Adrenal Corticosteroids Research Articles

Rodent models for studying steroids and hypertension: From fetal development to cells in culture

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11β (11β-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated. In a second transgenic model, we used a transgenic rat (TGR) that expresses an additional renin-2 gene primarily in the adrenal to study the role of adrenal renin in regulating adrenal steroidogenesis in vivo. Since plasma and urinary corticosteroid concentrations are elevated throughout the development of hypertension in these animals, we studied the effect of ACTH and Dexamethasone (DEX) on blood pressure and steroidogenesis. Daily injections of Dex suppressed the development of hypertension in TGR, but did not alter blood pressure in Sprague-Dawley (SD) control rats. This reduction in blood pressure was associated with reductions in plasma concentrations of corticosterone and 18-OH-DOC and of P450scc and P450c11β mRNAs. Surprisingly, plasma aldosterone concentrations and P450c11AS mRNA increased in TGR but not SD treated with Dex. Although Dex resulted in differences in the regulation of P450scc, P450c11β, and P450c11AS mRNAs between TGR and SD rats, regulation of these mRNAs by ACTH was similar in both strains of rats. These data provide evidence for the important role of adrenal renin and corticosteroids in the development of hypertension in TGR. Taken together, these model systems will continue to allow us to study the varied roles that steroid hormones play in hypertension.

Sympathoadrenal regulation of adrenocortical steroidogenesis.

Sympathoadrenal regulation of adrenocortical steroidogenesis was studied on a physiological, cellular, molecular and morphological level. The effects of nerve activation and of epinephrine (EPI) on adrenal corticosteroid release were compared in isolated perfused pig adrenals with preserved nerve supply. Splanchnic nerve activation as well as perfusion with EPI provoked a significant release of cortisol, aldosterone and androstenedione. In cultured bovine adrenocortical cells steroid secretion and accumulation of P450scc, P450(17) alpha, P450c21 and P450(11) beta mRNAs were studied after stimulation with EPI with or without propranolol or phentolamine. Incubation with EPI stimulated steroidogenesis and increased the levels of all four P450-mRNAs. The beta-adrenergic antagonist propranolol totally blocked the effects of EPI while the alpha-antagonist phentolamine had no effect. Using immunohistochemistry, adrenals were studied morphologically. The contact zones of the two cell types were investigated on an electron microscopical level. Cortical and medullary cells were closely interwoven with cortical and chromaffin cells in direct apposition, providing the possibility for paracrine interactions. It is concluded that the release of corticosteroids can be stimulated through the sympatho-adrenal system. The stimulatory action of EPI upon adrenal steroid formation and accumulation of all four P450-mRNAs requires beta-adrenergic receptors. Taking into consideration the close colocalization of cortical and medullary tissue, this stimulation may be mediated by chromaffin cells in a paracrine manner.

Neuronal Change in the Dentate and Hippocampus of Adrenalectomized and Adrenal Corticosteroid Injected Neonatal Rats

Neuronal Change in the Dentate and Hippocampus of Adrenalectomized and Adrenal Corticosteroid Injected Neonatal Rats

Anterior pituitary and adrenal cortical hormones accelerate or inhibit tadpole hindlimb growth and development depending on stage of spontaneous development or thyroxine concentration in induced metamorphosis

The effect of prolactin, growth hormone, and various adrenal corticoids on hindlimb growth, development, and differentiation was studied in Rana pipiens larvae. Experiments were performed at different stages of spontaneous development and during metamorphosis induced in premetamorphic tadpoles by various concentrations of exogenous T4. Prolactin at 10 micrograms/day inhibited the limb at spontaneous premetamorphosis, had no effect at prometamorphosis or when administered with 3.8 nM T4, and synergized with T4 at 63 nM T4 and above. Growth hormone (10 or 20 micrograms/day) promoted limb growth and development during premetamorphosis but had no effect on spontaneous or induced metamorphosis thereafter, nor did it stimulate limb epidermal differentiation. The adrenal corticoids inhibited limb growth and epidermal cell proliferation during pre- and prometamorphosis but had no effect on limb morphogenesis or differentiation. The depressive effect of corticoids during spontaneous metamorphosis is at least partly through thyroid inhibition since hydrocortisone significantly reduced follicle cell height, lumen diameter, and cell proliferation in the thyroid. During induced metamorphosis, steroids (0.29 microM), especially corticosterone and aldosterone, antagonized the effect of 0.38 to 1.2 nM T4 on the limb. All steroids except deoxycorticosterone synergized with 3.8 nM T4, and at 31 nM T4, approximating the climax level with permeability factors taken into account, all corticoids synergized with T4 to promote limb growth and development. Aldosterone antagonized T4 at a higher T4 level than the other corticoids. The effect of all steroids except corticosterone was also corticoid dose-dependent. The results show the importance of the T4 concentrations in interactions of T4 with other hormones and suggest a scheme for hormonal control of limb growth and morphogenesis during metamorphosis. During premetamorphosis growth hormone synergizes with low endogenous T4 to promote initial limb growth and development while prolactin opposes this action. During prometamorphosis, as growth hormone and prolactin become ineffective corticosteroids begin to synergize with the rising level of endogenous T4. At climax, prolactin also augments the action of T4 to bring about rapid hindlimb growth.

Adrenalectomy Selectively Regulates GABA A Receptor Subunit Expression in the Hippocampus

Hippocampal function is modulated by adrenal corticosteroids released in a diurnal rhythm or in response to stress. Hippocampal excitability is also modulated by the activity of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain. One mechanism of corticosteroid action in the hippocampus is likely to be via regulation of the GABA system, including corticosteroid regulation of GABA A receptor expression. The GABA A receptor is a heterooligomeric complex composed of subunits derived from a number of distinct genes. We examined the effects of short-term adrenalectomy and low-level corticosterone replacement on mRNA levels for 5 GABA A receptor subunits. In situ hybridization studies demonstrated that mRNA levels for GABA A receptor α1, α2, β2, and γ2 subunits were altered in the hippocampus of female rats by adrenalectomy. Levels of α1 and γ2 mRNA increased in CA3, α2 mRNA increased in the dentate gyrus, while β2 mRNA decreased in the dentate gyrus and CA2 relative to sham-operated animals following adrenalectomy. These effects were reversed by the addition of 100 μg/ml corticosterone to the drinking water. Adrenalectomy had no effect on the levels of β1 mRNA and no effect on any subunit examined in CA1 or the cingulate cortex. These data support the conclusion that corticosteroids can modulate hippocampal excitability through the site-specific regulation of the expression of specific GABA A receptor subunits. Corticosterone-induced changes in subunit expression might alter GABAergic synaptic inhibition by altering the density of GABA A receptors or altering the subunit composition and thereby the pharmacological properties of the receptors.

Hypothalamic thermal stimulation modulates vasopressin release in hyperosmotically stimulated rabbits

Under thermoneutral conditions conscious rabbits received systemic infusions of NaCl as hypertonic solution (90 mueq.min-1.kg body wt-1), which raised their plasma osmolality from 283 to 312 mosmol/kgH2O. Rabbits receiving isotonic saline served as controls. Hypertonic stimulation induced a 60% reduction of both respiratory frequency and evaporative water loss. Rectal temperature rose by 0.4 degrees C despite enhanced peripheral vasodilation as indicated by increased ear skin temperature. Plasma vasopressin (AVP), aldosterone (ALDO), and corticosterone (COR) were significantly elevated from 6 to 16 pg/ml, 90 to 180 pg/ml, and 17 to 40 ng/ml, respectively. To elucidate the importance of central temperature for AVP and adrenal corticosteroid release, hypothalamic thermal stimulations (20 min) were superimposed during established iso- and hyperosmotic steady-state conditions. Different from isosmotic controls, hyperosmotic animals responded to hypothalamic cooling (37 degrees C) with a significant decrease in plasma AVP from 16 to 13 pg/ml and to hypothalamic warming (41 degrees C) with a significant rise from 16 to 19 pg/ml. A weak temperature effect on COR release was also disclosed, especially of hypothalamic cooling, which significantly lowered plasma COR from 42 to 34 ng/ml. These results provide evidence for positive local temperature coefficients of hypothalamic control of AVP release and suggest a similar property also for the control of COR release by the hypothalamo-adenohypophysial axis.

Modulation of hippocampal long-term potentiation and long-term depression by corticosteroid receptor activation

Long-term potentiation (LTP) and long-term depression (LTD) are lasting changes in synaptic efficacy which may underlie memory and learning processes. Hippocampal LTP has been shown to vary inversely with the degree of stress or adrenal activity, and adrenal corticosteroids (CORT) have been strongly implicated in this process. The present in vitro study was undertaken to further examine the role of glucocorticoids in LTP, and to extend this analysis to heterosynaptic LTD. Animals were injected twice daily (s.c.) for 2 days prior to sacrifice with either the corticosteroid biosynthesis inhibitor metyrapone (200 mg/kg/day) or CORT (20 mg/kg/day). Noninjected and saline-injected controls were also examined. CA1 population spike amplitudes and field EPSP slopes were assessed in response to activation of two separate stratum radiatum inputs. One input received tetanic stimulation and both inputs were monitored for 30 min following tetanization to determine long-term changes in synaptic efficacy (homosynaptic LTP of tetanized synapses; heterosynaptic LTD of nontetanized synapses). Animals exhibiting low and high serum CORT titers exhibited significantly less LTP and LTD than did animals exhibiting moderate levels of CORT. In addition, in vitro perfusion of RU-28362, a Type II glucocorticoid receptor agonist, markedly reduced both LTP and LTD. There was no correlation between serum CORT and serum glucose titers, nor was there any correlation between serum glucose and either LTP or LTD. These results are consistent with recent reports of an inverted-U function for CORT levels versus primed-burst LTP (Bennett, Diamond, Fleshner, & Rose, 1991; Diamond, Bennett, Fleshner, & Rose, 1992) and further demonstrate that manipulation of corticosterone in adrenal-intact animals affects LTP and LTD in a similar fashion.

A clinical study of Pseudomonas pneumonia diagnosed by transtracheal aspiration

We performed a clinical study of 16 cases (18 episodes) of Pseudomonas pneumonia by transtracheal aspiration (TTA) from April 1983 to March 1993. The isolation rate of Pseudomonas aeruginosa (P. aeruginosa) among 235 episodes of pneumonias with positive microorganism by TTA was 7.7%. All patients had one or more underlying disease. The most frequent underlying disease was chronic lower respiratory tract infection, followed by lung epidermoid cell carcinoma. More than half of the cases had been given antibiotics prior to the occurrence of pneumonia, and administration of adrenal corticosteroid, heavy smoking habit, and aspiration were seen as other predisposing factors concerning the onset of pneumonias. Monomicrobial infection of P. aeruginosa was 61.1%, and polymicrobial infection containing P. aeruginosa was 38.9%. Community-acquired pneumonia was 61.1% and hospital-acquired pneumonia was 38.9%; the rates of polymicrobial infections and prior administration of antibiotics were higher in the latter group. Mortality due to Pseudomonas pneumonia was 27.8% and the levels of serum albumin and total protein at the onset of pneumonia were significantly lower in the fatal cases than in the recovered cases. It was considered that not only general underlying disease which weaken the immunological resistance of the host, but local bronchial lesion was also important to the onset of the Pseudomonas pneumonia. Also, nutrition is an important prognostic factor on the host's side.

Effect of metyrapone on tryptophan binding to rat hepatic nuclei

This study evaluated whether metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone), an inhibitor of endogenous adrenal corticosteroid synthesis via inhibition of cytochrome P-450-mediated steroid hydroxylation, would influence the binding of l-tryptophan to rat hepatic nuclei or nuclear envelopes. Previous publications have indicated that binding of l-tryptophan to hepatic nuclear envelope proteins was saturable, stereospecific, and of high affinity. In this study, we investigated whether metyrapone would influence l-tryptophan binding to rat hepatic nuclei or nuclear envelopes as assayed by in vitro l-(5- 3H)tryptophan binding. Our results indicate that the addition of metyrapone in vitro has little influence on l-(5- 3H)tryptophan binding to hepatic nuclei or nuclear envelopes. On the other hand, when metyrapone ( 1 mg 100 g body weight ) is tube-fed 30 minutes before killing, the isolated hepatic nuclei show decreased specific l-tryptophan binding (total binding minus nonspecific binding [using 2,000-fold excess of unlabeled l-tryptophan]) compared with controls. Also, addition of metyrapone in vitro to rat liver before homogenization and preparation of nuclei caused the nuclei to show decreased specific tryptophan binding compared with controls. Under these in vitro conditions, SKF 525A, another inhibitor of hydroxylation, showed inhibitory effects similar to those of metyrapone. Thus, metyrapone can interfere with rat liver nuclear envelope receptor binding to l-tryptophan, and possibly acts via its effects on hydroxylation. At high doses, metyrapone ( 20 mg 100 g body weight ) appears to inhibit tryptophan-induced stimulation of hepatic protein synthesis.

Modulation of carbachol responsiveness in rat CA1 pyramidal neurons by corticosteroid hormones

Pyramidal neurons in the rat CA1 hippocampal area contain membrane receptors for acetylcholine but also intracellular receptors for the adrenal corticosteroid hormone corticosterone, i.e., mineralocorticol receptors (MRs) and glucocorticoid receptors (GRs). In this in vitro study we investigated if occupation of MRs or GRs affects the responsiveness of CA1 pyramidal neurons to the cholinergic analogue carbachol. In slices from adrenally intact rats, where probably most of the MRs and a considerable degree of the GRs were occupied, carbachol (0.1–30 μM) induced a dose-dependent: (i) depolarization; (ii) reduction of the afterhyperpolarization and spike frequency accomodation associated with depolarizing current pulses; and (iii) reduction of the synaptically evoked EPSP, slow IPSP and (with higher doses) the fast IPSP. The carbachol responses in slices from adrenalectomized (ADX) rats, where both MRs and GRs are unoccupied, were generally similar to the responses in the adrenally intact controls. However, neurons recorded in slices from ADX rats 1–4 h after a brief (20 min) applications of 3 nM aldosterone, thus predominantly occupying MRs, showed a significant reduction of the carbachol (1 μM) induced depolarization, when compared to the adrenally intact group. By contrast, neurons recorded in ADX slices treated with 30 nM corticosterone, inducing simultaneous activation of MRs and GRs, displayed significantly larger carbachol-evoked depolarizations (1 and 3 μM) than neurons in the three previous experimental groups. Carbachol-induced actions on the afterhyperpolarization, accomodation and synaptically evoked responses did not consistently depend on steroid receptor occupation. The data suggest that under conditions of low adrenocorical activity, i.e., with predominant MR occupation, carbachol induced depolarization will be small, while a gradual increase of the adrenocortical activity, resulting in additional GR occupation, will enhance the carbachol responsiveness in CA1 neurons.

Direct action of metyrapone on brain: implication in feeding.

While the inhibitory effect of metyrapone on the biosynthesis of adrenal corticosteroid hormones is well known, the drug has not been tested for central actions. The present study is aimed at finding out the direct central action of metyrapone, if any, employing feeding behaviour as a test parameter. Low doses of metyrapone (10-1000 ng) administered via an i.c.v. route reduced the food intake in a dose dependent manner; the effect was functionally antagonized by concomitant administration of anti-CRF antisera. The results reveal for the first time, that metyrapone might be capable of exerting a direct action on the adrenal cortex.

Effects of Corticosterone on Social Behavior of Male Lizards

Adrenal corticoid release is a major component of the stress response which can affect many body functions including behavior. The purpose of our studies was to examine the effects of corticosterone (B) on both the agonistic and courtship components of social behavior in male side-blotched lizards ( Uta stansburiana). Of particular interest was the effect of B on plasma testosterone (T), a hormone known to influence aggression, and the importance of this action on the behavioral effects of B. Experiments included either castrated males, hormone (either B, T, or B + T)-implanted intact males, or sham males. Behavioral observations were recorded when these males were challenged with "immigrant" males; measurement of plasma steroids confirmed the efficacy of implants in elevating B and T. Castration, B implantation, and combined B and T implantation significantly reduced aggressive behavior to varying degrees, while T implants in intact animals had no effect. B implants significantly decreased plasma T levels (from 1.87 to 0.33 ng/ml), but this decrease was not essential for the inhibitory effect of B on aggression since B + T implantation also reduced aggression, even though plasma T was elevated above normal (67.6 ng/ml). In contrast, B implantation did not affect male courtship and copulatory behavior when males were presented with estrogenized females. These results suggest that the effect of B on social behavior is not through just a single route, that of decreasing plasma T, and that B can affect various intra- and intersexual behaviors differently.

Cardiac tamponade. A clinical or an echocardiographic diagnosis?

In most patients, cardiac tamponade should be diagnosed by a clinical examination that shows elevated systemic venous pressure, tachycardia, dyspnea, and paradoxical arterial pulse. Systemic blood pressure may be normal, decreased, or even elevated. The diagnosis is confirmed by echocardiographic demonstration of moderately large or large circumferential pericardial effusion and in most instances, of right atrial compression, abnormal respiratory variation in right and left ventricular dimensions, and in tricuspid and mitral valve flow velocities. Pulsus paradoxus may be absent with left ventricular dysfunction, atrial septal defect, regional tamponade, and positive-pressure breathing. Systemic venous pressure may be normal with localized tamponade of the left atrium or ventricle. Patients with moderately large or large pericardial effusions may have echocardiographic evidence of right atrial compression without clinical signs of elevated venous pressure or pulsus paradoxus. The majority of these patients have mild or moderate tamponade and if not subjected to pericardial drainage, should be observed closely. In some of these patients, when the etiology is known and the disease can be treated effectively with medication, e.g., nonsteroidal anti-inflammatory agents or adrenal corticosteroids in Dressler's syndrome or relapsing pericarditis, pericardial drainage may not be necessary.

Distribution of mineralocorticoid and glucocorticoid receptor mRNA along the nephron

In the present study, a competitive polymerase chain reaction (PCR) technique was used to quantitate the relative levels of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in microdissected nephron segments from the rat kidney and of MR mRNA from isolated principal and intercalated collecting duct cells from rabbit. RNA was isolated from cells and isolated tubules, cDNA was synthesized, and receptor cDNA was coamplified by PCR with a competitive control template. beta-Actin PCR products were also obtained from each nephron segment studied, to assess variations in RNA extraction and cDNA synthesis. MR mRNA, as determined by this competitive PCR technique, was 10-fold more abundant in cortical collecting duct (CCD), outer medullary collecting duct, and inner medullary collecting duct segments than in the proximal tubule and thick ascending limb segments (P < 0.05). Both principal and beta-intercalated cells of the CCD contained detectable levels of MR mRNA, although the levels in the principal cells were threefold higher (P < 0.01). GR mRNA was twofold more abundant in glomeruli, proximal tubule, and thick ascending limb segments than in the collecting duct segments (P < 0.05). In general, the distribution pattern of MR and GR mRNA is consistent with the distribution of adrenal corticosteroid function along the nephron.

Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor.

The human mineralocorticoid (hMR) and glucocorticoid (hGR) receptors mediate biological responses to adrenal corticosteroids and synthetic ligands. In transient transfection studies, corticosteroid-responsive promoters were used to monitor the hormone-dependent transcriptional regulatory properties of both receptors. The hMR mediates a lower stimulation of the transcription rate than the hGR and does not show cooperative activity on promoters containing multiple palindromic glucocorticoid-responsive elements. The functional importance of the amino-terminus in this differential response was demonstrated by hMR/hGR hybrid receptors in which this region was exchanged or deleted. These experiments revealed that the hMR amino-terminus does not provide the strong transactivation function present in the equivalent hGR domain and, in contrast to the hGR amino-terminus, interferes with the synergistic activity mediated by the DNA- and ligand-binding domains of both receptors.

Central Nervous System Aspergillosis following Steroidal Therapy for Allergic Bronchopulmonary Aspergillosis

A 52-year-old man with probable allergic bronchopulmonary aspergillosis (ABPA) was treated with adrenal corticosteroids. He subsequently developed central nervous system aspergillosis that was treated successfully with surgery and amphotericin B. Invasive aspergillosis is a rare complication following steroid therapy for ABPA.

A clinical study of chronic lower respiratory tract infections with Pseudomonas aeruginosa by transtracheal aspiration

We investigated the yearly changes of the incidence of Pseudomonas aeruginosa (P. aeruginosa) isolated from chronic lower respiratory tract infections (CLRTI), and also performed a clinical study on CLRTI with P. aeruginosa by transtracheal aspiration (TTA) to clarify the recent trend of P. aeruginosa infection in CLRTI and the predisposing clinical factors to the acute exacerbation. The isolation rate of P. aeruginosa among the total isolated bacteria in CLRTI between December 1978 and March 1983 was 8.4%, but it increased to 23.1% between April 1988 and March 1993. In 69 episodes (40 cases) of P. aeruginosa isolated from CLRTI between April 1983 and March 1993, monomicrobial infections of P. aeruginosa were 42 episodes (60.9%) and polymicrobial infections were 27 episodes (39.1%). When the diseases were classified into acute exacerbated and non-exacerbated phases, polymicrobial infections were seen more in the former phase, and the principal organisms detected with P. aeruginosa were Haemophilus influenzae and Streptococcus pneumoniae. In the acute exacerbated cases, predisposing conditions concerning the exacerbation were divided into four patterns: 1. polymicrobial infections with H. influenzae or S. pneumoniae, 2. after acute upper respiratory tract infections due to viral superinfection, 3. early phase from bacterial replacement by P. aeruginosa, 4. immunocompromised states such as adrenal corticosteroid administration or systemic underlying diseases. These results suggest that the importance of P. aeruginosa in CLRTI is increasing year by year and we must pay attention to the fact that P. aeruginosa alone may also cause acute exacerbation in the latter 2 patterns of the condition.

Lesions of the hippocampal efferent pathway (fimbria-fornix) do not alter sensitivity of adrenocorticotropin to feedback inhibition by corticosterone in rats.

The hypothalamic-pituitary-adrenal (HPA) axis controls the diurnal and stress-induced release of adrenal corticosteroids into the general blood circulation. In turn, corticosteroids inhibit the HPA axis under basal conditions and during stress through occupation of their receptors (types I and II) in the brain by closing a negative feedback loop. The primary site in the brain at which corticosteroids act to inhibit the HPA axis has not been identified. High concentrations of both types of receptors are found in neurons of the hippocampal formation, a structure which has been reported by some, but not others, to control activity within the HPA axis by serving as a major negative feedback site. In many of these past studies, blood was collected after extensive handling or exposure to ether, conditions which do not favor the detection of basal hormone concentrations. To address these controversies, we tested the feedback sensitivity of the anterior pituitary hormone responsible for corticosteroid production, adrenocorticotropin (ACTH), to corticosterone (B), the main corticosteroid in rats, in total fornix- and, as controls, cortex-lesioned rats. All rats were given vascular catheters to avoid any handling-induced differences in plasma B or ACTH when sampling blood. In some experiments, fornix- and cortex-lesioned rats were adrenalectomized and given 1 of 3 doses of exogenous B provided in a subcutaneous pellet to ensure that plasma B was equal in different lesion groups. We hypothesized that if the hippocampal formation were an important site of B-mediated inhibition of the HPA axis, fornix-lesioned rats would have higher plasma B as a result of increased endogenous secretion in the morning or the evening compared to cortex-lesioned rats in rats with adrenal glands. In addition, we hypothesized that adrenalectomized fornix-lesioned rats given the same low to moderate levels of exogenous constant B would have higher basal and stress-induced ACTH than cortex-lesioned rats. Diurnal plasma B was not affected by fornix lesions in intact rats. Moreover, basal ACTH measured in the morning and the evening and stress-induced ACTH was the same in adrenalectomized fornix- and cortex-lesioned rats with constant exogenous B. We conclude, therefore, that information about occupancy of B receptors in the hippocampus carried by the fornix primarily subserves functions which do not directly regulate activity in the HPA axis.

Intracellular localization of corticosteroid receptors in brain: potential interactions with signal transduction pathways.

Adrenal corticosteroids have diverse actions in the central nervous system (CNS). Glucocorticoids, the major adrenal corticosteroids, regulate the actions of several classical neurotransmitters and peptides, neuronal and glial proliferation and differentiation, neuronal survival, cognitive function, and behavior (1). Mineralocorticoids, e.g., aldosterone, regulate salt appetite and blood pressure (2, 3). As with other members of the steroid receptor superfamily, most actions of adrenal corticosteroids are mediated by intracellular receptors (4). Activated corticosteroid receptors bind to a glucocorticoid response element and interact with other transcription factors to regulate the expression of various genes (5–8). Two types of corticosteroid receptors have been described (7–9). A Type I receptor, which is identical to the classical mineralocorticoid receptor of the kidney, salivary glands, and colon, has a high affinity (KD = 0.5 nM) and low capacity for endogenous glucocorticoids in the brain. It binds...

Adrenal corticosteroid secretion in fetal sheep: pulsatile pattern at rest.

This study was undertaken to define the resting pattern of fetal pituitary-adrenocortical function. Experiments were performed at 127-145 days gestation in fetal sheep with chronic peripheral and adrenal cannulas inserted under halothane anesthesia. With the fetus in a baseline state, over 6 h, at 30-min intervals, maternal and fetal peripheral samples were collected for blood gases and cortisol (F), corticosterone (B), and adrenocorticotropic hormone (ACTH) concentrations, and three successive, 2-min adrenal samples were collected for determination of F and B secretion rates. We observed high-frequency, episodic bursts of F secretion. A lower frequency oscillation of F secretion, with a period of approximately 90 min, was defined by cosinor analysis. The mean amplitude of the oscillation increased from 45 to 507 ng/min with advancing gestation. The pattern of B secretion was similar to that for F but was quantitatively lower. An oscillatory period of approximately 90 min for plasma F was present in a majority of experiments. Pulsatile rhythms for ACTH were defined in 10 of 14 experiments, with periods ranging from 1.64 h in the least mature group to 2.37 h in the oldest fetus. Mean data revealed exponential increases in both F secretion and plasma ACTH from 129 to 145 days gestation.