Adrenal Corticosterone Levels Research Articles

Studies on Antinephritic Effect of TJ-8014, a New Japanese Herbal Medicine (4): Effects on Accelerated Passive Heymann Nephritis in Rats

We investigated the antinephritic effect of TJ-8014, in comparison to dipyridamole, on accelerated passive Heymann nephritis in rats. TJ-8014 (4.0 g/ kg/day, p.o.) given from the heterologous phase (from the day of injection of the antiserum against Fx1A) markedly inhibited the urinary protein excretion and the elevation of plasma cholesterol levels as well as glomerular histopathological changes. When the treatment was started from the autologous phase (from the 22nd day) after proteinuria was fully developed, TJ-8014 also showed a beneficial effect. Dipyridamole (0.4 g/kg/day, p.o.) had no effect when the treatment was started either from the heterologous or autologous phase. TJ-8014 decreased glomerular rat IgG and rat C3 deposits, although it affected neither the plasma antibody titer against rabbit γ-globulin nor the plasma complement level. TJ-8014 markedly prevented the reduction of plasma and adrenal corticosterone level as well as the reduction of renal blood flow of rats with nephritis. These results suggest that TJ-8014 may be a useful drug against idiopathic membranous nephropathy and the beneficial effect of this drug may be caused by the elimination of glomerular immune deposits and C3 through the increase in renal blood flow related to the enhanced release of adrenal corticosterone.

The determination of the adrenal medullary cell fate during embryogenesis

One subset of neural crest cells, the sympathoadrenal precursors, undergoes a switch in phenotype expression, when they invade the adrenal anlagen and become associated with adrenocortical cells. To investigate the mechanisms responsible for the conversion of noradrenaline synthesizing precursors to adrenaline producing endocrine chromaffin cells we studied the role of glucocorticoids on the initial induction of adrenaline synthesis in embryonic adrenals and cultures of highly purified chromaffin precursor cells. We could show that in vivo differentiation of rat chromaffin precursors commences between 16.3 and 17.3 days of gestation. While adrenaline and the activity of the enzyme phenylethanolamine N-methyltransferase (PNMT), which converts noradrenaline to adrenaline, were present at Embryonic Day 17.3 (E17.3), they were not detectable in E16.3 adrenals. Small amounts of corticosterone were present in E16.3 adrenals and plasma, but in parallel with the initial induction of adrenaline biosynthesis, a sharp rise in organ and plasma glucocorticoid levels occurred until E17.3. Chromaffin precursor cells, isolated at E16.3 and cultured for 4 days, failed to express PNMT activity and adrenaline. However, 0.1 n M dexamethasone was already sufficient for the initial induction of adrenaline and its synthesizing enzyme. Specific glucocorticoid binding of freshly isolated chromaffin (precursor) cells revealed a developmental increase during embryogenesis, yet no glucocorticoid binding sites were detectable in chromaffin precursor cells at E16.3. They appeared at E17.3 in parallel with the initial induction of adrenaline biosynthesis and the enormous rise of adrenal and plasma corticosterone levels. We therefore conclude that glucocorticoids are essential and sufficient to trigger the differentiation of noradrenergic sympathoadrenal precursors to adrenergic chromaffin cells after a functional glucocorticoid receptor system has been established.

Prenatal Ethanol Exposure Alters Adrenocortical Development of Offspring

Interactive effects of prenatal ethanol and maternal nutritional status on reproductive outcome and maternal and offspring adrenocortical activity were examined. Ethanol was administered to pregnant females in liquid diets (36% ethanol-derived calories) which were marginal or optimal in terms of requirements for pregnancy. Both pair-fed and ad libitum fed control groups were included. Females consuming ethanol from gestation Day 1 through parturition gained less weight, were delayed in parturition, and had fewer and smaller live born young than pair-fed or control females, regardless of whether they consumed marginal or optimal diets. Withdrawing ethanol on Day 21 of gestation attenuated many of ethanol's adverse effects on reproductive outcome. However, prenatal maternal ethanol intake altered adrenocortical activity/responsiveness of the mother, the fetus, and the preweaning offspring, regardless of maternal nutritional status. Relative adrenal weights and basal corticosterone levels were increased in the dam both prenatally and at parturition. Ethanol-exposed fetuses (A) had increased relative adrenal weights but lower basal corticosterone levels than pair-fed (PF) and control (C) fetuses on gestation Day 21. At birth, plasma and adrenal corticosterone levels were increased, while absolute adrenal weights and corticosterone binding globulin (CBG) binding capacity were decreased in A neonates. At 5 days of age, A pups showed reduced plasma corticoid responses to ether at 15 min poststress and to novelty or saline injection at 90-min post stress compared to PF and C pups. CBG binding capacity was also reduced in A pups. At 10 days of age, plasma corticosterone levels were lower overall in A and PF than in C pups following exposure to a number of different acute stressors while at 18 days plasma corticoids were decreased and adrenal corticosterone was increased in A compared to PF and/or C pups. These data support and extend previous studies indicating that in utero ethanol exposure alters postnatal adrenocortical development. This effect is specific to ethanol and unaltered by maternal nutritional status.

Studies on antinephritic effect of TJ-8014, a new Japanese herbal medicine, and its mechanisms (2): Effect on the release of corticosterone from adrenal glands.

In order to elucidate the mechanisms of the antinephritic action of TJ-8014, the effect of this drug on corticosterone release from the adrenal cortex was investigated by using normal rats and rats with original-type anti-GBM nephritis. When the serum corticosterone level was determined 5 hr after test drugs were given p.o. to normal rats, TJ-8014 at 0.5 and 2.0 g/kg significantly elevated the hormone level by 48% and 74%, respectively. Of the crude drugs that constitute TJ-8014, Bupleuri radix (SAIKO) and Glycyrrhizae radix (KANZOU) at 1.0 g/kg also significantly elevated the serum level. When TJ-8014 was given p.o. daily from the next day of anti-GBM serum injection to the 15th day, 2.0 g/kg/day of the drug inhibited the urinary protein excretion. In addition, TJ-8014 (2.0 g/kg/day) inhibited the decrease in the serum and adrenal corticosterone levels induced by nephritis. When corticosterone at 10 mg/kg was given s.c. daily from the next day of the anti-serum injection to the 10th day, it not only reduced proteinuria, but also inhibited glomerular histopathological changes. In contrast, metyrapone, a corticosterone synthetase inhibitor, at 100 mg/kg x 2/day, p.o., aggravated the nephritis. These results suggest that the antinephritic action of TJ-8014 may be partly due to the enhancement of the synthesis or release of corticosterone from the adrenal cortex.

Studies on Antinephritic Effect of TJ-8014, a New Japanese Herbal Medicine, and Its Mechanisms (2): Effect on the Release of Corticosterone from Adrenal Glands

AbstractIn order to elucidate the mechanisms of the antinephritic action of TJ-8014, the effect of this drug on corticosterone release from the adrenal cortex was investigated by using normal rats and rats with original-type anti-GBM nephritis. When the serum corticosterone level was determined 5 hr after test drugs were given p.o. to normal rats. TJ-8014 at 0.5 and 2.0 g/kg significantly elevated the hormone level by 48% and 74%. respectively. Of the crude drugs that constitute TJ-8014. Bupleuri radix (SAIKO) and Glycyrrhizae radix (KANZOU) at 1.0 g/kg also significantly elevated the serum level. When TJ-8014 was given p.o. daily from the next day of anti-GBM serum injection to the 15th day. 2.0 g/kg/day of the drug inhibited the urinary protein excretion. In addition. TJ-8014 (2.0 g/kg/day) inhibited the decrease in the serum and adrenal corticosterone levels induced by nephritis. When corticosterone at 10 mg/kg was given s.c. daily from the next day of the anti-serum injection to the 10th day, it not only reduced proteinuria, but also inhibited glomerular histopathological changes. In contrast, metyrapone, a corticosterone synthetase inhibitor, at 100 mg/kg × 2/day, p.o., aggravated the nephritis. These results suggest that the antinephritic action of TJ-8014 may be partly due to the enhancement of the synthesis or release of corticosterone from the adrenal cortex

Acute starvation affects rat adrenal steroidogenesis.

To determine how starvation affects adrenal steroidogenesis we measured the activities of 3 adrenal enzymes involved in corticosterone biosynthesis in a group of adult female rats. The animals were either starved for 7 days or fed ad libitum for the same period. Relative adrenal weight and plasma corticosterone levels were increased in the experimental group of animals compared to the control group (40 +/- 2 vs 27 +/- 1 mg/100 g body weight, P less than 0.001, and 45 +/- 4 vs 30 +/- 5 ng/dl, P less than 0.05 respectively). There were no differences in plasma ACTH levels between the groups (34 +/- 5 vs 26 +/- 4 pg/ml). 11-Hydroxylase activity was increased in the starved group of animals (18 +/- 3 vs 8 +/- 2 nmol/mg protein/min, P less than 0.01). 3 beta-Hydroxysteroid dehydrogenase and 21-hydroxylase activities were not different between the groups (19 +/- 2 vs 16 +/- 1 nmol/mg protein/min, and 100 +/- 10 vs 110 +/- 10 pmol/mg protein/min respectively). These results suggest that acute starvation in rats produces an increase in adrenal 11-hydroxylase activity.

Pentagastrin on neurotransmitter enzyme activities in the rat gastrointestinal tract.

The effects of three doses (5, 100, and 250 micrograms/kg) of pentagastrin on the activities of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE), the neurotransmitter enzymes that synthesize and degrade acetylcholine, and monoamine oxidase (MAO), the degradation enzyme for catecholamines, were investigated. Enzyme activities were assayed in 6 gastrointestinal segments of 21- and 28-day-old and adult rats. All animals were injected intraperitoneally for 7 days with pentagastrin, and the results were compared with age-matched controls receiving saline for 7 days. Plasma and adrenal corticosterone levels were measured. No consistent differences in adrenocortical variables existed between pentagastrin- and saline-treated animals. Similarly, no consistent pentagastrin dose responses of ChAT, AChE, and MAO activities were evident. However, at the highest dose pentagastrin generally produced increases in ChAT activities in 21- and 28-day-old rats, while producing decreases in AChE and MAO activities in 21-day-old rats and increases in 28-day-old animals. There were few significant differences in enzyme activities in adult rats receiving pentagastrin as compared to saline.

Stimulation of pituitary-adrenocortical system by cepharanthine

We observed that cepharanthine might exert its anti-allergic action by stimulating the secretion of corticosterone. The present experiments were carried out to investigate stimulation of the pituitary-adrenocortical system by cepharanthine. Administration of cepharanthine to rats produced increases in plasma and adrenal corticosterone levels. Administration of cepharanthine to propranolol pretreated rats also produced increases in plasma and adrenal corticosterone levels and plasma ACTH level. The elevation of corticosterone level induced by cepharanthine was considered to be the specific effect of cepharanthine. Cepharanthine did not increase plasma corticosterone level in rats in the state of dexamethasone suppression of the pituitary-adrenocortical system, in which the level was lowered. Administration of cepharanthine to Bordetella pertussis vaccine induced beta-adrenergic blocked rats also produced increases in plasma and adrenal corticosterone levels. The production and release of corticosterone from an adrenal cell suspension were not influenced by cepharanthine in vitro. These results suggest that cepharanthine stimulates the pituitary-adrenotropic function.

Studies on methyl-xanthines in intact and hypophysectomised rats: Differences in pharmacokinetics and adrenocortical response

The effects of caffeine (Cf), theophylline (Tph) and theobromine (Tb) on the adrenal cortex were studied. No direct effect (hypophysectomized : hypo(-) rats) was observed with any of the three methyl-xanthines (MX) after chronic oral administration (5 days). An indirect effect (via the hypothalamo-hypophyseal-adrenal axis) was found for theophylline : plasma and adrenal corticosterone levels were increased in intact rats, after acute or chronic treatment. The high toxicity of MX (mainly Tph) observed in hypo(-) rats prompted the study of pharmacokinetic parameters : the clearance was decreased and the half-life was increased by a factor 3 for Cf and 1.6 for Tph. Thus, the elimination of Cf and Tph was slowed down in hypo(-) rats.

Relationship of Plasma Corticosterone and Adrenal Cholesterol and Corticosterone to the Production of Soft-Shelled and Shell-Less Eggs

Two experiments were conducted to determine if plasma corticosterone and adrenal cholesterol and corticosterone levels differed among hens that laid soft-shelled (SS) or shell-less (SL) eggs when compared with hard-shelled (HS) egg layers. For Experiment 1, four groups of White Leghorn hens were bled at 22 to 34 weeks of age in the morning (0600 to 1200 hr) and at 66 to 74 weeks of age in the morning and evening (1500 to 1900 hr). Group 1 consisted of birds that had just laid SS or SL eggs, whereas Group 2 hens had SS or SL eggs in utero. Groups 3 and 4 represented hens with HS eggs in their uteri and hens that had just laid HS eggs, respectively. For Experiment 2, adrenal cholesterol and corticosterone levels were assayed in high (18+%) and low (0%) incidence SS plus SL egg layers at 73 and 78 weeks of age.Both younger and older hens that laid SS or SL eggs in the morning had similar plasma corticosterone concentrations when compared to HS egg layers. Morning plasma corticosterone levels were significantly higher among hens that laid an egg when compared to hens with eggs in utero, regardless of whether the egg was SS, SL, or HS. However, plasma corticosterone levels of hens producing SS or SL eggs in the evening were significantly higher than levels of hens that laid evening HS eggs. Evening HS egg layers demonstrated the oviposition related peak in plasma corticosterone, but concentrations were 1 ng/ml higher among the evening SS or SL egg layers. Adrenal cholesterol and corticosterone concentrations were similar between high and low incidence SS plus SL layers at either age. It is postulated that evening production of SS or SL eggs is a consequence of elevated plasma corticosterone.

Pharmacological studies on saiko-prescriptions. IV. Effect of shosaiko-to on swelling of rat hind paws induced by carrageenin

The effects of Shosaiko-to and its constituent crude drugs on the inflammatory responses were investigated in rats. The intraperitoneal administration of Shosaiko-to produced a dose-dependent inhibitory effect on the carrageenin-induced paw edema in rats. The suppression of the carrageenin-induced paw edema by Shosaiko-to decreased significantly in adrenalectomized rats. The elevations of serum and adrenal corticosterone levels were observed in rats treated with Shosaiko-to. Bupleuri Radix, Scutellariae Radix, Zingiberis Rhizoma and Ginseng Radix at an intraperitoneal dose of 100 mg/kg suppressed significantly carrageenin-induced paw edema, but Glycyrrhizae Radix, Zizyphi Inermi Fructus and Pinelliae Tuber did not. The active principles of Shosaiko-to producing anti-inflammatory effects were absorbed on Amberlite XAD-2 and eluted with ethanol. These results suggest that Shosaiko-to suppressed the carrageenin paw edema and that the anti-inflammatory action was partly due to an increase in adrenal function.

Relationships among adrenal weight, corticosterone, and stimulated adrenocorticotropin levels in rats.

Based on results of previous studies, we tested the hypothesis that increased adrenal weight in the absence of increased corticosterone secretion would inhibit the magnitude of the ACTH response to ether vapor. Adrenal hypertrophy was induced by treatment of rats for 3 days with aminoglutethimide, cyanoketone, or metyrapone, three agents that act to inhibit enzymes required for corticosterone synthesis. On the fourth day, resting plasma ACTH and corticosterone levels were normal; however, the logarithm of the ACTH response to ether was directly related to total adrenal weight. This result did not support the hypothesis. Unilateral adrenalectomy and treatment with cyanoketone resulted in total adrenal weight equivalent to that of control rats bearing two adrenals. Resting ACTH levels were normal, but stimulated ACTH was significantly greater in these rats than in controls or in rats with two adrenals, suggesting that there is an interaction between the effects of unilateral adrenalectomy and adrenal enzyme inhibition. As anticipated, adrenal hypertrophy with increased corticosterone production caused by ACTH infusion resulted in a significant negative relationship between resting and stimulated ACTH levels and adrenal weight. We conclude that when adrenals are enlarged by means that prevent excessive corticosterone secretion, there is a mechanism associated with the increase in adrenal weight that correlates directly with the magnitude of stimulated ACTH secretion. We have reexamined the results of our previous results in the light of these experiments.

Carbaryl-induced elevation of corticosterone level and cholinergic mechanism.

Administration of a single dose (200 mg/kg, p.o.) of carbaryl to rats produced a significant rise in adrenal and plasma corticosterone levels and an increase of tyrosine alpha-ketoglutarate transaminase activity in the liver cytosol. Synaptosomal acetylcholinesterase activity of the hypothalamic and the striatal regions of rat brain was decreased by carbaryl treatment under similar conditions. Pretreatment (0.5 h) with atropine sulphate (10 mg/kg, i.p.) failed to counteract the carbaryl-induced elevation of adrenal and plasma corticosterone levels and hence the liver tyrosine alpha-ketoglutarate transaminase activity. Present results suggest that the carbaryl-induced rise in the corticosterone level in the adrenal gland and plasma is not due to a cholinergic mechanism.

Suppression of adrenal cortical growth and differentiation in fetal rats exposed to dexamethasone.

AbstractThe effects of maternal dexamethasone (DEXA) administration during the last days of gestation on fetal adrenal growth and differentiation were studied. Timed pregnant rats were divided into three groups: (a) 21d DEXA‐3 received DEXA in drinking water (5 μg/ml) from days 18 to 21 of gestation; (b) 21d DEXA‐6 received the same dosage of DEXA from days 15 to 21 of gestation; and (c) 21d control received tap water throughout gestation. On gestation day 21, pregnant rats were decapitated and ble into heparinized tubes; their fetuses were excised, weighed, decapitated, and bled. Fetal adrenals were prepared for electron microscopy or weighed and frozen until assayed for corticosterone. Control adrenals were also collected on day 15 of gestation and processed for electron microscopy only. Fetal adrenals were fixed in 2.5% glutaraldehyde in 0.5 M cacodylate buffer, postfixed in 2% osmium tetroxide (OsO4), dehydrated, and embedded in Epon 812. Twenty‐one day (21d) fetal adrenal weights were 44% and 68% lower than control values for DEXA‐3 and ‐6, respectively. Fetal adrenal corticosterone levels were decreased by 70% and 89% for the respective groups. These observations correlated with ultrastructural findings of decreased mitochondrial number and size, altered orientation of the inner mitochondrial membrane, decreased lipid, and dilation of smooth endoplasmic reticulum (SER) in cortical fascicular cells of DEXA‐exposed fetuses. Ultrastructural changes in the 21d DEXA fetal adrenals resembled 15d day control fetal adrenals. The results suggest suppressed adrenocortical differentiation probably due to DEXA inhibition of the steroidogenic influence of the fetal pituitary on the developing adrenal gland in DEXA‐exposed fetuses.

Plasma and adrenal corticosterone concentrations and liver glycogen content in premature mice at birth and during neonatal development

The concentrations of corticosterone in the plasma and adrenal glands and the content of glycogen in the liver were estimated from birth to day 6 after birth in surviving premature mice removed by Caesarean section on day 19 of pregnancy and submitted to reanimation during 30 min; the neonates were nourished by nursing mothers from 30 min after birth. A group of full-term newborns was removed by Caesarean section on day 20 of pregnancy and killed 30 min after reanimation. Premature mice were characterized by neonatal changes of three parameters used. The plasma corticosterone level reached a peak in the first 6 h after birth, then decreased until day 6. The adrenal corticosterone level did not vary significantly 30 min after birth, then decreased progressively until day 2. The liver glycogen content, very high on day 19 of pregnancy, increased 30 min after birth, then fell sharply until day 2. In full-term newborns removed by Caesarean section and killed 30 min after reanimation the plasma corticosterone level increased, whereas the adrenal corticosterone level and the liver glycogen content did not decrease. The adrenal gland of surviving premature mice was able to respond to the stress induced by the reanimation; the stimulation of glucocorticoid function was similar in both neonates.

Effects of clorgyline and deprenil on corticosterone levels in rats

Adrenal and plasma corticosterone levels were measured in adult female rats after i.p. administration of specific MAO inhibitors: clorgyline (IMAO-A) and deprenil (IMAO-B). Brain and adrenal MAO activity was also determined. The IMAO effect was found to depend on 3 interrelated factors: (a) dose of drug, (b) time after injection, (c) specificity in MAO inhibition. One hour after injection, clorgyline (1 and 2.5 mg/kg) but not deprenil (20 mg/kg), appeared to inhibit the adrenocortical stress response to i.p. injection. At higher doses, MAO-B inhibition by deprenil (40 mg/kg) induced a moderate but sustained increase in corticosterone levels, while MAO-A inhibition by clorgyline (5, 10, 20 mg/kg) resulted in a large and sharp rise. This effect of clorgyline was potentiated with α-methyl-p-tyrosine and blocked with p-chlorophenylalanine. On this basis, the involvement of serotonergic mechanisms could be considered to explain the stimulatory effect of clorgyline on adrenal cortical function.

Relationships between circadian cycles of rat adrenal cholesterol ester metabolizing enzymes, cholesterol, ascorbic acid, and corticosteroid secretion

The circadian changes in rat adrenal cholesterol ester (CE) metabolism have been studied and related to the circadian changes in adrenal ascorbic acid and corticosterone levels and plasma corticosterone levels. Significant declines in the ratio of CE/C. cholesterol esterase (CEase) and acyl CoA: cholesterol acyl transferase (ACAT) activities occur during the peak and declining phases of adrenal and plasma corticosteroids, suggesting that when there is a decreased need for steroid precursors the amount of stored CE is decreased, and that the enzymes involved in CE metabolism decline in activity. Adrenal ascorbic acid has a biphasic rhythm with peaks at 0900 and 2200 h. The rhythm of ascorbic acid appears to be inverse to that of ACAT activity, suggesting possible relationships between the two parameters.

The effect of long-term chlorpromazine and desipramine treatment on adrenal corticosterone, cyclic AMP, and cholesterol distribution in rats.

1. Male rats were injected intraperitoneally with chlorpromazine (10 mg/kg) and desipramine (10 mg/kg), respectively, twice daily for 2 weeks. 2. The adrenal corticosterone concentrations were significantly lowered in chlorpromazine- and desipramine-treated rats. 3. Large dose of corticotrophin would increase the adrenal corticosterone level in chlorpromazine-treated but the adrenal response was significantly less than in the untreated controls. 4. The adrenal cyclic AMP level was similar in treated and control rats and the adrenal response to corticotrophin was not decreased at the cyclic AMP level. 5. The cholesteryl ester concentrations in the adrenals were significantly increased by drug treatment, although the free cholesterol concentrations were unchanged in the cytosol and mitochondrial cell fractions. 6. The possible site of action of chlorpromazine in suppressing corticosterone production is discussed.

A change in the adrenocortical response in perinatal rat offspring given betamethasone 17,21-dipropionate.

The potent synthetic glucocorticoid betamethasone 17,21-dipropionate (BMDP) produces adrenal hypertrophy in the rat foetus at late pregnancy by mediation of the hypothalamo-pituitary system, but causes adrenal atrophy, and acts as a normal glucocorticoid, in the adult rat. The change of the adrenal cortical response to the BMDP treatment was investigated in perinatal rat offspring. The pituitary ACTH potency was also determined in rat foetus treated with BMDP. The time course of the adrenal corticosterone level after the BMDP treatment was similar to that of the plasma level on day 19 to 21 in the rat foetus from the adrenalectomized mother, both decreased at 2 h, but rose gradually at 4 h to 6 h, exceeding the control level at 24 h and 48 h after the BMDP treatment. The pituitary ACTH potency in the foetus decreased at 24 h and 48 h after the BMDP treatment, suggesting that ACTH released from the foetal pituitary stimulated adrenal corticoidogenesis. Maternal adrenalectomy did not essentially alter this stimulating activity of BMDP, which appeared in the perinatal rat offspring, only when BMDP was administered during the foetal period. These findings suggest that the hypothalamo-pituitary adrenocortical response to the treatment with BMDP drastically changes at the early neonatal age.

Adrenal hormones and brain catecholamines responses to morning and afternoon immobilization stress in rats

The response of adrenal hormones and brain catecholamines to immobilization stress, applied in the morning or in the afternoon, was studied in rats. Immobilization induced greater increments in plasma corticosterone in the morning than in the afternoon; i.e. when the basal levels of this hormone were low rather than high. There was no significant difference between the plasma and adrenal corticosterone levels of the morning and those of the afternoon-stressed rats. Decreases in brain norepinephrine were observed in both groups (a.m. and p.m.) of immobilized rats, but no variations in dopamine concentration were detected. Immobilization led to a decline in the adrenal epinephrine level in the morning but no significant variation was observed in the afternoon-stressed rats.