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The effect of sodium depletion on the conversion of corticosterone to aldosterone has been examined in vivo using the adrenal transplants of two sheep. [3H]Corticosterone was infused continuously directly into the adrenal gland via the carotid artery over a period of 30 min. and the total adrenal effluent was collected via the jugular vein in six consecutive 5-min. samples. The conversion of [3H]corticosterone to [3H]aldosterone and the endogenous output of aldosterone was measured in each sample using a double isotope derivative method and the specific activity of the aldosterone calculated. Radioactive conversion of B → aldosterone reached equilibrium within 10 min. of the start of infusion and remained constant over a period of 10–25 min. Aldosterone secretion was also constant during the first 25 min. of infusion.

In the same sheep the mean percentage conversion increased as aldosterone secretion rose over a range of 2–12 μg./hr. With more severe sodium depletion, i.e. with aldosterone secretion rates of 12–16 μg./hr., conversion decreased to that found in the sodium replete state. The specific activity of the aldosterone was constant throughout the mildly deplete range (2–12 μg./hr.) but fell with severe sodium depletion. In the sodium replete range (0–2 μg./hr.) before the introduction of a parotid fistula, the specific activity was the same as in the mildly deplete state. After the introduction of a parotid fistula the specific activity increased as the secretion decreased from 2 to 0 μg.

The validity of the approach and interpretation of the results in terms of the biosynthetic pathways involved are discussed.

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PW Raven, S Kapas, M Carroll, and JP Hinson

Stimulation of aldosterone by a serine protease, trypsin, was first reported in 1982, although the mechanism of this effect was unclear. Recently, a family of protease-activated receptors (PARs) has been described and four members of the family characterised and cloned, including the previously recognised thrombin receptor. This study investigated whether PARs mediate the action of trypsin on aldosterone secretion. Using intact rat adrenal capsular tissue, thrombin was found to increase aldosterone secretion, and the effects of trypsin on aldosterone secretion were confirmed. Both trypsin and thrombin were shown to activate phospholipase C, as measured by an increase in inositol triphosphate turnover by adrenal capsular tissue. It was also shown that U73122, a phospholipase C inhibitor, attenuated the aldosterone response to trypsin. These effects were consistent with the activation of a PAR. Northern blot analysis revealed the presence of mRNA encoding PAR-1, but not PARs-2, -3 or -4 in the adrenal capsule/zona glomerulosa. Messenger RNA encoding PAR-1 was increased by dietary sodium depletion, consistent with previous reports of an increased response to trypsin after sodium depletion. These data suggest that the actions of trypsin on aldosterone secretion are mediated by PAR-1.

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Elika Missaghian, Petra Kempná, Bernhard Dick, Andrea Hirsch, Rasoul Alikhani-Koupaei, Bernard Jégou, Primus E Mullis, Brigitte M Frey, and Christa E Flück

The CYP17A1 gene is the qualitative regulator of steroidogenesis. Depending on the presence or absence of CYP17 activities mineralocorticoids, glucocorticoids or adrenal androgens are produced. The expression of the CYP17A1 gene is tissue as well as species-specific. In contrast to humans, adrenals of rodents do not express the CYP17A1 gene and have therefore no P450c17 enzyme for cortisol production, but produce corticosterone. DNA methylation is involved in the tissue-specific silencing of the CYP17A1 gene in human placental JEG-3 cells. We investigated the role of DNA methylation for the tissue-specific expression of the CYP17A1 gene in rodents. Rats treated with the methyltransferase inhibitor 5-aza-deoxycytidine excreted the cortisol metabolite tetrahydrocortisol in their urine suggesting that treatment induced CYP17 expression and 17α-hydroxylase activity through demethylation. Accordingly, bisulfite modification experiments identified a methylated CpG island in the CYP17 promoter in DNA extracted from rat adrenals but not from testes. Both methyltransferase and histone deacetylase inhibitors induced the expression of the CYP17A1 gene in mouse adrenocortical Y1 cells which normally do not express CYP17, indicating that the expression of the mouse CYP17A1 gene is epigenetically controlled. The role of DNA methylation for CYP17 expression was further underlined by the finding that a reporter construct driven by the mouse −1041 bp CYP17 promoter was active in Y1 cells, thus excluding the lack of essential transcription factors for CYP17 expression in these adrenal cells.

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Ministry of Agriculture and Fisheries, Ruakura Agricultural Research Station, Private Bag, Hamilton, New Zealand

(Received 23 August 1974)

The foetal adrenals are important in initiating parturition in sheep (Liggins, Fairclough, Grieves, Kendall & Knox, 1973) and goats (Thorburn, Nicol, Bassett, Shutt & Cox, 1972). Indirect evidence suggests that the foetal adrenals may be involved in the termination of pregnancy in the cow. Such evidence includes prolongation of pregnancy when foetal pituitary function is impaired (Kennedy, Kendrick & Stormont, 1957; Holm, 1958), and the induction of parturition by administering either corticotrophin (Welch, Frost & Bergman, 1973) or dexamethasone (Hunter, Welch, Fairclough, Barr & Seamark, 1974) to the foetal calf.

Comline, Silver, Nathanielsz & Hall (1973) have noted a two- to threefold increase in foetal cortisol levels in prematurely calving cows. These authors conclude that this comparatively small rise in foetal cortisol levels casts doubt on whether the foetal adrenal cortex is

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Measurement of minute amounts of adrenocorticotrophic hormone (ACTH) in body fluids at present depends upon biological assay. We here report a very sensitive method of ACTH assay using the transplanted gland in sheep whose ACTH secretions have been suppressed with 16α-methyl-9α-fluoro-Δ1 cortisol (dexamethasone).

The animals used were three Merino ewes. The left adrenal had been transplanted to a vascular anastomosis with the left carotid and jugular vessels and enclosed in a skin loop 4–8 months previously, using the technique of McDonald, Goding & Wright (1958). The right adrenal was removed 2–4 weeks later. Experiments were conducted on each animal in turn at monthly intervals, when blood was collected from the adreno-jugular vein before and after carotid-arterial injections of test fluid. A fluorescent technique (De Moor, Raskin & Steeno, 1960) was used to measure cortisol—the main glucocorticoid secreted by the sheep (Bush & Ferguson, 1953)—in 2 ml. samples of adrenal

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Adrenal cells were prepared from non-pregnant (anoestrous) sheep, from ewes at days 50, 100 and 130 of pregnancy and at term, and from animals at 1–5 days post partum. The ability of the cells to respond to adrenocorticotrophin (ACTH1–24), α-melanocyte-stimulating hormone (α-MSH), or combinations of these peptides has been examined in vitro. There was a progressive rise in the basal output of cortisol during pregnancy and in the absence of adrenocorticotrophin the cortisol output from adrenal cells of late pregnant and post-partum sheep was significantly greater than that from the non-pregnant animals. Adrenocorticotrophin increased cortisol output by adrenal cells at all times tested. In anoestrous sheep the amount of ACTH required to produce half the maximum output of steroid (ED50) was 8 pg/ml. The ED50 increased in early pregnancy to 112 pg/ml and then fell to < 5 pg/ml between day 100 and term. At term both the stimulation ratio and the absolute increment in cortisol output elicited by a maximal concentration of ACTH were greater than at any other time tested in pregnant or non-pregnant sheep. Cortisol output during pregnancy was not increased by α-MSH, although at term the stimulatory effect of ACTH1–24 was partially antagonized by α-MSH.

These results suggest that there may be an increase in the responsiveness of the maternal adrenal during pregnancy, although the factor(s) responsible remains unknown.

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Damian G Romero, Ming Yi Zhou, Licy L Yanes, Maria W Plonczynski, Tanganika R Washington, Celso E Gomez-Sanchez, and Elise P Gomez-Sanchez

Regulators of G-protein signaling (RGS proteins) interact with Gα subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)–ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

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The major steroid products of the rat adrenal gland were studied both in vitro and in vivo. It was found that these methods gave similar results with regard both to the nature of the compounds produced and to their relative proportions. In particular, the status of 11-desoxycorticosterone as a physiologically important adrenal product is discussed, and it is concluded that this compound, as well as aldosterone, may possibly be instrumental in controlling electrolyte flux in the rat.

Open access

Tingting Yang, Min He, Hailiang Zhang, Paula Q Barrett, and Changlong Hu

Aldosterone, which plays a key role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal cortex. Exaggerated overproduction of aldosterone from ZG cells causes primary hyperaldosteronism. In ZG cells, calcium entry through voltage-gated calcium channels plays a central role in the regulation of aldosterone secretion. Previous studies in animal adrenals and human adrenal adrenocortical cell lines suggest that the T-type but not the L-type calcium channel activity drives aldosterone production. However, recent clinical studies show that somatic mutations in L-type calcium channels are the second most prevalent cause of aldosterone-producing adenoma. Our objective was to define the roles of T and L-type calcium channels in regulating aldosterone secretion from human adrenals. We find that human adrenal ZG cells mainly express T-type CaV3.2/3.3 and L-type CaV1.2/1.3 calcium channels. TTA-P2, a specific inhibitor of T-type calcium channel subtypes, reduced basal aldosterone secretion from acutely prepared slices of human adrenals. Surprisingly, nifedipine, the prototypic inhibitor of L-type calcium channels, also decreased basal aldosterone secretion, suggesting that L-type calcium channels are active under basal conditions. In addition, TTA-P2 or nifedipine also inhibited aldosterone secretion stimulated by angiotensin II- or elevations in extracellular K+. Remarkably, blockade of either L- or T-type calcium channels inhibits basal and stimulated aldosterone production to a similar extent. Low concentrations of TTA-P2 and nifedipine showed additive inhibitory effect on aldosterone secretion. We conclude that T- and L-type calcium channels play equally important roles in controlling aldosterone production from human adrenals.

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Ding Xie and Wendy B Bollag

Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension.