Adrenal Corticosteroids Research Articles

Alterations in maternal plasma corticosterone levels following treatment with phenytoin

The mechanisms of the embryotoxic effects of the anticon vulsant drug, phenytoin (PHT), are unknown. Glucocorticoids and PHT demonstrate similar embryopathic effects and strain sensitivity in that A J mice are very sensitive to the embryopathic effects of synthetic glucocorticoids and PHT while C67BL 6 (B6) mice are comparatively resistant to both. It is possible that teratogenic consequences of PHT are not a result of drug interaction at the target site but are mediated indirectly by glucocorticoids. In this study, PHT was administered by intraperitoneal injection at 25 (a nonteratogenic dose) or 75 mg/kg body weight (a teratogenic dose) to pregnant A J mice on Day 10 of gestation. Mice of the B6 strain received the drug at 75 mg/kg on Day 10. Control mice received vehicle (pH 11.0 distilled water). Dams were killed at various times after the injection; plasma samples were obtained, and corticosterone levels were determined by radioimmunoassay. In control animals, maternal plasma corticosterone levels were elevated soon after dosing but gradually declined, except for an apparent circadian rhythm effect seen in samples obtained in the afternoon. Administration of a nonteratogenic dose of PHT to A J mice caused a temporary increase in plasma corticosterone levels which decreased to the control level between 6 and 24 hr following dosing. Treatment with a teratogenic dose in A J mice led to plasma levels that remained elevated for the entire 48-hr period examined in this study. In B6 mice, treatment with 75 mg/kg increased plasma corticosterone levels for 24 hr, after which they declined to the control value by 30 hr. The adrenal corticosteroid response of A J mice to PHT appeared to be much more sensitive than that of B6 mice, and there appeared to be a relationship between plasma levels of PHT and corticosterone. The lengthy increase in plasma corticosterone during organogenesis may be a factor in the increased incidence of cleft lip and palate seen after administration of PHT to A J mice.

The increase in hepatic tyrosine aminotransferase activity by ethanol administration involves an acceleration of enzyme synthesis

The present study was conducted to examine the nature of the increase in tyrosine aminotransferase (TAT) activity by acute ethanol administration. A significant rise in aminotransferase activity was observed as early as 1 hr after intact rats were gavaged with ethanol. Ethanol administration also increased TAT activity in adrenalectomized rats. Inhibition of ethanol metabolism by pyrazole administration had no effect on the ethanol-induced increase in TAT activity. Immunochemical analyses revealed that the enhancement of TAT activity in ethanol-fed rats correlated with an increase in aminotransferase protein. Measurement of the rate of TAT synthesis showed that in ethanol-fed rats, [3H]leucine was incorporated into the aminotransferase protein at a higher rate than in controls by a factor which was similar to the enhancement in enzyme activity. Our findings indicate that an acceleration of TAT synthesis fully accounts for the increase in TAT activity during the early stage of enzyme induction. TAT induction by ethanol administration is not dependent upon an increase in adrenal corticosteroid production, nor does it require ethanol metabolism.

New rat model of Pneumocystis carinii infection.

Rats free of latent Pneumocystis carinii organisms were immunosuppressed with adrenal corticosteroids and transtracheally injected with P. carinii. These animals subsequently developed P. carinii pneumonia. Infection was accomplished by using organisms from infected rat lung or from culture. Diffuse infection was produced with no significant differences in the numbers of organisms found in various lobes of the lungs. Infections progressed over time so that by 6 weeks postinoculation all animals were heavily infected. Infection by transtracheal injection has three advantages over current models. First, transtracheal injection provides a reliable model which is not dependent on naturally occurring latent Pneumocystis infection. Second, transtracheal injection allows the perpetuation of specific Pneumocystis strains. Third, transtracheal injection is a more rapid and economical means of producing severe Pneumocystis pneumonia.

Effect of vitamin E on vitamin C-induced lymphocytopenia.

Large daily doses of vitamin C resulted in lymphocytopenia in stressed mice caused by excessive plasma levels of adrenal corticosteroids. Vitamin C plus E resulted in less severe lymphocytopenia because vitamin E has a lymphoproliferative effect.

Hormonal Interaction in Amphibian Metamorphosis

SYNOPSIS. The climactic stages of amphibian metamorphosis constitute a period characterized by radical morphological changes that are driven primarily by the thyroidal hormones. Radioimmunoassays show that levels of thyroid hormones (TH) rise to a peak during metamorphic climax. Accompanying peaks are reported for ACTH, adrenal corticoids (AC), insulin (I) and prolacdn (PRL). AC enhance the metamorphic action of TH by increasing their binding to nuclei of target cells. TH, in turn, act to raise levels of AC by stimulating the differentiation of the median eminence thus facilitating the flow of a CRF from the hypothalamus to the adenohypophysis, by synergizing with ACTH and bystimulation of the interrenals through some other route. During the metamorphic period, at least as far as climax, PRL antagonizes TH, perhaps at the thyroidal level and certainly at the level of target cells. PRL may antagonize by inhibiting induction of hydrolytic enzymes by TH, by alteration of hydromineral responses or by altering levels of binding of TH to receptors. The antagonistic action of PRL is mimicked by cAMP. A surge of PRL that is released into the plasma during metamorphic climax seemingly produces no antagonistic effect on thyroidal actions.

Reduction by acute restraint of noradrenaline sensitivity in the isolated pacemaker of the rat

Acute restraint stress induced subsensidvity of the isolated pacemaker of the rat to the chronotropic effect of noradrenaline and reduced the affinity of atrial β 1-adrenoceptors for metoprolol. The effects of restraint stress were abolished two days after bilateral adrenalectomy. The controlled venous infusion of noradreaaline plus adrenaline was without effect on the atrial sensitivity to noradrenaline and the pA 2 value of metoprolol. It is concluded that the effects of restraint stress on atrial β 1-adrenoceptors are mediated at least partially by adrenal corticosteroids.

The human leucocyte sodium pump in Cushing's syndrome.

Because corticosteroids have important effects on sodium homeostasis, we studied leucocyte 22Na efflux in patients with Cushing's syndrome. The ouabain-sensitive 22Na+ efflux rate constant was raised in Cushing's syndrome (mean +/- SD 2.84 +/- 0.32 vs 2.35 +/- 0.53/h, P less than 0.001, n = 15). This efflux rate constant correlated with the urinary free cortisol (rs = 0.61, P less than 0.02), but less significantly with the 0900 h plasma cortisol (rs = 0.46, P less than 0.08). There was no correlation with the supine plasma aldosterone. Intracellular sodium content was significantly lower in Cushing's syndrome (21.1 +/- 4.6 vs 27.8 +/- 9.5 mmol/kg dry weight, P less than 0.01), with a raised intracellular potassium to sodium content ratio (16.1 +/- 3.3 vs 12.9 +/- 3.6, P less than 0.01). After treatment of the Cushing's syndrome by trans-sphenoidal adenomectomy or adrenalectomy, these defects in cellular sodium balance were corrected. Thus, the distribution of sodium between intra- and extracellular fluid may be affected by adrenal corticosteroids via an action on the sodium pump.

Repeated swimming stress and responsiveness of the isolated rat pacemaker to the chronotropic effect of noradrenaline and isoprenaline: Role of adrenal corticosteroids

1. 1. Repeated swimming stress (three daily sessions) resulted in an increased plasma corticosterone level and subsensitivity of the isolated rat pacemaker to noradrenaline and isoprenaline. 2. 2. Repeated swimming stress was found to decrease the affinity of β 1-adrenoreceptors for metoprolol. 3. 3. Bilateral adrenalectomy performed 2 days before repeated swimming stress abolished the development of pacemaker subsensitivity to noradrenaline and isoprenaline and the decrease in β 1-adrenoreceptors affinity for metoprolol. 4. 4. It is concluded that adrenal corticosteroids, at least partially, mediate the swimming stress-induced subsensitivity of the isolated rat pacemaker to noradrenaline and isoprenaline.

Maternal modulation of pituitary-adrenal activity during ontogeny.

The fundamental contribution of adrenal corticoid steroid hormones (CORT) in the regulation of a wide range of physiological and behavioral phenomena have now been well documented (Munck et al., 1984). Hormones secreted from the adrenal cortex have been shown to be essential for gene expression, metabolic processes, functions of the immune system and effect of brain function which concern not only the regulation of the adrenal cortex but also contribute to specific aspects of behavior, including learning and memory. In view of the profound role that these hormones play in the regulation of bodily functions, it is not surprising that the regulation of their secretion has been studied extensively. Studies of regulation have been conducted at every level of the regulatory system which includes the adrenal, pituitary, hypothalamus, and many other structures in the central nervous system. Based primarily on the classic contributions of Hans Selye, secretion of these hormones have generally been associated with stressful events. Early stress research emphasized that responses of the organism to a wide variety of stimuli were non-specific. These studies demonstrated increased activity in the adrenal cortex to a variety of “physical” stressors (Selye, 1950). However, in 1975, Mason suggested that much of the early research on stress, especially that involving exposure to a variety of physical stimuli, shared one important characteristic. One of the primary qualities of the stressful experience was exposure of the animal to a novel strange or unfamiliar environment. Therefore, a common element that may have accounted for the adrenal responses was the psychological relevance of the event rather than the particular physical stressors to which they were exposed. Mason was able to demonstrate that exposure of the animals to different physical stimuli, including heat, cold, reduction of caloric intake, was not always accompanied by activation of CORT (corticosterone-cortisol = CORT) particularly, when the stress was imposed in such a way that the animal could not readily detect changes in the environment.

Human corticotropin releasing hormone: Clinical studies in patients with affective disorders, alcoholism, panic disorder and in normal controls

Bardeleben, Ulrich von and Florian Holsboer: Human Conicotropin Releasing Hormone: Clinical Studies in Patients with Affective Disorders, Alcoholism, Panic Disorder and in Normal Controls. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12 (Suppl): S165–S187 1. 1. The 41 amino acid peptide human corticotropin releasing hormone (h-CRH) and its ovine analogue o-CRH are regulators of proopiomelanocortin (POMC) derived neuropeptides and neurosteroids of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis such as beta-endorphine, corticotropin (ACTH) and corticosteroids modulating concomitantly hormonal and behavioral systems in animal and man, e.g. adaptation to stress. 2. 2. Challenge tests employing h-CRH stimulation with or without different kinds of pretreatment in affective disorders, alcoholism, and panic disorder demonstrate LHPA alterations that are induced by dysregularions in the limbic area. In depression, the enhanced secretory activity of pituitary corticotrophs or altered feedback regulation is compatible with endogenous CRH hypersecretion followed by enhanced production of proopiomelanocortin whose fragments activate synthesis and release of adrenal corticosteroids. These effects are accompanied by development of a functional hyperplasia of the adrenocortex and/or down-regulation of pituitary CRH-receptors and/or reduced negative feed back capacity of limbic glucocorticoid receptor containing neurones particularly in the hippocampus. Similar disturbances are found in hypercortisolemic patients withdrawn from alcohol and are less pronounced in patients with panic disorder. 3. 3. Repetitive h-CRH administration to normal controls induces sleep-EEG and neuroendocrine effects resembling those in depression. 4. 4. Adrenocortical hormones act back on neurotransmitter/receptor sites of brain systems relevant for neuropharmacoloy (e.g. GABA receptor activity in anxiety disorders and affective disorders). 5. 5. The neuroendocrine approach to the LHPA axis is of value to uncover several aspects of pathology underlying various psychiatric diseases.

Clinical consequences of abrupt drug withdrawal.

Syndromes due to the abrupt withdrawal of drug treatment occur mainly with adrenal corticosteroids and agents with an action on either the cardiovascular system or central nervous system. The abrupt withdrawal of antihypertensive therapy typically results in symptoms of overactivity in the sympathetic nervous system. Clonidine and beta-adrenoceptor antagonists are clinically the most important of these agents, but numerous other drugs have been implicated. Overall, the problem is small when viewed in the context of the huge scale of prescribing of antihypertensive medicines. A more serious problem is the occurrence of crescendo angina following the abrupt withdrawal of beta-adrenoceptor antagonists. Although other factors may be involved, adaptive up-regulation of beta-adrenoceptor density is the most likely cause of crescendo angina, and renders the patient more susceptible to sympathetic nervous stimulation following withdrawal of treatment. Besides leading to a recrudescence of the disease being treated, the withdrawal of corticosteroids can cause a variety of syndromes. In particular, problems can arise as a result of treatment-induced suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Another steroid withdrawal syndrome of unknown aetiology, without significant abnormalities of the HPA axis occurring, has been described. Benign intracranial hypertension may rarely follow steroid withdrawal in children. The syndromes associated with withdrawal of drugs which have an action on the CNS are poorly understood. Withdrawal of neuroleptic drugs can be followed by symptoms that resemble those described following withdrawal of anticholinergic drugs, and those agents with the greatest muscarinic-receptor-blocking properties are those which are most frequently implicated. However, the less common withdrawal dyskinesias are thought to reflect up-regulation of dopaminergic receptors during long term treatment. Gastrointestinal symptoms predominate following the abrupt withdrawal of antidepressants but hypomania and an 'akathisia-like' syndrome have been reported. Barbiturates are no longer recommended as hypnotics because of severe effects of withdrawal and the existence of safer alternatives. Short acting barbiturates can be withdrawn by replacement with either phenobarbitone (phenobarbitol) or diazepam and subsequent gradual reduction in dose. The recognition of dependency on benzodiazepines has been slow because of the similarity of mild withdrawal symptoms to the original problem which led to treatment being offered.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of carrageenin-induced pedal oedema in rats by immobilisation stress.

The effect of immobilisation stress on acute pedal inflammation induced by carrageenin, and the mechanism of stress-induced anti-inflammatory effect, were investigated in male Wistar strain albino rats. Carrageenin-induced pedal inflammation oedema was attenuated by immobilisation stress in a time-dependent manner, when the rats were restrained for 30 min, 1 h, and 2 h immediately after the induction of the inflammation. Pentobarbitone exhibited significant anti-inflammatory effect of its own in an anaesthetic dose and also inhibited stress (1 h)-induced attenuation of the inflammation. Likewise, lignocaine, injected behind the knee joint of the inflamed limb, attenuated the inflammation and also inhibited the stress-induced anti-inflammatory effect. These findings indicate the importance of the central nervous system (CNS) and the afferent/efferent neural pathways from and to the inflammatory site, in inflammation and in stress-induced anti-inflammatory effect. Earlier studies from this laboratory have shown that the central noradrenergic, histaminergic, serotonergic and GABA-ergic neurotransmitter systems have a modulatory anti-inflammatory effect on carrageenin-induced pedal oedema. Since all these neurotransmitter systems have been reported to be activated by stress, their role was assessed in the inflammation-attenuation effect of immobilisation stress. The present studies indicate that, of these neurotransmitters, only the central noradrenergic system is involved in the anti-oedema effect of stress. Endogenous opioid peptides may also be involved in the stress-inflammation interaction, since naloxone inhibited the stress effect. Bilateral adrenalectomy and peripheral chemical sympathectomy, induced by i.p. administration of 6-hydroxydopamine, augmented carrageenin oedema and antagonised the stress-induced anti-inflammatory effect. However, metyrapone, an inhibitor of endogenous corticoid synthesis, failed to inhibit the stress effect. These findings indicate that the sympatho-medullary system, which is known to be activated during stress, is responsible for the observed anti-inflammatory effect of immobilisation stress, rather than augmented release of adrenal corticoids. It is suggested that the observed inflammation reducing effect of immobilisation stress is a consequence of increased central noradrenergic and peripheral sympatho-medullary activity.

Estrogen binding macromolecules in hypothalamus-preoptic area of male and female gray short-tailed opossums ( Monodelphis domestica)

Estrogen binding sites in the hypothalamus -preoptic area (HPOA) of adult male and female gray opossums ( Monodelphis domestica) were characterized by incubating cytosols from gonadectomized animals with [ 3H]estradiol (E 2) in the presence or absence of excess unlabeled E 2. Scatchard analyses revealed that HPOA cytosols from both males and females contained high concentrations (25–30 fmol/mg protein) of binding sites with a very high affinity ( K d = 0.08 – 0.12 n M) for E 2. There was no sex difference in either the number or the affinity of estrogen binding sites. Competition studies indicated that estrogen agonists and antagonists displaced [ 3H]E 2 from binding sites in HPOA cytosols more effectively than did progestins, androgens, or adrenal corticoids. These data suggest that the HPOA of both male and female gray opossums contains macromolecules with several of the steroid binding properties characteristic of estrogen receptors.

Differential regulation of beta-adrenergic receptor-coupled adenylate cyclase by thyroid hormones in rat liver and heart: possible role of corticosteroids.

Thyroid hormone regulation of beta-adrenergic receptor-coupled adenylate cyclase activity was studied in rat liver and heart particulate fractions. Thyroidectomy (Tx) increased isoproterenol-stimulated cAMP accumulation in the liver and decreased it in the heart. Administration of L-thyroxine (L-T4) or L-3,3',5-triiodothyronine (L-T3) reversed these changes in both liver and heart. The changes observed in liver beta-receptor-coupled adenylate cyclase activity after Tx were similar to those reported after adrenalectomy (ADX). Thus the hypothesis was considered that these changes with altered thyroid status are produced indirectly through alteration in adrenal corticosteroids. Hydrocortisone in Tx rats decreased liver isoproterenol-stimulated adenylate cyclase activity but had no significant effect on the heart. Serum corticosterone levels were decreased significantly (by 34%) in Tx rats, as compared to euthyroid rats. Administration of L-T4 to Tx rats doubled the serum corticosterone levels. In Tx-ADX rats, L-T4 had no significant effect on liver beta-receptor-coupled adenylate cyclase. However, L-T4 significantly increased heart beta-receptor-coupled adenylate cyclase in these animals. Dexamethasone, but not deoxycorticosterone, decreased liver isoproterenol-stimulated cAMP accumulation in Tx animals to the same extent as was observed with L-T4 and hydrocortisone. Thus overall the results indicate that in the liver, as opposed to the heart, thyroid hormones regulate beta-adrenergic receptor-coupled adenylate cyclase indirectly through corticosteroids. Glucocorticoid rather than mineralocorticoid activity seems to be responsible for this regulation.

Functions and dysfunctions of receptors for adrenal corticoids in the central nervous system

Glucocorticoids (GC) have several known effects on the function of the nervous system, and GC receptors have been identified in regions responding to hormonal action. In the spinal cord, GC receptors have been characterized in vitro, which share several biochemical properties in common with receptors in better studied areas such as the hippocampus. Moreover, enzymes which are induced by GC in the hippocampus, such as glycerolphosphate dehydrogenase and ornithine decarboxylase, are also under specific GC control in the spinal cord. Yet GC receptors in the latter tissue divert from those in hippocampus during some in vivo as well as in vitro studies. In vivo, uptake of [ 3H]corticosterone by purified cell nuclei was 5–8-fold higher in the hippocampus as compared to the cord. In vitro, a higher percentage of GC receptors previously transformed by heating, showed affinity towards DNA-cellulose in the spinal cord than in the hippocampus. The enzyme RNAse A effectively increased receptor binding to DNA-cellulose in hippocampus, whereas the cord was insensitive to its action. These results suggest that there is a “receptor dysfunction” in the spinal cord, the significance of which is poorly understood in terms of the accepted model of steroid hormone action.

Sympathoadrenal mechanisms in cardiovascular responses to naloxone after hemorrhage.

Five rabbits were allotted to each of six treatments on a matched-individual basis. Treatments were none, sham, total adrenalectomy with adrenocorticoid replacement, intravenous guanethidine (15 mg X kg-1 X day-1), adrenalectomy + guanethidine, and adrenal medullectomy. The conscious rabbits were bled 20 ml/kg over 5 min. Naloxone (6 mg/kg) was injected intravenously. The responses of arterial pressure and of plasma epinephrine (E) and norepinephrine (NE) concentrations were measured. Factorial analysis was used to calculate the effects of sympathetic noradrenergic nerves (SYM) and the adrenal medulla (ADR) on the responses. In combination, SYM + ADR fully accounted for the pressor response observed in normal and sham-treated rabbits. SYM and ADR each made independent and approximately equal contributions to the response, but the SYM X ADR interaction was strongly antagonistic. The responses of plasma E and NE were fully accounted for by the adrenal glands and sympathetic nerves, respectively. The pressor responses after total adrenalectomy and adrenal medullectomy were similar. Thus hemorrhage-stimulated adrenal corticosteroid release was not essential to naloxone's action, and adrenal enkephalins were not responsible for naloxone's action on sympathetic pathways.

Stress-induced alteration of T-lymphocyte subsets and humoral immunity in mice.

Effects of acute rotational stress on the tissue distribution of lymphocyte subpopulations, and the capacity to mount a humoral immune response were examined in normal and adrenalectomized mice. The splenic lymphocyte population showed a significant alteration in its content of T lymphocytes in normal, but not adrenalectomized animals subjected to rotational stress. Thus adrenal steroids may influence lymphocyte subpopulations in animals responding to stress. Humoral immune responsiveness of splenic lymphocytes was assessed by a direct lymphocyte plaque forming cell assay following immunization with sheep erythrocytes. The peak number of lymphocytes forming antibody to sheep erythrocytes found in spleens of animals subjected to stress begun 24 hours after antigen inoculation was 50% of the number observed in animals immunized and stressed simultaneously (p less than .001). No effect of adrenalectomy on the reduction in the numbers of antibody forming lymphocytes was observed. We conclude that stress can modify immune responsiveness by a number of mechanisms, some of which are independent of adrenal corticosteroid action.

Regulation by adrenal corticosteroids of sodium and potassium transport in loop of Henle and distal tubule of rat kidney.

Studies were conducted to examine the effects of adrenalectomy (ADX) and selective, physiological adrenal corticosteroid replacement on sodium and potassium transport by the superficial loop of Henle and distal tubule of rat kidney in vivo. In the loop of Henle, ADX inhibited sodium reabsorption by 33%. Whereas dexamethasone had no effect on reabsorption, aldosterone increased sodium transport to control levels. Thus, physiological levels of mineralocorticoids, but not glucocorticoids, control a fraction of sodium reabsorption in the loop of Henle. ADX also inhibited potassium reabsorption in the loop of Henle. Both dexamethasone and aldosterone reversed the inhibition, although only aldosterone increased reabsorption to control levels. In the distal tubule, ADX reduced sodium reabsorption by 44%. Both aldosterone and dexamethasone stimulated reabsorption: however, only aldosterone increased transport to control. Potassium secretion by the distal tubule was also reduced 34% by ADX. Aldosterone, but not dexamethasone, stimulated secretion. Thus, physiological levels of aldosterone regulate a fraction of sodium reabsorption and potassium secretion in the distal tubule.

Vitamin C and immunosuppression

Large daily doses of vitamin C resulted in severe lymphocytopenia in stressed mice. A characteristic biochemical expression of stress is an abrupt increase in adrenal corticosteroids in blood plasma which is always preceeded by a release of vitamin C by the adrenals. It is hypothesized that large doses of vitamin C maintain high levels of plasma corticosteroids which inturn may reduce the organism's immune response when stress is present.

Plasma growth hormone, insulin, glucocorticoids and thyroid hormones in large, medium and small breeds of steers with and without an estradiol implant

Growth hormone secretory patterns and plasma concentrations of insulin, adrenal corticosteroids, thyroxine and triiodothyronine were measured in three types of steers with and without estradiol implants. The three types of cattle were large (Simmental), medium (Limousin) and small (Angus) frame size with medium, low and high propensity to deposit fat. Simmental steers had higher (P<.01) concentrations of growth hormone and lower (P<.01) concentrations of insulin as compared with Angus. Implanting the steers with estradiol increased (P<.01) growth hormone concentrations in all three groups, tended to decrease glucocorticoids and had no effect on insulin or thyroid hormone concentrations. There tended to be less frequent release of growth hormone, with secretory spikes of greater magnitude in the Simmental steers. The implants tended to increase the frequency of release of growth hormone in all three groups.