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PubMed1989

Inflammatory competence of fetal rat: acute-phase plasma protein response of the fetus treated by turpentine in utero.

Using crossed immunoelectrophoresis, immunoelectrodiffusion, autoradiography, and equilibrium binding techniques, we demonstrate that the rat fetus, directly challenged in utero at 18 days by a single subcutaneous turpentine injection, presents a complex acute-phase plasma inflammatory response. A number of fetal serum proteins, 48 h after the injection, increase in concentration by factors of about 2-5. These positive acute-phase reactants (APR) are alpha 1-acute-phase globulin (alpha 1-AP), alpha 2-macroglobulin (alpha 2-M), alpha 1-acid glycoprotein (alpha 1-AG), haptoglobin (Hp), and hemopexin (Hpx). A number of proteins decrease, behaving like negative APRs. These are albumin, alpha 1-fetoprotein (AFP), transferrin, GHR-P63, thyroxine-binding prealbumin (TBPA), and transcortin (CBG). The marked fall in concentration of two of the high-affinity hormone-binding proteins of the fetal rat, i.e., the estrophilic AFP and TBPA, induce significant decreases (by 25-40%) of the estrogen- and thyroxine-binding abilities of the fetal serum. While the plasma inflammatory response of the fetus is qualitatively similar to that of the adult, the fetal reactions are, as a rule, quantitatively weaker. The characteristics of the plasma inflammatory response of the fetus are discussed in relation to the highly dynamic state of its development.

Acute-Phase Proteins↗
PubMed1986

Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats.

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPLC and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.

Adrenalectomy↗
PubMed1982

Nonlinear plasma protein binding and haemodialysis clearance of prednisolone.

The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10-100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8 +/- 4.4 micrograms/min, mean +/- SE), was predictable from the afferent-efferent blood concentration differences (20.1 +/- 4.8 micrograms/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1 +/- 3.0 micrograms/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r2 = 0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r2 = 0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.

Blood Proteins↗
PubMed1982

[Pharmacokinetics of prednisolone in adrenal insufficiency ].

Prednisolone was measured in serum and urine after oral and intravenous administration of prednisone and prednisolone in 16 patients with adrenal insufficiency and after bilateral adrenalectomy. Thus, the problem of cross-reactivity with endogenous steroids, the main factor disturbing the measurement of prednisolone, was completely eliminated. Prednisolone was detected by a simple competitive protein-binding radioassay. Distribution, elimination and other bioavailability parameters were calculated from the obtained data. No significant differences between serum levels were detected after oral administration of these drugs. Peak levels were reached after 2-3 h. After 5, 7.5 and 10 mg prednisone peak serum levels averaged 11.9 +/- 2.2, 15.9+/-3.4 and 21.5+/-5.9 microgram/dl, respectively. Prednisolone was still detectable 24 h after administration of 10 mg. The plasma half-time of approximately 5 1/2 h suggests that prednisolone is present in serum far about 2 days after application of higher doses. Since prednisolone interferes in most assays for cortisol, prednisone therapie has to be stopped at least 2 days before cortisol determinations. Urinary excretion was proportional to the applicated doses. The metabolic clearance rate of prednisolone was decreased (56.0+/-7.2 1/24 h/m2) in patients with adrenal insufficiency. This can be attributed to alterations in corticosteroid metabolism, probably due to an increased transcortin production.

Administration, Oral↗
PubMed1983

Isoelectric focusing of steroid hormone receptors in slabs of polyacrylamide gel.

Isoelectric focusing in 1-2 mm thick slabs of polyacrylamide gel is a versatile and specific method for quantitation and characterization of estrogen, mineralocorticoid, progestin, and glucocorticoid receptors. This method has been used for routine measurements of estrogen receptor in human breast cancer in Stockholm since 1976. It is also used for quantitation of estrogen receptor in fine needle biopsies from breast cancer tissue. Isoelectric focusing in gel slabs allows rapid separation (1.5 hr) of receptors from other non-receptor proteins that bind steroid hormones, such as transcortin and sex hormone-binding globulin. The tritium-labeled steroid-receptor complex is localized by slicing the gel followed by radioactivity analysis in a liquid scintillation counter. The isoelectric point of the tritium peak is determined with a surface electrode. The isoelectric point serves as a qualitative control. Thus, only one analysis is needed for each receptor quantitation, provided that a saturating concentration of tritiated ligand is used for receptor binding. This means that a minimal amount of tissue is needed for one receptor analysis with isoelectric focusing.

Acrylic Resins↗
PubMed1975

A rapid method for the measurement of estradiol and hydrocortisone levels in maternal and fetal blood and amniotic fluid.

Estradiol and hydrocortisone levels in maternal and fetal (umbilical cord) blood in human pregnancy can be simultaneously assessed by this method. Chromatography on microcolumns of Sephadex LH-20 with benzene:methanol (85:15) as developing solvent is used to separate estradiol, hydrocortisone, and isatin (a yellow-colored substance used as marker) from interfering steroids. Human late pregnancy plasma is used as the source of both sex hormone-binding globulin and transcortin for the competitive protein-binding assay of estradiol and hydrocortisone, respectively. The method is rapid enough to permit the monitoring of a high-risk pregnancy for plasma estradiol levels on a daily basis. The method is sensitive enough to permit assessment of perinatal adrenocortical function. Hydrocortisone levels can be measured in as little as 3 ml. of amniotic fluid obtained by amniocentesis and preliminary results indicated that hydrocortisone can be determined in as little as 0.1 ml. of fetal scalp blood or newborn baby blood.

Amniotic Fluid↗
PubMed1985

Steroid metabolism by human chorion laeve from dichorionic twin pregnancies.

Certain steroid metabolic properties of chorion laeve from dichorionic twin pregnancies were examined to determine whether they were present in chorion not contaminated by decidua or serum. In the chorion situated between the two amniotic sacs and not in contact with decidua, aryl sulfatase, 3 beta-hydroxysteroid dehydrogenase, and aromatase activities were found. This indicates that these reactions are present in chorion laeve and were not previously ascribed to this tissue because of decidual contamination. Specific cortisol binding was also present in this area of chorion laeve, which excludes serum contamination. It is suggested that the specific steroid-binding protein in the membranes may be derived from the transcortin-like protein present in amniotic fluid.

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Evidence for differences in the steroid binding domains of the glucocorticoid receptor versus the idiotype antibody.

Triamcinolone acetonide (TA), coupled to bovine serum albumin, was used to obtain a polyclonal anti-TA antibody in the rabbit. This idiotype differed from rat glucocorticoid receptor and transcortin in several respects. RU 38486, a synthetic antagonist with high affinity for the receptor, could neither bind the anti-TA antibody nor displace the idiotype bound 3H-TA. Similarly, corticosterone, the natural rodent ligand, had no affinity for the idiotype. These results imply differences in the conformation and topology of the corticoid binding domains, contrary to the current notion where all agonists and antagonists would saturate an identical configuration.

Animals↗
PubMed1985

Sexual dimorphism of glucocorticoid binding in rat brain.

Glucocorticoids bind with high affinity to intracellular receptors located in high density within discrete regions of the rodent and primate brain. The binding of [3H]corticosterone was compared in the brains of male vs female rats. The number and affinity of cytosol receptors in the hippocampus and hypothalamus were examined in vitro. The cytosolic binding capacity of the hippocampus is greater in the female than in the male. This difference in binding capacity is not dependent on the presence of gonadal steroids: the effect of gonadectomy was not significant for either sex. The difference is not due to transcortin since the binding capacity of [3H]dexamethasone is also greater in the female hippocampus. Receptor affinity in the female hippocampus is half that of the male value. In the hypothalamus, the dimorphism is in the opposite direction: the number of [3H]corticosterone cytosolic binding sites was found to be greater in the male. The male hypothalamus also showed a greater affinity for [3H]corticosterone than did the female. Ovariectomy increased the number of binding sites in the female hypothalamus. In vivo nuclear uptake of a tracer dose of [3H]corticosterone was determined in animals having intact gonads. The percent of tissue [3H]corticosterone present in cell nuclei from 4 brain regions, including the hippocampus and hypothalamus, was calculated per unit DNA. The concentrations of [3H]corticosterone in nuclei relative to tissue homogenates were higher in females than males for the 4 brain regions, but not for the pituitary or liver. The data are interpreted as suggesting that glucocorticoid secretion under basal conditions and during stress may differentially effect specific brain structures in male vs female rats.

Amygdala↗
PubMed1982

Metabolic effects of the triphasic oral contraceptive Trigynon.

Effects of Trigynon, a triphase low-dose oral contraceptive, containing ethinylestradiol and l-norgestrel in various proportions, on testosterone binding globulin, transcortin, thyroxine, free testosterone, free cortisol and free thyroxine as well as on plasma lipids and glucose tolerance were studied in 12 normal women treated for 3-6 months. Trigynon appears to have dominant estrogenic effects as evidenced from the increase in transport proteins and the decrease in free testosterone concentration. Plasma lipids were not significantly influenced; glucose tolerance was slightly, but not significantly decreased.

Adult↗
PubMed1984

In vitro binding of tritiated glucocorticoids directly on unfixed rat brain sections.

We describe a new technique for measuring specific in vitro binding of tritiated adrenal steroids on unfixed cryostat brain sections. The specific binding of [3H]corticosterone represents about 70% of the initial binding. Kinetic studies show that specific binding for [3H]corticosterone reaches equilibrium after 15 min incubation at room temperature. Scatchard analysis of [3H]corticosterone in vitro binding gives a linear plot with an apparent dissociation constant (Kd) and a number of binding sites (Bmax) in the range of 10(-8) M and 100 fmol/mg protein, respectively. [3H]Dexamethasone binding under the same conditions gives a similar Kd and a Bmax of 55 fmol/mg protein. The order of potency for the relative binding affinity for [3H]corticosterone labeled sites is as follows: corticosterone greater than progesterone, dexamethasone, RU 38486 (a "pure" antiglucocorticoid), RU 26988 (a "pure" glucocorticoid), aldosterone greater than estradiol, testosterone. Anatomical studies reveal that sections at the level of the hippocampus bind more [3H]corticosterone and [3H]dexamethasone in vitro than more rostral sections taken at the level of the septum. Adrenalectomy increases the capacity of [3H]corticosterone to bind to these sites and perfusion of the brain to remove transcortin and other blood proteins does not modify [3H]corticosterone binding. We conclude that it is possible to measure in unfixed frozen brain sections glucocorticoid binding sites.

Adrenalectomy↗
PubMed1989

Mineralocorticoid specificity of renal type I receptors: binding and metabolism of corticosterone.

In cytosol preparations renal mineralocorticoid receptors have equivalent affinity for aldosterone and corticosterone; in vivo, such receptors are clearly aldosterone-selective. To explore this difference, we have compared the binding of both steroids in kidney slices, high speed supernatants and true cytosols in vitro, in the presence of RU28362 to exclude steroids from Type II glucocorticoid receptors, and/or in the presence of cortisol 17 beta-COOH to exclude corticosterone from transcortin. In addition, we have explored the effect of tissue preparation and cortisol 17 beta-COOH on the level of activity of the renal enzyme 11 beta-OH steroid dehydrogenase. The results of the present studies support the hypothesis that the predominant aldosterone specific-conferring mechanism for renal Type I receptors in vivo in the enzyme 11 beta-OH steroid dehydrogenase, and underline the potential difficulties in interpreting studies which include multiple potential ligands to multiple potential binding sites.

Aldosterone↗
PubMedDate not supplied

Postnatal handling attenuates certain neuroendocrine, anatomical, and cognitive dysfunctions associated with aging in female rats.

Hippocampal degeneration with aging is associated with increased hypothalamic-pituitary-adrenal (HPA) activity and, in male rats, both are attenuated by postnatal handling. Considering the important sex differences in the effects of handling and in HPA responses to stress in older rats, we have examined the effects of postnatal handling on aging in females. Female, Long-Evans rats were handled (H) during the first 3 weeks of life and later compared with nonhandled (NH) controls at various ages. Handling resulted in permanently increased hippocampal type II, glucocorticoid receptor binding. Relative to H females, NH females showed increased basal corticosterone levels in later life and hypersecreted corticosterone following stress at all ages examined. Both effects are similar to those reported in males. However, unlike males, H and NH females did not differ in corticosterone levels achieved during stress, a finding that may be related to sex-dependent effects of handling on pituitary transcortin receptors. There were no differences in hippocampal neuron density in 6-month-old animals. However, the older NH animals showed considerable neuron loss in the CA1 and CA3 hippocampal cellfields. There was little or no neuron loss in the H animals. Finally, the NH animals exhibited age-related spatial memory impairments, such that by 24 months of age the performance of the NH females was profoundly worse than that of the younger NHs and same-aged H animals. These data suggest that early handling permanently alters CNS systems that regulate hypothalamic-pituitary-adrenal (HPA) function, although the effect may depend on the gender of the animal. In both males and females, however, handling appears to prevent (or minimize) increased adrenal secretion in later life and to attenuate hippocampal cell loss and spatial memory impairments.

Aging↗
PubMed1977

Heterogeneity of steroid hormone receptor in adult rat lung cytosol.

Chromatography on cellulose DEAE-52 columns revealed that the glucocorticoid receptor for rat lung cytosol consisted of a component in the 0.001 M prewash, revealed with synthetic steroids and natural mineralocorticoids, a second component eluted with 0.04 M PO4, labelled with triamcinolone, dexamethasone, and a third moiety in the 0.06 M PO4 region, evident with natural glucocorticoids (corticosterone, cortisol) as well as mineralocorticoids (aldosterone, deoxycorticosterone). The third component coeluted with rat blood serum transcortin in double labelled experiments. Rate lung was devoid of another component in the 0.02 M PO4 found in rat liver supernate and of the mineralocorticoid receptor evident only in rat kidney. Chromatography on Sephadex G-200 columns revealed a shift of radioactivity from a higher to a lower molecular weight region in the presence of 0.4 M KCl. Collectively, these studies indicate the subunit nature of the lung receptor as evidenced in most tissues hitherto tested. Moreover, polymorphism within a given subunit component can not be revealed by competition alone, as attempted by others, but can be revealed under selected conditions of physical separation.

Aldosterone↗
PubMed1981

Characterization of an antiserum against the glucocorticoid receptor.

An immunoglobulin (IgG) fraction from serum of a rabbit immunized with a highly purified preparation of glucocorticoid receptor from rat liver cytosol contained specific antibodies to glucocorticoid receptor. This was shown following incubation of the [3H]triamcinolone acetonide-glucocorticoid receptor (TA-GR) complex with the IgG fraction by (I) adsorption of the [3H]triamcinolone acetonide-glucocorticoid receptor (TA-GR) complex with the IgG fraction by (I) adsorption of the [3H]TA-GR-antibody complex to protein A linked to Sepharose, (II) an increased sedimentation rate of the [3H]TA-GR-antibody complex compared to that of the [3H]TA-GR complex, and (III) an increased molecular size of the [3H]TA-GR-antibody complex when compared to that of the [3H]TA-GR complex as judged from gel filtration. The antibody fraction was characterized with regard to titer, cross-reactivity and specificity. The antibodies cross-reacted with the glucocorticoid receptor from various rat tissues (liver, thymus and hippocampus), as well as with the glucocorticoid receptor from human normal lymphocytes, chronic lymphatic leukemia cells and human hippocampus. In the rat liver, the antibody bound to both the nuclear and the cytosolic glucocorticoid receptor (stokes radius 6.1 nm). It did not cross-react with the proteolytic fragments of the glucocorticoid receptors, the 3.6 nm complex or the 1.9 nm complex. Binding of the antibodies was not seen to the androgen, estrogen or progestin receptors in rat or to rat serum transcortin. With an indirect competitive ELISA (enzyme-linked immunosorbent assay) combined with various separation techniques, based on different physicochemical principles, it was shown that the glucocorticoid receptor was the only detectable antibody binding protein from rat liver cytosol using this assay system. These findings also indicate an immunochemical similarity between glucocorticoid receptors in different tissues as well as in different species, but not between glucocorticoid receptors and other steroid hormone receptor proteins. The cytosolic and nuclear glucocorticoid receptors in rat liver were shown to be immunochemically similar.

Animals↗
PubMed1988

Paradoxical differences in the receptor binding of two new antimineralocorticoids.

Two synthetic derivatives of spironolactone were used to examine various aspects of the mineralocorticoid receptor structure and function. Introduction of a propyl residue in the 7-position of spironolactone produced a molecule (RU 26752) that saturated the aldosterone specific receptor in the 1-10 nM range, and another, more abundant species in the 10-100 nM range which had little affinity for the natural hormone. The specificity for both sites was increased when the methoxycarbonyl group was introduced in the 7-position (ZK 91587). Neither antagonist exhibited affinity for blood serum transcortin or receptors in non-target organs like the lung and the liver. RU 26752-receptor complex was more unstable than the hormone-receptor complex at 35 degrees C but underwent comparable thermal activation as evidenced by binding to DNA cellulose and the 7 S to 4 S shift on sucrose gradients. In contrast, ZK 91587 did not permit thermal activation and greatly labilized the receptor at 35 degrees C. In ion exchange chromatography, two peaks were observed with unactivated ZK 91587-receptor complex, but RU 26752 was bound exclusively to the component eluted with high salt. Molecular filtration revealed two peaks of bound radioactivity with both antimineralocorticoids. These studies reveal important differences in the mechanism of action of two antagonists differing solely in the residue in position 7 of the spironolactone molecule. Such differences could be exploited to purify the mineralocorticoid receptor and clinically to prescribe the appropriate drug with greater precision.

Adrenalectomy↗
PubMed1989

Mating suppresses splenic natural killer cell activity in male golden hamsters.

The possibility that sexual behavior is associated with changes in natural killer cell activity was explored using a 4-h chromium-51 release assay. Mated male Golden Hamsters (Mesocricetus auratus) showed a significant suppression of natural killer cell activity 2 h after sexual activity relative to matched Virgin controls. Natural killer cell activity returned to control levels by 16 h postmating. The suppression of natural killer cell activity did not correlate with changes in plasma cortisol, transcortin, or testosterone levels, or with ejaculatory or intromissive behaviors. Administration of 0.40 mg/100 g of testosterone also suppressed natural killer activity at 2 h.

Animals↗
PubMed1982

The effects of estrogen on adrenal androgens in oophorectomized women.

The serum levels of adrenal androgens (aa) are lower in oophorectomized (OO) than in ovulating (OV) women. This study was carried out in an effort to further investigate these findings and to study the effects of administration of estrogen on the levels of aa in OO women. Ten OO and seven OV women participated in this study in which aa were measured basally and after stimulation with adrenocorticotropic hormone (ACTH), both before and 4 weeks after conjugated estrogens (CE). Seven women received 0.625 mg of CE, and five received 2.5 mg of CE. Compared to OV women, OO women had significantly lower levels of androstenedione (Adione), dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), testosterone (T), delta 5-androstenediol (Adiol), and 17 beta-estradiol (E2) (p less than 0.01). In response to ACTH, OO women had smaller responses to Adione (p less than 0.05), DHEA (p less than 0.005), DHEA-S (p less than 0.01), 17-OH progesterone (17 Prog) (p less than 0.01), and 17-OH pregnenolone (17 Preg) (p less than 0.1). Furthermore, after ACTH, the ratio of 17 Prog/Adione was significantly higher in OO women (p less than 0.01), thus suggesting reduced 17,20-demolase (17,20D?) activity. Similarly, OO women had higher ratios of 127 Preg/17 Prog (p less than 0.1), DHEA/Adione (p less than 0.01), and Adiol/T (p less than 0.01), thereby suggesting reduced 3 beta ol dehydrogenase-isomerase (3 beta ol) activity. In response to CE, there was a dose-related increase in aa and cortisol. After 2.5 mg of CE, aa were significantly higher and similar to those levels in OV women. despite the known increases in sex hormone binding globulin-finding capacity and transcortin after estrogen, unbound T increased slightly, as did urinary free cortisol in women treated with 2.5 mg of CE. After treatment with estrogen, there was a dose-related change in the ACTH-stimulated steroid ratios that indicated and increase in 17,20D and 2 beta ol activities. In women who were gien 2.5 mg of CE, these enzyme activities were similar to those in OV women.

Adrenal Glands↗