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At least 19 recordsLinked to original sources
PubMed1993

5 alpha-Dihydro-11-deoxycorticosterone as a mineralocorticoid agonist and antagonist: evidence for a weak mineralocorticoid as an antagonist of potent mineralocorticoids.

To evaluate the possibility that 5 alpha-dihydro-11-deoxycorticosterone (5 alpha-DH-DOC), a weak mineralocorticoid, is an antagonist of a more potent mineralocorticoid, aldosterone, 0.25 microgram aldosterone was injected into adrenalectomized rats simultaneously with 200-800 micrograms 5 alpha-DH-DOC and urinary Na/K ratio and Na and K excretion were evaluated. Urinary Na/K ratio and Na excretion were significantly lower than those of control rats regardless of whether rats were treated with 0.25 microgram aldosterone alone or 400-800 micrograms 5 alpha-DH-DOC alone. Urinary Na/K ratio and Na excretion of rats given a combination of 0.25 microgram aldosterone plus 400-800 micrograms 5 alpha-DH-DOC were significantly higher than those of rats given 0.25 microgram aldosterone alone. None of the treatment caused significant changes in urinary K excretion. The results demonstrate that 5 alpha-DH-DOC, a weak mineralocorticoid, is an antagonist of the sodium-retaining action of a more potent mineralocorticoid, aldosterone. Progesterone which has weak mineralocorticoid activity is also known as an antagonist of more potent mineralocorticoids. The results of the present study demonstrate further evidence that weak mineralocorticoids may work as antagonists of more potent mineralocorticoids.

Aldosterone↗
PubMed1990

Apparent mineralocorticoid excess, pseudohypoaldosteronism, and urinary electrolyte excretion: toward a redefinition of mineralocorticoid action.

Patients with apparent mineralocorticoid excess (AME) have low or absent activity of the enzyme 11 beta OH steroid dehydrogenase (11SD), and inappropriately high intrarenal levels of cortisol resulting in Na+ retention and hypertension. Pseudohypoaldosteronism (PHA), in contrast, is characterized by salt wasting despite hyperaldosteronemia, reflecting low or absent mineralocorticoid receptors (MR). Although AME is presumed to reflect inappropriate cortisol occupancy of MR, several features also suggest inappropriate occupancy of glucocorticoid receptors (GR). To test this possibility, we administered carbenoxolone, which is known to block 11SD, to four patients with PHA, and observed marked mineralocorticoid effects, e.g., antinatriuresis and elevated plasma bicarbonate. To further test the possibility that occupancy of renal GR may induce a classical mineralocorticoid response, we administered the highly specific glucocorticoid RU 28362 to adrenalectomized rats and showed that it has profound antinatriuretic effects. Finally, by selectively blocking MR with RU 28318 or GR with RU 38486, we have shown that corticosterone, the physiologic glucocorticoid in rats, has an antinatriuretic effect in adrenalectomized rats via either MR or GR occupancy. Previous studies have clearly shown that MR are inherently nonselective and have equivalent intrinsic affinity for aldosterone, corticosterone, and cortisol. The present studies suggest that this nonselectivity includes the nuclear response element to which either MR or GR may bind to elicit a mineralocorticoid effect, and further underscore the importance of the enzyme 11SD in the specific mineralocorticoid action of aldosterone.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Mineralocorticoid hypertension and congenital deficiency of 11 beta-hydroxysteroid dehydrogenase in a family with the syndrome of 'apparent' mineralocorticoid excess.

The so-called syndrome of 'apparent mineralocorticoid excess' (AME) is a rare cause of endocrine hypertension thought to result from a defect in the peripheral conversion of cortisol to cortisone. Less than 30 cases have been described. From a consanguineous marriage we present a family comprising 2 and probably 3 affected cases of AME. The index case is a 4-year-old boy with mineralocorticoid hypertension, short stature, failure to thrive, hypokalaemic nephropathy and osteopenia. The ratio of the urinary excretion of tetrahydrocortisone/tetrahydrocortisols was reduced at 0.05 (reference range 1.77-2.11), and the plasma half-life of 3H-11 alpha-cortisol elevated at 152 minutes (reference range 30-50) indicative of severe 11 beta-hydroxysteroid dehydrogenase deficiency. Plasma cortisol concentrations were normal and daily secretion rate reduced. Dexamethasone administration induced a natriuresis in keeping with the observation that cortisol itself is the implicated mineralocorticoid. Treatment with amiloride lowered blood pressure, increased potassium levels, and resulted in an increase in growth rate. The boy's twin brother died at the age of 3.5 years following a trivial diarrhoeal illness and was almost certainly affected. AME was also diagnosed in a younger brother (age 17 months), but both parents are normal. Congenital deficiency of 11 beta-hydroxysteroid dehydrogenase should be considered in any child with mineralocorticoid hypertension and failure to thrive. As cortisol is the 'offending' mineralocorticoid in this condition, the term 'apparent' mineralocorticoid excess is perhaps obsolete.(ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Mineralocorticoid (type I) receptors in the olfactory mucosa of the mammal: studies with [3H]aldosterone and the anti-mineralocorticoid spironolactone.

High-affinity, specific binding sites to mineralocorticoids, with characteristics of mineralocorticoid (type I) receptors, have been found in the mammalian olfactory mucosa. In the presence of RU 28362, which blocks low-affinity binding of the labeled hormone to glucocorticoid (type II) receptors, Scatchard analysis of the specific [3H]aldosterone binding indicates that aldosterone binds to a single class of high-affinity (type I) sites with a dissociation constant, Kd, of 1.2 x 10(-9) M and a maximum number of binding sites, Bmax, of 63 fmol/mg dry tissue. Time course of association of [3H]aldosterone and its binding sites showed maximal binding by 30 min at 25 degrees C which remained unchanged up to 90 min. Competition studies performed with 1 x 10(-7)-1 x 10(-5) M spironolactone, a competitive mineralocorticoid antagonist, showed a dose-response reduction of [3H]aldosterone binding, implying that in the olfactory mucosa this compound behaves as an aldosterone antagonist. These results demonstrate significant [3H]aldosterone binding to receptors of high affinity and mineralocorticoid specificity and suggest that the olfactory mucosa is a target site for mineralocorticoid action.

Aldosterone↗
PubMed2006

Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: Beneficial effects of mineralocorticoid receptor blocker.

Cardiac aldosterone levels have not been evaluated in diastolic heart failure (DHF), and its roles in this type of heart failure remain unclear. This study aimed to detect cardiac aldosterone by use of a liquid chromatographic-mass spectrometric method and to assess the effects of mineralocorticoid receptor blockade on hypertensive DHF. Dahl salt-sensitive rats fed 8% NaCl diet from 7 wk (hypertensive DHF model) were divided at 13 wk into three groups: those treated with subdepressor doses of eplerenone (12.5 or 40 mg x kg(-1) x day(-1)) and an untreated group. Dahl salt-sensitive rats fed 0.3% NaCl diet served as controls. Cardiac aldosterone was detected in the DHF rats but not in the control rats, with increased ventricular levels of mineralocorticoid receptor. Cardiac levels of 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone were not different between the control and DHF rats, but the tissue level of corticosterone that has an affinity to mineralocorticoid receptor was 1,000 times as high as that of aldosterone. Aldosterone synthase activity and CYP11B2 mRNA were undetectable in the ventricular tissue of the DHF rats. Administration of eplerenone attenuated ventricular hypertrophy, ventricular fibrosis, myocardial stiffening, and relaxation abnormality, leading to the prevention of overt DHF. In summary, the myocardial aldosterone level increased in the DHF rats. However, its value was extremely low compared with corticosterone, and no evidence for enhancement of intrinsic myocardial aldosterone production was found. The upregulation of mineralocorticoid receptor may play a central role in the pathogenesis of DHF, and blockade of mineralocorticoid receptor is likely an effective therapeutic regimen of DHF.

Aldosterone↗
PubMed1972

Effect of administered mineralocorticoids or ACTH in pregnant women. Attenuation of kaliuretic influence of mineralocorticoids during pregnancy.

The role of augmented aldosterone production in pregnancy is poorly understood. Whereas some consider aldosterone secretion in pregnancy excessive, others suggest that this is a compensatory phenomenon. According to yet another view, mechanisms other than the renin-angiotensin-aldosterone system control sodium homeostasis in pregnancy. Metabolic balance studies were performed on 14 3rd trimester women. Mineralocorticoid activity was experimentally increased by administering desoxycorticosterone acetate, 9alpha-fluorocortisol acetate, or ACTH for 4-12 days. Administration of mineralocorticoid or ACTH consistently caused sodium retention. During this mineralocorticoid-induced volume expansion, aldosterone excretion decreased markedly. Natriuresis, which followed discontinuance of the drug, continued while aldosterone excretion, although greatly diminished compared to control values, was greater than that found in normal, nonpregnant individuals. This saline diuresis did not subside until aldosterone excretion returned to its previously high control values. These observations support the concept of the physiological role of increased aldosterone production in pregnancy. Results further revealed a marked dissociation between antinatriuretic and kaliuretic effects of corticoids. Potassium balance was virtually unaltered during continued mineralocorticoid or ACTH administration, despite initially high or abruptly increased sodium intakes. Finally, mineralocorticoid escape was induced by continued desoxycorticosterone acetate therapy in two male volunteers. Kaliuresis occurred which was subsequently abolished when progresterone was administered. Sodium excretion, however, was virtually unaltered. These data, mimicking results observed in gravidas, suggest that progesterone is an important determinant of potassium homeostasis in pregnant women.

Adolescent↗
PubMed1996

Human mineralocorticoid receptor interacts with actin under mineralocorticoid ligand modulation.

The human mineralocorticoid receptor of the steroid receptor family contains a modular structure with domain E which is considered to be a hormone binding domain. Recombinant protein approaches enabled us to clearly determine that this domain is also able to interact with F-actin (Kd about 2 microM) and G-actin. Moreover, it was revealed that this mineralocorticoid receptor domain/actin interaction was modulated by specific mineralocorticoid ligands. Agonist (aldosterone) steroid binding almost totally (91%) abolished the interaction with F-actin, while antagonist (progesterone) binding allowed more than 30% of this binding. Steroid modulation of the interaction between domain E and actin indicated that this actin binding is specific and could be essential for cellular mineralocorticoid receptor activity.

Actins↗
PubMed1981

Mineralocorticoid receptors in rat anterior pituitary: toward a redefinition of "mineralocorticoid hormone".

There is increasing evidence that a pituitary factor(s) in addition to ACTH can influence aldosterone secretion. By analogy with glucocorticoids and ACTH, such a factor(s) may be under mineralocorticoid negative feedback control, presumably via specific mineralocorticoid receptors. We here report studies in which mineralocorticoid receptors in the anterior pituitary are described and clearly distinguished from glucocorticoid receptors. Pituitary mineralocorticoid receptors closely resemble those previously reported in rat kidney and salivary gland in terms of their affinity for aldosterone, the hierarchy of affinities they display for other steroids, and their sedimentation values on sucrose density gradients.

Aldosterone↗
PubMed1992

Mineralocorticoids and mineralocorticoid receptors in mononuclear leukocytes in patients with pregnancy-induced hypertension.

To examine the role of mineralocorticoids in the pathophysiology of pregnancy-induced hypertension (PIH), we studied plasma aldosterone and 18-hydroxycorticosterone levels in 25 women with PIH and 25 normal pregnant women, as controls. Furthermore, we evaluated the mineralocorticoid receptor (MR) status in mononuclear leukocytes in the 2 groups. MR count was significantly (P less than 0.0005) decreased in the PIH group (148 +/- 9 binding sites/cell) compared with the control group (300 +/- 17 binding sites/cell; mean +/- SEM). Plasma aldosterone in women with PIH was 281 +/- 61 pmol/L; in normal pregnant women it was 697 +/- 172 pmol/L (P less than 0.025). Plasma 18-hydroxycorticosterone was also significantly (P less than 0.025) lower (PIH, 1071 +/- 149 pmol/L; controls, 1907 +/- 318 pmol/L). These values were determined at the onset of clinical symptoms of PIH. These results cannot be explained by receptor down-regulation due to higher levels of mineralocorticoids in PIH; a hitherto unknown mineralocorticoid may, thus, be responsible for the hypertension and altered MR status.

18-Hydroxycorticosterone↗
PubMed1992

Evidence for cortisol as the mineralocorticoid in the syndrome of apparent mineralocorticoid excess.

The hypothesis that cortisol is the functioning mineralocorticoid in the syndrome of apparent mineralocorticoid excess was tested by suppressing its secretion with dexamethasone. The subjects were two siblings with the type 2 form of this syndrome in which the defect in the peripheral metabolism of cortisol lies predominantly in ring A reduction but not in 11 beta-hydroxy dehydrogenation of cortisol to cortisone. Low dosage dexamethasone improved the hypokalemia within several days and hypertension was corrected after 3 weeks of treatment. Mineralocorticoid manifestations remained in remission during 10 yr of therapy with the synthetic glucocorticoid during which normal growth and development were restored. The effectiveness of dexamethasone supports the hypothesis that cortisol is the functioning mineralocorticoid in the AME syndrome.

Adolescent↗
PubMed2000

The N-terminal domain of the mineralocorticoid receptor modulates both mineralocorticoid receptor- and glucocorticoid receptor-mediated transactivation from Na/K ATPase beta1 target gene promoter.

Mineralocorticoid and glucocorticoid hormones activate the expression of the Na/K ATPase beta1 through direct binding of the mineralocorticoid receptor (MR) and glucocorticoid receptors (GR) to a mineralocorticoid- and glucocorticoid-responsive element in the beta1 promoter region, but activation of the beta1 promoter is inhibited by coexpression of both receptors. Here, using a series of mutated and chimeric receptors, we show that the N-terminal region of MR mediates an inhibitory effect on MR and GR activation from the beta1 promoter, in CV-1 cells. Deletion of the N-terminal region of MR (1-603) enhanced MR activation four-fold. Activation by chimeric MR, in which the N-terminus of GR replaces the N-terminal region of MR, was threefold that of wild-type MR. In addition, whereas coexpression of wild-type MR and GR was inhibitory, coexpression of chimeric MR and wild-type GR was nearly equal to that of MR. By contrast, mutated GR lacking its N-terminal region (1-420) was less efficient than the wild type in activating this promoter. These results demonstrate that the N-terminal domains of MR and GR have opposite transactivation properties and that MR region 1-603 is indeed inhibitory for both MR- and GR-mediated regulation of the Na/K ATPase beta1 gene promoter.

Cell Line↗
PubMed1999

[Mineralocorticoid-like hypertension. "Apparent mineralocorticoid excess". A hereditary type of hypertension?].

The syndrome of apparent mineralocorticoid excess is a form of hypertension inherited in an autosomal recessive manner. It results from mutations in the gene encoding the kidney isoenzyme of 11 beta-hydroxysteroid dehydrogenase. A number of different mutations have been described. Affected patients present with hypertension, hypokalemia and low levels of plasma renin and aldosterone. The severity of cases vary according to the degree of reduced activity of the enzyme. Treatment with potassium-sparing diuretics is effective. Four young adults with moderate hypertension are presented. They all had hypokalemia, low renin and low aldosterone. The THF + allo-THF/THE ratio was normal or slightly elevated. Treatment with amiloride was effective. They are suspected to be mild cases of the syndrome of apparent mineralocorticoid excess.

Adolescent↗
PubMed1991

The "mineralocorticoid-like" actions conferred on corticosterone by carbenoxolone are inhibited by the mineralocorticoid receptor (type I) antagonist RU28318.

We have previously demonstrated, in adrenalectomized male rats, that the liquorice derivative carbenoxolone (CS) can confer mineralocorticoid (MC)-like activity upon the glucocorticoid corticosterone (B) and amplify the Na(+)-retaining actions of aldosterone (Aldo) and deoxycorticosterone (DOC). The purpose of the present study was to determine whether the MC-like effects of B and the amplified actions of ALDO and DOC in the presence of CS are mediated via the occupation of type I (MC) receptors. In adrenalectomized male rats, B (100 micrograms/rat) alone produced a significant kaliuresis, but no antinatriuresis. This kaliuresis was blocked by the type I (MC) receptor antagonist RU28318 (300 micrograms/rat). In the presence of CS (2.5 mg/rat), B produced a significant Na+ retention, and the kaliuretic activity of B was significantly enhanced. This CS-induced antinatriuresis produced by B was significantly reduced by RU28318, as was the amplified kaliuresis. The MC effects of either Aldo (0.05 micrograms/rat) or DOC (5 micrograms/rat) alone were, as expected, reduced by RU28318 (300 micrograms/rat). As previously reported, CS amplified only the Na(+)-retaining actions of Aldo and DOC, and it was also possible to reduce these amplified effects with RU28318. The present study demonstrates that in the presence of CS, the MC actions of B, Aldo, and DOC are mediated to a large extent via the occupation of type I (MC) receptors.

Adrenalectomy↗
PubMed1986

The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess: physiological and pathological implications.

The affinity and the capacity of mineralocorticoid receptors (MR) in human mononuclear leukocytes (HML) were determined in 9 patients with Conn's syndrome (PA) and in 3 patients with pseudohypoaldosteronism (PHA). The number of binding sites per cell was 136 +/- 39 (mean +/- SD) in PA. One case with PHA had no MR, and of the other 2 patients, one had 50 and the other 55 receptors per cell. The capacity of normal controls ranged from 200 to 400 receptors per cell (n = 20). We conclude that the etiology of PHA is due to a lack of MR in the target tissues and that a down regulation of MR may exist in PA.

Adult↗
PubMed1991

Two uncommon causes of mineralocorticoid excess. Syndrome of apparent mineralocorticoid excess and glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism is an inherited form of mineralocorticoid excess associated with moderate overproduction of aldosterone, in which biochemical and clinical remission is dramatically induced by small amounts of glucocorticoids. The disorder is associated with characteristic overproduction of 18-hydroxycortisol and 18-oxocortisol, which must now be regarded as an essential diagnostic feature and also as an aid in the detection of the disorder in the face of partial clinical expression.

Glucocorticoids↗
PubMed2004

Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties.

BACKGROUND: Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco- and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable. METHOD: We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRalpha expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate). RESULTS AND CONCLUSIONS: While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the Delta1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16alpha-methyl or 16beta-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone.The MC potency of a steroid is increased by a 9alpha- or a 6alpha-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9alpha-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.

Animals↗