ml, respectively; the 3H-thymidine uptake was 8402 cpm, and the dexamethasone receptor activity was 137 fmol/mg protein. These lethal concentrations of dexamethasone are probably higher than can be tolerated by systemic delivery. However, it remains to be seen whether the interstitial administration of dexamethasone could achieve local concentrations resulting in the oncolysis of malignant gliomas. The clinical significance of these findings will depend on the local tolerance of normal brain parenchyma to very high doses of dexamethasone. A review of some of the literature is included.

Brain Neoplasms↗
PubMed1981

Effects of dexamethasone 17-esters on adrenal weight and hydrolysis of glucocorticoid 17-esters in rat fetuses.

Prednisolone was detected in the brain of rat fetus subcutaneously administered prednisolone 17-acetate. After the subcutaneous injection of betamethasone 17-propionate or dexamethasone 17-propionate to rat fetus, the unchanged steroid was detected mainly in the brain. The hydrolytic rates of prednisolone 17-acetate, betamethasone 17-esters (acetate, propionate) and dexamethasone 17-esters (acetate, propionate, valerate) in the livers of rat fetuses were studied. Prednisolone 17-acetate was hydrolyzed to prednisolone very rapidly. Betamethasone 17-esters and dexamethasone 17-esters were hydrolyzed more slowly. The hydrolytic rate of dexamethasone acetate among the dexamethasone 17-esters was the most rapid, followed by propionate and valerate. The adrenals of rat fetuses became significantly atrophied after subcutaneous administration of dexamethasone and its 17-esters. The simultaneous administration of betamethasone 17, 21-dipropionate and its metabolite betamethasone impaired the hypertrophic effect of the former on the adrenal weights of rat fetuses. The effects of the hydrolytic rate of these glucocorticoid 17-esters and of C16-methyl conformation on the hypothalamo-pituitary-adrenal system in rat fetuses are discussed.

Adrenal Glands↗
PubMed1986

Comparison between the effects of dexamethasone and indomethacin on bone wound healing.

The area of wound holes made in the parietal bone of 4-week-old rats was measured at 1, 2 and 4 weeks after the operation using Alizarin red S staining without the use of histological sections. Dexamethasone and indomethacin were administered s.c. after the operation every day except Sunday. The inhibitory action of dexamethasone on bone wound healing was stronger than that of indomethacin, as was its inhibitory action on skin wound healing. Inhibition of the age-related decrease in radiolucency of femurs and some changes in serum calcium level were also observed by dexamethasone administration, but not by indomethacin. These results suggest that dexamethasone inhibits bone wound healing through its effects on calcium metabolism in addition to its general inhibitory action on wound healing which is shared with indomethacin. Dexamethasone also strongly inhibited the decrease in Alcian blue stainability which occurs with an increase in age, both in the normal portion and in the wound hole portion of the calvaria, whereas indomethacin showed a weak inhibitory effect only in the wound hole portion. This result suggests that one of the mechanisms by which dexamethasone inhibits bone wound healing may be based on the retardation of mineralization caused by the inhibition of removal of acid mucopolysaccharide.

Animals↗
PubMed2000

Dexamethasone or triamcinolone increases follicular development in immature female rats.

We have previously reported that dexamethasone increased follicle-stimulating hormone (FSH) secretion via suppression of inhibin in immature female rats. In the present study, we investigated the effects of dexamethasone or triamcinolone on follicular development and ovarian functions (estradiol and inhibin secretion) in equine chorionic gonadotropin (eCG)-primed immature female rats. Dexamethasone significantly increased the number of ovulated oocytes in immature female rats treated with 5 i.u. eCG. Serum concentration of FSH in eCG-treated female rats was increased by administration of dexamethasone or triamcinolone, showing the peak value at 9 h after its administration, although the levels of inhibin markedly decreased at that time. Serum concentrations of inhibin and estradiol in eCG-treated female rats increased at 24 h after administration of dexamethasone or triamcinolone. These results demonstrate that dexamethasone or triamcinolone increases FSH secretion, and the excess amount of FSH strongly stimulates follicular development cooperating with exogenous eCG.

Animals↗