THE EFFECT OF NADPH ON STEROIDOGENESIS BY THE HUMAN ADRENAL GLAND IN VIVO

The melanocortin-2-receptor (MC2R)/MC2R accessory protein (MRAP) complex is critical to the production of glucocorticoids from the adrenal cortex. Inactivating mutations in either MC2R or MRAP result in the clinical condition familial glucocorticoid deficiency. The localisation of MC2R together with MRAP within the adrenal gland has not previously been reported. Furthermore, MRAP2, a paralogue of MRAP, has been shown in vitro to have a similar function to MRAP, facilitating MC2R trafficking and responsiveness to ACTH. Despite similar MC2R accessory functions, in vivo, patients with inactivating mutations of MRAP fail to be rescued by a functioning MRAP2 gene, suggesting differences in adrenal expression, localisation and/or function between the two MRAPs. In this study on the rat adrenal gland, we demonstrate that while MRAP and MC2R are highly expressed in the zona fasciculata, MRAP2 is expressed throughout the adrenal cortex in low quantities. In the developing adrenal gland, both MRAP and MRAP2 are equally well expressed. The MC2R/MRAP2 complex requires much higher concentrations of ACTH to activate compared with the MC2R/MRAP complex. Interestingly, expression of MC2R and MRAP in the undifferentiated zone would support the notion that ACTH may play an important role in adrenal cell differentiation and maintenance.

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Adrenocortical metabolism of angiotensin in sheep with adrenal transplants.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1978.235.5.e525 ◽

1978 ◽

Vol 235 (5) ◽

pp. E525

Author(s):

S Lun ◽

E A Espiner ◽

D S Hart

Keyword(s):

Blood Flow ◽

Adrenal Gland ◽

Secretion Rate ◽

Aldosterone Secretion ◽

Adrenal Tissue ◽

Rate Analysis ◽

Venous Plasma

Conscious trained sheep with adrenal gland autotransplants in cervical skin loops were used to study adrenocortical metabolism and clearance of angiotensin (AII) administered by constant systemic infusion. For comparative purposes similar experiments were undertaken in five control sheep with skin loops but no cervical adrenal tissue. During AII infusions (0.33 microgram/min for 30 min), loop venous-arterial AII ratios (0.42--0.62 were similar in both groups of sheep. Measured AII clearances across the skin loop in sheep with and without adrenal transplants were 400--600 and 100--150 pg/min, respectively, which correlated with blood flow (r = 0.79), but showed no relation to aldosterone secretion rate. Analysis of AII immunoreactive fragments showed similar proportions of octa-, hepta-, and hexapeptide fractions (64, 26, and 5%, respectively) in adrenal arterial, adrenal venous, and systemic venous plasma. These studies do not support selective heptapeptide uptake or metabolism by adrenal tissue in vivo and indicate that specific adrenal binding of AII is likely to be less than 400 pg/min at arterial AII concentrations approximating 120 pg/ml.

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Angiotensin II infusion in vivo does not modulate cortisol secretion in the late-gestation ovine fetus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.2.r357 ◽

1998 ◽

Vol 275 (2) ◽

pp. R357-R362 ◽

Cited By ~ 1

Author(s):

Kirsten R. Poore ◽

I. Ross Young ◽

Benedict J. Canny ◽

Geoffrey D. Thorburn

Keyword(s):

Angiotensin Ii ◽

Adrenal Gland ◽

Late Gestation ◽

Treatment Groups ◽

Arterial Blood ◽

Basal Cortisol ◽

Ovine Fetus

Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long been proposed that the fetal adrenal gland may be under inhibitory influences during late gestation. In vitro evidence has suggested that angiotensin II may be such an inhibitory factor and may help to prevent a premature increase in cortisol concentrations. The aim of this study was to test the effect of angiotensin II infusion in vivo on basal cortisol concentrations and fetal adrenal responsiveness to an ACTH-(1—24) challenge. Fetuses received a continuous infusion of either angiotensin II (100 ng ⋅ min−1 ⋅ kg−1; n = 7) or saline (2 ml/h; n = 4), which commenced at 140 days of gestation (GA) and continued for a total of 50 h. Adrenal responsiveness to the administration of ACTH-(1—24) (5 μg/kg) was determined during angiotensin II or saline infusions at both 2 and 48 h after infusion onset. Angiotensin II had no significant effect on adrenal responsiveness after acute (2 h) or chronic (48 h) infusion. There was no effect of saline or angiotensin II infusion on basal immunoreactive ACTH or cortisol concentrations after 2 h, but there was a significant increase in basal cortisol concentrations in both treatment groups by 48 h, probably reflecting the normal rise in cortisol concentrations at this GA. Mean arterial blood pressure was significantly increased in angiotensin II-infused fetuses only. This study has therefore found no evidence to suggest that angiotensin II infusion in vivo modulates fetal basal cortisol concentrations or adrenal responsiveness in the last week of gestation, in contrast with previous in vitro studies. These results throw into question the proposed role of angiotensin II as a negative modulator of adrenal function in the ovine fetus.

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EFFECTS OF HYDROXYSTEROID DEHYDROGENASE INHIBITORS ON IN-VITRO AND IN-VIVO STEROIDOGENESIS IN THE OVINE ADRENAL GLAND

Journal of Endocrinology ◽

10.1677/joe.0.0920205 ◽

1982 ◽

Vol 92 (2) ◽

pp. 205-212 ◽

Cited By ~ 12

Author(s):

P. SINGH-ASA ◽

G. JENKIN ◽

G. D. THORBURN

Keyword(s):

Adrenal Gland ◽

Incubation Medium ◽

Bovine Serum ◽

Hydroxysteroid Dehydrogenase ◽

Inhibitory Effect ◽

Bovine Serum Albu ◽

Stimulatory Action ◽

Adrenal Steroidogenesis

The effectiveness of trilostane and azastene as inhibitors of adrenal steroidogenesis was compared by in-vitro and in-vivo methods. A radioimmunoassay was developed for the measurement of cortisol in ovine plasma, incubation medium and tissue extract using a specific antiserum raised against cortisol 21-acetate,3-carboxymethyloxime : bovine serum albu Trilostane (20 μmol/l) decreased cortisol synthesis and release both in unstimulated and in ACTH-stimulated adrenal tissues in vitro. The same concentration of azastene had a lesser effect on unstimulated adrenals and was completely ineffective in blocking the stimulatory action of ACTH. In vivo, trilostane suppressed adrenal steroidogenesis in pregnant and cyclic ewes but the suppression in pregnant ewes was over a longer period, and after lower doses. It is concluded that trilostane had an inhibitory effect on ovine adrenal steroidogenesis both in vitro and in vivo.

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Effect of in Vivo Treatment with Delta9-THC on Mice Adrenal Gland

European Psychiatry ◽

10.1016/s0924-9338(09)70704-7 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

E. Moura ◽

C. Esteves-Pinto ◽

M.P. Serrão ◽

I. Azevedo ◽

M. Vieira-Coelho

Keyword(s):

Adrenal Gland ◽

Hpa Axis ◽

Chronic Administration ◽

Test Results ◽

Gland Weight ◽

Adrenal Gland Weight ◽

Reduce Activity ◽

Student’S T ◽

Student’S T Test

Introduction:The efficacy of antidepressants has been linked in part to their ability to reduce activity of the hypothalamic-pituitary-adrenal (HPA) axis; however, the mechanism by which antidepressants regulate the HPA axis is largely unknown. Recent research has demonstrated that endocannabinoids can regulate the HPA axis and exhibit antidepressant potential.Aim:The purpose of this study was therefore to evaluate the effect of chronic administration of delta-9-tetrahydrocannabinol (delta9-THC) on the adrenal gland of mice.Methods:Delta9-THC (10 mg/kg, 1 THC:1 chremophor:18 saline) or vehicle (CT, 1 chremophor:18 saline) was administered i.p. for 10 days to C57Bl6 mice aged 15 weeks. At the end of the study rats were placed in metabolic cages. Noradrenaline (NA) and adrenaline (AD) levels in samples and tissues were evaluated by HPLC-ED. Statistical analysis was done by ANOVA followed by Student's t test. Results are presented as mean±SEM.Results:Treatment with delta9-THC did not produce changes in mice weight (CT: 25±1; delta9-THC: 24±1 g, n=5-6) but produced a significant reduction in adrenal gland weight (CT: 1.4±0.2; delta9-THC: 0.6±0.1* mg, n=5-6, *P˂0.01). However, treatment with delta9-THC did not produce significant changes in NA and AD adrenal content (NA: 7.5±2.1, 5.3±0.6; AD: 14.1±1.1, 11.1±2.1 nmol, CT and delta9-THC respectively, n=5-6) or in NA and AD urine levels (NA: 0.88±0.06, 1.18±0.17; AD: 0.64±0.07, 0.81±0.09 nmol/24h, CT and delta9-THC respectively, n=5-6).Conclusion:Chronic treatment with delta9-THC reduces adrenal gland weight in mice. These results suggest that endocannabinoids may act directly at the adrenal gland to regulate the HPA axis.

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Adrenal Cell Aldosterone Production Is Stimulated by Very-Low-Density Lipoprotein (VLDL)

Endocrinology ◽

10.1210/en.2011-1752 ◽

2012 ◽

Vol 153 (2) ◽

pp. 721-731 ◽

Cited By ~ 21

Author(s):

Yewei Xing ◽

William E. Rainey ◽

John W. Apolzan ◽

Omar L. Francone ◽

Ruth B. S. Harris ◽

...

Keyword(s):

Adrenal Gland ◽

Primary Cultures ◽

Signal Transduction Pathway ◽

Free Calcium ◽

Low Density ◽

Dependent Manner ◽

Very Low Density Lipoproteins ◽

Concentration Dependent Manner ◽

Adrenal Cells

Very low-density lipoproteins (VLDL) are a class of large lipoprotein synthesized in the liver. The key function of VLDL, in vivo, is to carry triglyceride from the liver to adipose tissue. As a steroidogenic organ, the adrenal gland mainly uses lipoproteins as sources of cholesterol. Although VLDL receptors have been detected in the human adrenal, the function of VLDL in the adrenal gland remains unknown. Herein, we used primary cultures of human and bovine adrenal cells and the adrenocortical cell line H295R as models to determine the effects of VLDL on adrenal steroidogenesis. Our studies revealed that VLDL significantly increased aldosterone synthesis in all of the models tested. This increase was largely due to VLDL's stimulation of the expression of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2). VLDL increased CYP11B2 mRNA expression in a concentration-dependent manner. Effects of VLDL on CYP11B2 transcript levels were not additive with angiotensin II or potassium but were additive with the cAMP pathway agonists ACTH and forskolin. Nifedipine completely inhibited the effects of VLDL on CYP11B2 mRNA, suggesting that calcium is the main signal transduction pathway used by VLDL in adrenal cells. Indeed, VLDL increased cytosolic free calcium levels. An in vivo study conducted in sucrose-fed rats showed a positive correlation between elevated triglyceride (VLDL) levels in plasma and CYP11B2 expression in the adrenal. In conclusion, we have shown that VLDL can stimulate aldosterone synthesis in adrenocortical cells by increasing StAR and CYP11B2 expression, an event likely mediated by a calcium-initiated signaling cascade.

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Adrenocorticotrophic hormone (ACTH) stimulation of sheep fetal adrenal cortex can occur without increased expression of ACTH receptor (ACTH-R) mRNA

Reproduction Fertility and Development ◽

10.1071/rd01046 ◽

2002 ◽

Vol 14 (1) ◽

pp. 1 ◽

Cited By ~ 10

Author(s):

A. M. Carter ◽

Y. M. Petersen ◽

M. Towstoless ◽

D. Andreasen ◽

B. L. Jensen

Keyword(s):

Adrenal Gland ◽

Mrna Expression ◽

Ribonuclease Protection Assay ◽

Acth Stimulation ◽

Cortical Cells ◽

Fetal Plasma ◽

Chain Cleavage ◽

Ribonuclease Protection ◽

Sheep Fetus

In the present study, it was hypothesized that the adrenocorticotrophin hormone receptor (ACTH-R) would be up-regulated in the adrenal gland of the sheep fetus following infusion of physiological amounts of ACTH, as shown for adrenal cortical cells in culture. In chronically catheterized sheep, an intravenous infusion of ACTH1–24 was given to 6 fetuses for 24 h at a rate of 0.5 g h–1, starting on Day 126 or 127 of gestation (term ~147 days). Four control fetuses received an infusion of vehicle (saline). Total RNA was extracted from the fetal adrenal glands by the guanidinium thiocyanate method. Expression of specific mRNAs was determined by ribonuclease protection assay using cRNA probes directed against: ACTH-R; the steroid enzymes side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17 α-hydroxylase (P450c17) and 21β-hydroxylase (P450c21); and β-actin. Ratios of mRNA expression to β-actin mRNA expression (arbitrary units) were calculated to correct for differences in RNA quality between samples. The concentration (mean SEM) of immunoreactive cortisol in fetal plasma was greater after ACTH infusion than after vehicle infusion (47 3 v. 13 2 ng mL–1 respectively; (P<0.001). Adrenal expression of P450scc and P450c21 mRNA increased after ACTH infusion (P<0.05), whereas expression of P450c17 and 3β-HSD mRNA was unchanged. There was no difference in ACTH-R mRNA expression between ACTH- and vehicle-infused fetuses (254 48 v. 305 76 arbitrary units respectively). It was concluded that ACTH is able to increase plasma cortisol concentrations in the sheep fetus by up-regulating cortisol synthesis in the adrenal gland, but that in vivo this does not require up-regulation of ACTH-R mRNA.

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IN VITRO AND IN VIVO EFFECT OF GROWTH HORMONE ON ALDOSTERONE SECRETION

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y60-133 ◽

1960 ◽

Vol 38 (1) ◽

pp. 1069-1075

Author(s):

O. J. Lucis ◽

E. H. Venning

Keyword(s):

Growth Hormone ◽

Adrenal Gland ◽

Human Growth Hormone ◽

Human Growth ◽

Secretion Rate ◽

Aldosterone Secretion ◽

Hypophysectomized Rats

Porcine, monkey, and human growth hormone have no effect on the in vitro secretion of aldosterone by the rat adrenal gland. When monkey growth hormone is injected into hypophysectomized rats, the adrenals of these animals secrete, under in vitro conditions, increased amounts of aldosterone with no change in the secretion rate of corticosterone. The plasma of these rats contains a substance which appears to stimulate the secretion of aldosterone in the adrenals of normal rats.

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