Potential Mineralocorticoids Research Articles

Efficacy and Safety of Oral Eplerenone in Acute Central Serous Chorioretinopathy: A Randomised Controlled Study

Introduction: Acute Central Serous Chorioretinopathy (CSCR) is an important form of acquired maculopathy that usually presents as localised serous detachment of the neurosensory retina. Although, the disease is typically self limiting over a period of 2-3months, a percentage of patients ultimately develop chronic RPE changes. Eplerenone, a potential Mineralocorticoid Receptor (MR) antagonist, may play a role in regulating choroidal vascularity and modifying the disease in chronic CSCR. Aim: To assess the safety and efficacy of oral eplerenone medication in acute CSCR. Materials and Methods: This was a randomised controlled trial that included 162 eyes of 162 patients with acute CSCR. Patients were divided into two groups– Group-A, which received oral Eplerenone, and Group-B, which received Placebo therapy. Each group comprised 81 eyes. Best Corrected Visual Acuity (BCVA), Central Macular Thickness (CMT), and serum potassium (K+) levels were measured at baseline and monthly intervals for three consecutive months. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) Statistics version 20 software (IBM Corp., Armonk, NY, USA). A p-value less than 0.05 was considered statistically significant. Results: The differences in CMT in Group-A and Group-B were 279±56.41µm and 207±68.88 µm (p<0.01) at the end of the first month and 361±33.56 µm and 278±46.27 µm at three months (p<0.01), respectively. The average BCVA improvement in Group-A and Group-B was 6.05 lines and 4.21 LogMAR lines, respectively, at the conclusion (p=0.002). Deterioration to chronicity was seen in 3.7% of the eyes in Group A and 17.3% of the eyes in Group B. The increase in Serum K+ at three months was 0.61±0.27 mg/dL in Group-A and 0.1±0.21 mg/dL in Group-B (p=0.03). Conclusion: Eplerenone is a safe and effective first-line treatment option for acute CSCR, leading to faster and higher resolution with protection from progression to chronicity.

Vascular cell-specific roles of mineralocorticoid receptors in pulmonary hypertension.

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients.

Evolution of the Mineralocorticoid Receptor.

The mineralocorticoid receptor (MR) and its kin, the glucocorticoid receptor (GR) evolved from an ancestral corticoid receptor (CR) in a cyclostome (jawless fish) through gene duplication and divergence. Distinct MR and GR orthologs first appear in cartilaginous fishes, such as sharks, skates, rays and chimaeras. Although aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, is not synthesized by cyclostomes or cartilaginous fishes, cyclostome CR and cartilaginous fish MR and GR are activated by aldosterone. Aldosterone first appears in lungfish, lobe-finned fish that are forerunners of terrestrial vertebrates. Further sequence divergence of the MR and GR in terrestrial vertebrates led to emergence of aldosterone as a selective ligand for the MR. Interestingly, ray-finned fish do not synthesize aldosterone, leaving the identity of their physiological mineralocorticoid(s) unresolved. Several steroids: cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone activate fish MR and are potential mineralocorticoids in ray-finned fish. Here we review the evolution of the MR in cartilaginous fish, terrestrial vertebrates and ray-finned fish, and discuss new insights into progesterone activation of the MR in ray-finned fish.

Development of hyperkalemia following treatment with dapagliflozin (DAPA) in a patient with type 2 diabetes after bilateral adrenalectomy.

Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is known to have a beneficial diuretic effect, in addition to a glucose-lowering effect. Although SGLT2 inhibitor has been reported, the increase of hyperkalemia in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors, their mechanism of action is unclear. We report the first case of a type 2 diabetes (T2DM) patient with potential mineralocorticoid deficiency who developed hyperkalemia after administration of DAPA. A 79-year-old woman underwent bilateral adrenalectomy for uncontrolled hypercortisolism due to an inoperable recurrence of Cushing's disease, and she was subsequently maintained on replacement therapy with glucocorticoid. She was diagnosed as having T2DM at 71years of age and was treated with sitagliptin and miglitol. Since she presented with weight gain of about 5kg over 6months and her HbAlc level increased over 12%, 5mg/day DAPA was added to her daily regimen. After the start of DAPA treatment, she developed hyperkalemia (6.5mEq/L) with increased plasma renin activity of 53.1ng/mL/h. She was diagnosed with aldosterone deficiency and started on fludrocortisone 0.1mg daily, after which the hyperkalemia improved immediately. In this case, DAPA treatment could potentially increase the requirement for mineralocorticoid replacement, directly suggesting that the SGLT2 inhibition-induced natriuretic effect is accompanied by compensatory activation of the RAAS axis, which is essential to keep the serum potassium level within the normal range. Therefore, physicians should be careful about the development of hyperkalemia in patients when SGLT2 and RAAS inhibitors are used in combination.

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.

Synthesis of a deuterium-labeled cortisol for the study of its rate of 11β-hydroxy dehydrogenation in man

11β-Hydroxy dehydrogenation of cortisol to cortisone is specifically impaired in the syndrome of apparent mineralocorticoid excess. This defect bears on the pathogenesis of the disorder by unmasking the potential mineralocorticoid agonism of unmetabolized cortisol at or near mineralocorticoid target tissues. A specific index of this defect is provided by measurement of the formation of tritiated water following the administration of [ 3H]11α-cortisol. We have explored the use of a non-radioactive tracer to follow this unidirectional dehydrogenation reaction but because of the relatively lower sensitivity of measurement of 2H 2O compared to 3H 2O in body fluids, use of the corresponding [ 2H]11α-cortisol was not feasible. We have devised instead a method incorporating additional deuterium atoms into cortisol to measure unidirectional 11β-hydroxy dehydrogenation not by the formation of labeled water but by the determination of the dehydrogenated cortisol product from its residual deuterium content. Cortisol-d 4 metabolized to cortisone-d 3 is conveniently measured by the techniques of organic mass spectrometry. The synthesis of cortisol-9α,11α,12α12β-d 4 and the validation of its isotopic distribution by mass spectrometry and nuclear magnetic resonance is described.

Mineralocorticoid and Renal Receptor Binding Activity of 21-Deoxyaldosterone

Since several aldosterone metabolites are known to be active, we have assessed the mineralocorticoid biological and renal receptor binding activities of the aldosterone metabolites, 21-deoxyaldosterone (21-deoxy-Aldo), 21-deoxytetrahydroaldosterone (21-deoxy-THAldo), and 3 alpha, 5 beta-tetrahydroaldosterone (THAldo). We synthesized these steroids by bioreduction of aldosterone with intestinal bacteria. Mineralocorticoid agonist activity of 21-deoxy-Aldo, 21-deoxy-THAldo and THAldo, determined by bioassay using adrenalectomized rats, was 1-5%, less than 0.01%, and 0.1-0.5% that of aldosterone, respectively. 21-Deoxy-Aldo showed no antagonist activity. The relative affinity in competing with [3H]aldosterone for binding to mineralocorticoid receptors in adrenalectomized rat kidney cytosols was 94%, less than 0.01%, and less than 0.01% that of aldosterone. The relative binding affinity for rat renal glucocorticoid receptors was 23%, less than 0.01%, and less than 0.01% that of dexamethasone, and for corticosteroid-binding globulin 17%, less than 0.01%, and less than 0.01% that of cortisol. These results show that the naturally occurring steroid, 21-deoxy-Aldo, possesses mineralocorticoid agonist activity which is equivalent to that of 11-deoxycorticosterone, and has substantial affinity for rat renal mineralocorticoid and glucocorticoid receptors. The results also implicate the pathophysiological role of 21-deoxy-Aldo as a potential mineralocorticoid in 21-hydroxylase deficiency, where urinary excretion of this steroid is invariably elevated.

Pathogenesis of the Type 2 Variant of the Syndrome of Apparent Mineralocorticoid Excess*

The syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxydehydrogenation of cortisol to cortisone. Studies in this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. This view reconciled developing evidence that the mineralocorticoid receptor itself could not distinguish between mineralocorticoids and glucocorticoids. The syndrome occurs in two forms. In both forms there is decreased turnover of a normal level of plasma cortisol, consistent with the view that delayed removal of the glucocorticoid from strategic receptor sites unmasks its potential mineralocorticoid agonism. In the type 1 variant, impaired 11 beta-hydroxydehydrogenation is reflected by an elevated cortisol/cortisone metabolite ratio. In three patients with the type 2 variant, this ratio was normal, suggesting that the rate of 11 beta-hydroxydehydrogenation was unimpaired. The hypertension and hypokalemic alkalosis of both forms are improved by spironolactone, but patients with the type 2 variant have responded somewhat better to the suppression of cortisol by dexamethasone.

Dihydrocortisol: A potential mineralocorticoid

The finding of abnormal metabolism of cortisol in a low-renin, low-aldosterone, hypertensive child with the stigmata of hypermineralocorticoidism led us to examine the mineralocorticoid activity of several cortisol metabolites. Of these metabolites, dihydrocortisol (DHF) possessed mineralocorticoid activity as determined by several assays. In competition assays with [ 3H]-aldosterone or [ 3H]-dexa-methasone in rat kidney slices, the relative affinities for the respective cytoplasmic receptors were as follows: mineralocorticoid receptor-aldosterone (1.00) > cortisol (0.20) > 5α-DHF (0.083) > 5β-DHF (0.042) and glucocorticoid receptor-dexamethasone (1.00) > cortisol (0.10) > 5α-DHF (0.002) > 5β-DHF (0.001). On the basis of these receptor assays 5α-DHF and possibly 5β-DHF were potential mineralocorticoids but probably weak glucocorticoids. The free serum concentration probably determines the biologically-effective steroid concentration. Accordingly, the affinity of these cortisol metabolites for corticosteroid binding globulin (CBG) was determined as well. In competition assays with [ 3H]-cortisol for binding to purified human CBG, the relative affinities were: cortisol (1.00) > 5 α- DHF (0.083) = 5 β- DHF (0.083). The enhanced free concentration of both cortisol metabolites should allow greater access to cellular receptors. Since binding to receptors does not indicate whether the bound steroid will have agonist, antagonist, or mixed agonist-antagonist properties, the metabolites were further tested in two physiological assays. In the isolated toad bladder, at a concentration 500 × that of aldosterone, cortisol, 5α-DHF and 5β-DHF stimulated active Na + transport measured as the short-circuit current in the following order: aldosterone (1.00) > cortisol (0.80) > 5α-DHF (0.65) > 5β-DHF (none). Infusion of cortisol, 5α- and 5β-DHF into adrenalectomized rats at concentrations 100 × that of aldosterone, produced the following relative changes in K/Na urinary ratios: aldosterone (1.00) > cortisol (0.60) > 5α-DHF (0.38) > 5β-DHF (0.28). Of the observed changes, only the 5β-DHF value was not statistically significant. These results imply that 5α-DHF should be considered a potential mineralocorticoid.