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Sample records for hyperaldosteronism

  1. Hyperaldosteronism - primary and secondary

    MedlinePlus

    ... JavaScript. Hyperaldosteronism is a disorder in which the adrenal gland releases too much of the hormone aldosterone into ... hyperaldosteronism is due to a problem of the adrenal glands themselves, which causes them to release too much ...

  2. [Primary hyperaldosteronism in cats].

    PubMed

    Willi, B; Kook, P H; Quante, S; Boretti, F; Sieber-Ruckstuhl, N S; Grest, P; Scherrer, O; Riond, B; Hofmann-Lehmann, R; Nussberger, J; Reusch, C E

    2012-12-01

    Primary hyperaldosteronism is a clinical syndrome characterized by an elevated aldosterone secretion by the adrenals. The present case series describes 7 cats with primary hyperaldosteronism, which were presented between 2002 and 2011. Common clinical symptoms were weakness, anorexia, cervical ventroflexion and blindness. All cats showed hypokalemia. In 6 cats, blood pressure was determined: 5 cats showed hypertension, of which 4 animals exhibited retinal detachment and blindness. In the ultrasonographic examination, unilateral adrenomegaly was present in 6 cats whereas one animal showed normal adrenals. In 4 cats, the serum aldosterone concentration was above the reference range. Five cats underwent unilateral adrenalectomy, which was accomplished uneventfully and returned the electrolytes back to normal. Histopathological examination of the adrenals revealed 2 carcinomas and 4 adenomas; one cat with ultrasonographic normal adrenals exhibited bilateral nodular hyperplasia.

  3. Hyperaldosteronism in pregnancy.

    PubMed

    Escher, Geneviève

    2009-04-01

    Aldosterone is a key regulator of electrolyte and water homeostasis and plays a central role in blood pressure regulation. Hormonal changes during pregnancy, among them increased progesterone and aldosterone production, lead to the required plasma volume expansion of the maternal body as an accommodation mechanism for fetus growth. This review discusses the regulation of aldosterone production by aldosterone synthase (CYP11B2); the impact on aldosterone secretion due to the presence of a chimeric gene originating from a crossover between CYP11B1 and CYP11B2 in glucocorticoid remediable aldosteronism (GRA) - the inherited form of hypertension; enhanced aldosterone production in aldosterone-producing adenoma (APA); and idiopathic hyperaldosteronism (IHA). Features of hyperaldosteronism are also found in patients with apparent mineralocorticoid excess (AME), in which glucocorticoids exacerbate activation of the mineralocorticoid receptor (MR) because of a defect in the 11beta-hydroxysteroid dehydrogenase type 2 enzyme. Regulation of aldosterone production and tissue-specific activation of the mineralocorticoid receptor are prerequisites for optimal control of body fluids and blood pressure during pregnancy and contribute largely to the wellbeing of the mother-to-be.

  4. Hyperaldosteronism: diagnosis, lateralization, and treatment.

    PubMed

    Harvey, Adrian M

    2014-06-01

    Primary hyperaldosteronism is an important and commonly unrecognized secondary cause of hypertension. This article provides an overview of the current literature with respect to screening, diagnosis, and lateralization. Selection and outcomes of medical and surgical treatment are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. [Primary hyperaldosteronism due to unilateral adrenal hyperplasia with surgical resolution].

    PubMed

    Rubio-Puchol, O; Garzón-Pastor, S; Salom-Vendrell, C; Hernández-Mijares, A

    Unilateral adrenal hyperplasia is a rare cause of primary hyperaldosteronism (around a 3%) that has surgical treatment. A case of a patient with hypertension resistant to conventional therapy in treatment with 7 drugs who presented with primary hyperaldosteronism due to unilateral adrenal hyperplasia is presented. A left adrenalectomy was performed, and the patient had a good clinical response, with no need of any drug after 2 years of surgery. Unilateral adrenal hyperplasia is a different entity and it is not an asymmetric variant of the bilateral adrenal hyperplasia. In the study of patients with primary hyperaldosteronism and imaging tests with absence of adenoma is a diagnosis that must be considered before cataloguing patients with bilateral adrenal hyperplasia and start a medical treatment, because unilateral adrenal hyperplasia would have a surgical resolution.

  6. Prevalence of primary hyperaldosteronism in a systemic arterial hypertension league.

    PubMed

    Ribeiro, Maria Jacqueline Silva; Figueiredo Neto, José Albuquerque de; Memória, Edson Viriato; Lopes, Maíra de Castro; Faria, Manuel dos Santos; Salgado Filho, Natalino; Oliveira, Thiara Castro de

    2009-01-01

    Until recently, primary hyperaldosteronism was considered a rare cause of secondary hypertension. However, in recent years, many studies have suggested that this disease can affect up to 20% of hypertensive individuals. To determine the prevalence of primary hyperaldosteronism in hypertensive patients treated at the hypertension league of a university hospital. Serum aldosterone and plasma renin activity levels were measured in 105 patients while they were undergoing standard antihypertensive treatment, with the exception of those using betablockers and spironolactone, in fasting condition and after rest in the supine position for 20 minutes. Those with an aldosterone/plasma renin activity ratio > 25 were submitted to the saline suppression test and, after the confirmation of the autonomy of aldosterone secretion, a computed tomography of the adrenals was performed. The results are presented as percentages and means and standard deviations. Of the 105 patients, 6.54% presented refractory hypertension. Nine presented an aldosterone/plasma renin activity ratio > 25 (8.5% of the total). Of these, 08 were submitted to the saline suppression test and 01 (with refractory hypertension) had the diagnosis of primary hyperaldosteronism confirmed (0.96% of the total). A computed tomography of the adrenals was performed, which showed normal results. The prevalence of primary hyperaldosteronism in the studied sample was 0.96% of the total. However, when only the patients with refractory hypertension were evaluated, the prevalence was 14.3%.

  7. Adrenal Diagnostics: An Endocrinologist's Perspective focused on Hyperaldosteronism.

    PubMed

    Fuller, Peter J

    2013-11-01

    The era of sophisticated high resolution imaging with the consequent identification of previously unrecognised adrenal masses (adrenal incidentalomas), has emphasised the need for an appropriate biochemical approach to define adrenal function. The focus of this testing is on catecholamines from the adrenal medulla (testing that has been rendered relatively straightforward by plasma metanephrine measurements) and the physiological corticosteroids, cortisol and aldosterone, synthesised by the adrenal cortex. The diagnosis of hypercortisolism remains a challenge and has been extensively reviewed. In the context of hypertension and an adrenal incidentaloma, the exclusion of hyperaldosteronism has an importance beyond simple blood pressure control. This review focuses on the recommended approaches to both the diagnosis of hyperaldosteronism and the characterisation of its aetiology. Monogenetic causes of mineralocorticoid hypertension are discussed as are recent developments with respect to both the molecular aetiology and the differential diagnosis of aldosterone-producing adenomas.

  8. Adrenal Diagnostics: An Endocrinologist’s Perspective focused on Hyperaldosteronism

    PubMed Central

    Fuller, Peter J

    2013-01-01

    The era of sophisticated high resolution imaging with the consequent identification of previously unrecognised adrenal masses (adrenal incidentalomas), has emphasised the need for an appropriate biochemical approach to define adrenal function. The focus of this testing is on catecholamines from the adrenal medulla (testing that has been rendered relatively straightforward by plasma metanephrine measurements) and the physiological corticosteroids, cortisol and aldosterone, synthesised by the adrenal cortex. The diagnosis of hypercortisolism remains a challenge and has been extensively reviewed. In the context of hypertension and an adrenal incidentaloma, the exclusion of hyperaldosteronism has an importance beyond simple blood pressure control. This review focuses on the recommended approaches to both the diagnosis of hyperaldosteronism and the characterisation of its aetiology. Monogenetic causes of mineralocorticoid hypertension are discussed as are recent developments with respect to both the molecular aetiology and the differential diagnosis of aldosterone-producing adenomas. PMID:24353356

  9. Primary hyperaldosteronism in the cat: a series of 13 cases.

    PubMed

    Ash, Roderick Andrew; Harvey, Andrea M; Tasker, Séverine

    2005-06-01

    Thirteen cases of feline primary hyperaldosteronism were diagnosed based on clinical signs, serum biochemistry, plasma aldosterone concentration, adrenal imaging and histopathology of adrenal tissue. Two cases presented with blindness caused by systemic hypertension, whilst the remaining 11 cases showed weakness resulting from hypokalaemic polymyopathy. Elevated concentrations of plasma aldosterone and adrenocortical neoplasia were documented in all cases. Seven cases had adrenal adenomas (unilateral in five and bilateral in two) and six had unilateral adrenal carcinomas. Three cases underwent medical treatment only with amlodipine, spironolactone and potassium gluconate; two cases survived for 304 and 984 days until they were euthanased because of chronic renal failure, whilst the third case was euthanased at 50 days following failure of the owner to medicate the cat. Ten cases underwent surgical adrenalectomy following a successful stabilisation period on medical management. Five cases remain alive at the time of writing with follow-up periods of between 240 and 1803 days. Three cases were euthanased during or immediately following surgery because of surgical-induced haemorrhage. One cat was euthanased 14 days after surgery because of generalised sepsis, whilst the remaining cat was euthanased 1045 days after surgery because of anorexia and the development of a cranial abdominal mass. It is recommended that primary hyperaldosteronism should be considered as a differential diagnosis in middle-aged and older cats with hypokalaemic polymyopathy and/or systemic hypertension and should no longer be considered a rare condition.

  10. Primary hyperaldosteronism: comparison of CT, adrenal venography, and venous sampling

    SciTech Connect

    Geisinger, M.A.; Zelch, M.G.; Bravo, E.L.; Risius, B.F.; O'Donovan, P.B.; Borkowski, G.P.

    1983-08-01

    Twenty-nine patients with primary hyperaldosteronism were evaluated with computed tomography (CT), adrenal venous sampling, and adrenal venography. Twenty-three patients had aldosteronomas and six had bilateral adrenocortical hyperplasia. Sixteen (70%) of the adenomas were accurately located by CT. All nodules of 1.5 cm or larger diameter and 50% of nodules 1.0 to 1.4 cm in diameter were demonstrated. Nodules of less than 1.0 cm in diameter generally were not detected. High-resolution CT appeared more sensitive than standard CT (75% vs 58%). Adrenal venous sampling for aldosterone assay was the most sensitive of the three methods, localizing 22 (96%) of the 23 adenomas. Eighteen (78%) of the adenomas were identified by adrenal venography, although two patients with bilateral cortical hyperplasia were mistakenly diagnosed as having a small adenoma. No such false-positive studies were encountered with CT or adrenal venous sampling.

  11. [Hypokalemia, a key clinical data for diagnosing primary hyperaldosteronism].

    PubMed

    Rodríguez Maya, B; Rodríguez Goncer, I; Diego Hernández, C

    2016-01-01

    We report a case of a 37 year-old man with a long history of hypertension under treatment, who was admitted at our institution with intense fatigue and weakness of lower limbs. The laboratory results at Emergency Department showed severe hypokalemia. A study of secondary hypertension was carried out. With the initial suspicion of primary hyperaldosteronism, complete blood test was done including plasma renine activity, which was completely suppressed, and plasma aldosterone concentration, which resulted normal. Likewise, an abdomen CT was performed and revealed a left adrenal mass consistent of suprarrenal adenoma. Therefore, a salt loading suppression test was done with subsequent measure of plasmatic renine activity, which was still suppressed, plasma aldosterone concentration, that persisted normal, and a 24-h urinary aldosterone excretion rate, which was clearly high, supporting the suspected diagnosis. After the adrenalectomy, the patient remained asymptomatic with normal blood pressure without treatment and with normal serum potassium levels.

  12. Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk.

    PubMed

    Abad-Cardiel, María; Alvarez-Álvarez, Beatriz; Luque-Fernandez, Loreto; Fernández, Cristina; Fernández-Cruz, Arturo; Martell-Claros, Nieves

    2013-01-01

    Primary hyperaldosteronism is the most common cause of secondary hypertension. Elevated aldosterone levels cause heart damage and increase cardiovascular morbidity and mortality. Early diagnosis could change the course of this entity. The objective of this report was to study the clinical characteristics, cardiac damage and cardiovascular risk associated with primary hyperaldosteronism. We studied 157 patients with this diagnosis. We analyzed the reason for etiological investigation, and the routinely performed tests, including echocardiography. We used a cohort of 720 essential hypertensive patients followed in our unit for comparison. Compared with essential hypertensive patients, those with hyperaldosteronism were younger (56.9 [11.7] years vs 60 [14.4] years; P<.001), had higher blood pressure prior to the etiological diagnosis (136 [20.6] mmHg vs 156 [23.2] mmHg), more frequently had a family history of early cardiovascular disease (25.5% vs 2.2%; P<.001), and had a higher prevalence of concentric left ventricular hypertrophy (69% vs 25.7%) and higher cardiovascular risk. Specific treatment resulted in optimal control of systolic and diastolic blood pressures (from 150.7 [23.0] mmHg and 86.15 [14.07] mmHg to 12.69 [15.3] mmHg and 76.34 [9.7] mmHg, respectively). We suspected the presence of hyperaldosteronism because of resistant hypertension (33.1%), hypokalemia (38.2%), and hypertensive crises (12.7%). Only 4.6% of these patients had been referred from primary care with a suspected diagnosis of hyperaldosteronism. Hyperaldosteronism should be suspected in cases of resistant hypertension, hypokalemia and hypertensive crises. The diagnosis of hyperaldosteronism allows better blood pressure control. The most prevalent target organ damage is left ventricular hypertrophy. Copyright © 2012 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  13. A case of insulin edema with inappropriate hyperaldosteronism.

    PubMed

    Kalambokis, G; Tsatsoulis, A; Economou, G; Tsianos, E V

    2004-11-01

    Edema of variable severity is an uncommon complication of insulin treatment. Increased sodium reabsorption, transient proteinuria and hypoalbuminemia are the most frequently reported laboratory disorders at the time of edema formation. This case report describes a 44-yr-old man with a 4-month history of anorexia, polyuria, polydipsia and weight loss of 25 kg who presented with diabetic ketoacidosis. On admission, there were no clinical or laboratory signs of volume depletion. Following insulin treatment he developed marked insulin edema and a cluster of abnormalities, including decreased sodium excretion, hypokalemia, hypouricemia, proteinuria, hypoalbuminemia and anemia. The diagnostic work-up showed the presence of high renin and aldosterone values despite the absence of evident hypovolemia and no evidence of gastrointestinal, cardiovascular, renal, thyroid, hepatic or other endocrine disorder. Complement values were normal; autonomic neuropathy and venoocclusive intraabdominal lesions were excluded and no other drugs except insulin were administered. Initiation of spironolactone was associated with prompt resolution of the edema and gradual correction of the laboratory abnormalities. Our findings show that hyperaldosteronism may occur in patients with insulin edema, even in the absence of volume depletion, contributing to the development of increased sodium reabsorption and of other laboratory disorders.

  14. KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension.

    PubMed

    Manichaikul, Ani; Rich, Stephen S; Allison, Matthew A; Guagliardo, Nick A; Bayliss, Douglas A; Carey, Robert M; Barrett, Paula Q

    2016-08-01

    Blood pressure (BP) is a complex trait that is the consequence of an interaction between genetic and environmental determinants. Previous studies have demonstrated increased BP in mice with global deletion of TASK-1 channels contemporaneous with diverse dysregulation of aldosterone production. In humans, genome-wide association studies in ≈100 000 individuals of European, East Asian, and South Asian ancestry identified a single nucleotide polymorphism (SNP) in KCNK3 (the gene encoding TASK-1) associated with mean arterial pressure. The current study was motivated by the hypotheses that (1) association of KCNK3 SNPs with BP and related traits extends to blacks and Hispanics, and (2) KCNK3 SNPs exhibit associations with plasma renin activity and aldosterone levels. We examined baseline BP measurements for 7840 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), and aldosterone levels and plasma renin activity in a subset of 1653 MESA participants. We identified statistically significant association of the previously reported KCNK3 SNP (rs1275988) with mean arterial pressure in MESA blacks (P=0.024) and a nearby SNP (rs13394970) in MESA Hispanics (P=0.031). We discovered additional KCNK3 SNP associations with systolic BP, mean arterial pressure, and hypertension. We also identified statistically significant association of KCNK3 rs2586886 with plasma aldosterone level in MESA and demonstrated that global deletion of TASK-1 channels in mice produces a mild-hyperaldosteronism, not associated with a decrease in renin. Our results suggest that genetic variation in the KCNK3 gene may contribute to BP variation and less severe hypertensive disorders in which aldosterone may be one of several causative factors. © 2016 American Heart Association, Inc.

  15. Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

    PubMed Central

    Pascoe, L; Jeunemaitre, X; Lebrethon, M C; Curnow, K M; Gomez-Sanchez, C E; Gasc, J M; Saez, J M; Corvol, P

    1995-01-01

    Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP11B1/CYP11B2 gene which has arisen from an unequal crossing over between the two CYP11B genes in a previous meiosis. We have studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed, giving a rare opportunity to study the regulation and action of the hybrid gene causing the disease. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. In cell culture experiments hybrid gene expression was stimulated by ACTH leading to increased production of aldosterone and the hybrid steroids characteristic of glucocorticoid-suppressible hyperaldosteronism. The genetic basis of the adrenal pathologies in this family is not known but may be related to the duplication causing the hyperaldosteronism. Images PMID:7593610

  16. Iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a concurrent diagnosis of primary hyperaldosteronism.

    PubMed

    Larouche, V; Snell, L; Morris, D V

    2015-01-01

    Myxoedema madness was first described as a consequence of severe hypothyroidism in 1949. Most cases were secondary to long-standing untreated primary hypothyroidism. We present the first reported case of iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a second concurrent diagnosis of primary hyperaldosteronism. A 29-year-old woman presented with severe hypothyroidism, a 1-week history of psychotic behaviour and paranoid delusions 3 months after treatment with radioactive iodine ablation for Graves' disease. Her psychiatric symptoms abated with levothyroxine replacement. She was concurrently found to be hypertensive and hypokalemic. Primary hyperaldosteronism from bilateral adrenal hyperplasia was diagnosed. This case report serves as a reminder that myxoedema madness can be a complication of acute hypothyroidism following radioactive iodine ablation of Graves' disease and that primary hyperaldosteronism may be associated with autoimmune hyperthyroidism. Psychosis (myxoedema madness) can present as a neuropsychiatric manifestation of acute hypothyroidism following radioactive iodine ablation of Graves' disease.Primary hyperaldosteronism may be caused by idiopathic bilateral adrenal hyperplasia even in the presence of an adrenal adenoma seen on imaging.Adrenal vein sampling is a useful tool for differentiating between a unilateral aldosterone-producing adenoma, which is managed surgically, and an idiopathic bilateral adrenal hyperplasia, which is managed medically.The management of autoimmune hyperthyroidism, iatrogenic hypothyroidism and primary hyperaldosteronism from bilateral idiopathic adrenal hyperplasia in patients planning pregnancy includes delaying pregnancy 6 months following radioactive iodine treatment and until patient is euthyroid for 3 months, using amiloride as opposed to spironolactone, controlling blood pressure with agents safe in pregnancy such as nifedipine and avoiding β blockers

  17. Iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a concurrent diagnosis of primary hyperaldosteronism

    PubMed Central

    Snell, L; Morris, D V

    2015-01-01

    Summary Myxoedema madness was first described as a consequence of severe hypothyroidism in 1949. Most cases were secondary to long-standing untreated primary hypothyroidism. We present the first reported case of iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a second concurrent diagnosis of primary hyperaldosteronism. A 29-year-old woman presented with severe hypothyroidism, a 1-week history of psychotic behaviour and paranoid delusions 3 months after treatment with radioactive iodine ablation for Graves' disease. Her psychiatric symptoms abated with levothyroxine replacement. She was concurrently found to be hypertensive and hypokalemic. Primary hyperaldosteronism from bilateral adrenal hyperplasia was diagnosed. This case report serves as a reminder that myxoedema madness can be a complication of acute hypothyroidism following radioactive iodine ablation of Graves' disease and that primary hyperaldosteronism may be associated with autoimmune hyperthyroidism. Learning points Psychosis (myxoedema madness) can present as a neuropsychiatric manifestation of acute hypothyroidism following radioactive iodine ablation of Graves' disease.Primary hyperaldosteronism may be caused by idiopathic bilateral adrenal hyperplasia even in the presence of an adrenal adenoma seen on imaging.Adrenal vein sampling is a useful tool for differentiating between a unilateral aldosterone-producing adenoma, which is managed surgically, and an idiopathic bilateral adrenal hyperplasia, which is managed medically.The management of autoimmune hyperthyroidism, iatrogenic hypothyroidism and primary hyperaldosteronism from bilateral idiopathic adrenal hyperplasia in patients planning pregnancy includes delaying pregnancy 6 months following radioactive iodine treatment and until patient is euthyroid for 3 months, using amiloride as opposed to spironolactone, controlling blood pressure with agents safe in pregnancy such as nifedipine and avoiding

  18. Increased dietary sodium is related to severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism.

    PubMed

    Pimenta, Eduardo; Stowasser, Michael; Gordon, Richard D; Harding, Susan M; Batlouni, Michel; Zhang, Bin; Oparil, Suzanne; Calhoun, David A

    2013-04-01

    Obstructive sleep apnea (OSA) is a strong and independent risk factor for the development of hypertension, particularly resistant hypertension, and cardiovascular diseases. Patients with resistant hypertension have a high prevalence of OSA in association with elevated aldosterone levels, high salt intake, and salt-sensitive BP. The objective of this study was to determine whether dietary salt and aldosterone are associated with severity of OSA in patients with resistant hypertension. Ninety-seven patients with resistant hypertension were prospectively evaluated by overnight polysomnography and 24-h urinary sodium and aldosterone levels while maintaining their usual diet. Hyperaldosteronism was defined as a plasma renin activity of < 1 ng/mL/h and urinary aldosterone level of ≥ 12 μg/24 h. Overall, patients' mean clinic BP was 156.3 ± 22.4/88.9 ± 13.3 mm Hg while taking an average of 4.3 ± 1.1 antihypertensive medications. Prevalence of OSA was 77.3%. Twenty-eight (28.9%) patients had hyperaldosteronism. Urinary sodium level was an independent predictor of severity of OSA only in patients with hyperaldosteronism. The findings suggest that dietary salt is related to the severity of OSA in patients with resistant hypertension and hyperaldosteronism. The results support dietary salt restriction as a treatment strategy for reduction of OSA severity in these patients.

  19. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.

    PubMed

    Martínez-Martínez, Ernesto; Calvier, Laurent; Fernández-Celis, Amaya; Rousseau, Elodie; Jurado-López, Raquel; Rossoni, Luciana V; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; Cachofeiro, Victoria; López-Andrés, Natalia

    2015-10-01

    Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension. © 2015 American Heart Association, Inc.

  20. Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the rat.

    PubMed

    Martin-Fernandez, Beatriz; Miana, María; De Las Heras, Natalia; Ruiz-Hurtado, Gema; Fernandez-Velasco, María; Bas, Manuel; Ballesteros, Sandra; Lahera, Vicente; Cachofeiro, Victoria; Delgado, Carmen

    2009-06-01

    Accumulating evidence supports the importance of aldosterone as an independent risk factor in the pathophysiology of cardiovascular disease. It has been postulated that aldosterone could contribute to ventricular arrhythmogeneity by modulation of cardiac ionic channels. The aim of this study was to analyse ex vivo the electrophysiological characteristics of the L-type cardiac calcium current (I(CaL)) in a model of hyperaldosteronism in the rat. Aldosterone was administered for 3 weeks, and cardiac collagen deposition and haemodynamic parameters were analysed. In addition, RT-PCR and patch-clamp techniques were applied to study cardiac L-type Ca(2+) channels in isolated cardiomyocytes. Administration of aldosterone induced maladaptive cardiac remodelling that was related to increased collagen deposition, diastolic dysfunction and cardiac hypertrophy. In addition, ventricular myocytes isolated from the aldosterone-treated group showed increased I(CaL) density and conductance and prolongation of the action potential duration. No changes in kinetics or in voltage dependence of activation and inactivation of I(CaL) were observed, but relative expression of Ca(V)1.2 mRNA levels was higher in cardiomyocytes isolated from the aldosterone-treated group. The present study demonstrates that aldosterone treatment induces myocardial fibrosis, cardiac hypertrophy, increase of I(CaL) density, upregulation of L-type Ca(2+) channels and prolongation of action potential duration. It could be proposed that aldosterone, through these mechanisms, might exert pro-arrhythmic effects in the pathological heart.

  1. G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism.

    PubMed

    Ye, Ping; Mariniello, Barbara; Mantero, Franco; Shibata, Hirotaka; Rainey, William E

    2007-10-01

    The source of aldosterone in 30-40% of patients with primary hyperaldosteronism (PA) is unilateral aldosterone-producing adenoma (APA). The mechanisms causing elevated aldosterone production in APA are unknown. Herein, we examined the expression of G-protein-coupled receptors (GPCRs) in APA and demonstrated that when compared with normal adrenals, there is a general elevation of certain GPCR in many APA and/or ectopic expression of GPCR in others. RNA samples from normal adrenals (n = 5), APAs (n = 10), and cortisol-producing adenomas (CPAs; n = 13) were used on 15 genomic expression arrays, each of which included 223 GPCR transcripts presented in at least 1 out of 15 of the independent microarrays. The array results were confirmed using real-time RT-PCR (qPCR). Four GPCR transcripts exhibited a statistically significant increase that was greater than threefold when compared with normal adrenals, suggesting a general increase in expression when compared with normal adrenal glands. Four GPCR transcripts exhibited a > 15-fold increase of expression in one or more of the APA samples when compared with normal adrenals. qPCR analysis confirmed array data and found the receptors with the highest fold increase in APA expression to be LH receptor, serotonin receptor 4, GnRH receptor, glutamate receptor metabotropic 3, endothelin receptor type B-like protein, and ACTH receptor. There are also sporadic increased expressions of these genes in the CPAs. Together, these findings suggest a potential role of altered GPCR expression in many cases of PA and provide candidate GPCR for further study.

  2. The clinical utility of two renin mass methods to detect primary hyperaldosteronism compared with renin activity.

    PubMed

    Wedatilake, Yehani N; Scanlon, Mike J; Barnes, Sophie C

    2011-05-01

    Primary hyperaldosteronism (PHA) is characterized by a raised plasma aldosterone concentration (PAC) with suppressed plasma renin activity (PRA). We evaluated two renin mass methods for PHA detection compared with the PAC:PRA ratio. Samples from patients attending a specialist hypertensive clinic were analysed by Liaison automated chemiluminescent immunoassay and Diagnostic Systems Laboratories (DSL) immunoradiometric assay (IRMA) for renin mass; I(-125) radioimmunoassay of angiotensin I generated from endogenous angiotensinogen for PRA; Siemens Coat-a-count radioimmunoassay for PAC. Subjects included those on β-blockers which suppress renin, causing an equivalent biochemical picture to PHA. Aldosterone/renin ratios (ARR) were calculated for PRA, DSL and Liaison methods. The first 100 subjects were used to identify cut-off ratios ensuring maximum specificity at 100% sensitivity for PHA detection. This cut-off was retested in a subsequent population (n = 43). A Liaison renin of 5 ng/L separated PRAs of ≤0.5 from ≥0.6 pmol/mL/h. The DSL method had greater scatter. In population 1 (18 PHA), cut-off ratios of >118 pmol/ng (Liaison) and >60 pmol/ng (DSL) gave specificities of 58.5% and 61%, respectively, with 100% sensitivity. If criteria for PHA included PAC ≥350 pmol/L and excluded β-blocked subjects, specificity increased to 95.1% and 90% for Liaison and DSL, respectively. In population 2 (6 PHA), specificities for Liaison and DSL ARRs were 86.4% and 78.3%. Using the ratio with PAC and β-blocker criteria, specificities for Liaison and DSL were 97.3% and 86.5%, respectively. The Liaison ARR used with PAC and β-blocker criteria provided an automatable alternative to identify the same patients as the PAC:PRA ratio.

  3. Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease.

    PubMed

    Lai, Silvia; Petramala, Luigi; Mastroluca, Daniela; Petraglia, Emanuela; Di Gaeta, Alessandro; Indino, Elena; Panebianco, Valeria; Ciccariello, Mauro; Shahabadi, Hossein H; Galani, Alessandro; Letizia, Claudio; D'Angelo, Anna Rita

    2016-07-01

    Hypertension is commonly associated with autosomal dominant polycystic kidney disease (ADPKD), often discovered before the onset of renal failure, albeit the pathogenetic mechanisms are not well elucidated. Hyperaldosteronism in ADPKD may contribute to the development of insulin resistance and endothelial dysfunction, and progression of cardiorenal disease. The aim of study was to evaluate the prevalence of primary aldosteronism (PA) in ADPKD patients and identify some surrogate biomarkers of cardiovascular risk.We have enrolled 27 hypertensive ADPKD patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, evaluating the renin-angiotensin-aldosterone system (RAAS), inflammatory indexes, nutritional status, homocysteine (Hcy), homeostasis model assessment-insulin resistance (HOMA-IR), mineral metabolism, microalbuminuria, and surrogate markers of atherosclerosis [carotid intima media thickness (cIMT), ankle/brachial index (ABI), flow mediated dilation (FMD), renal resistive index (RRI) and left ventricular mass index (LVMI)]. Furthermore, we have carried out the morpho-functional magnetic resonance imaging (MRI) with high-field 3 T Magnetom Avanto.We have divided patients into group A, with normal plasma aldosterone concentration (PAC) and group B with PA, present in 9 (33%) of overall ADPKD patients. Respect to group A, group B showed a significant higher mean value of LVMI, HOMA-IR and Hcy (P = 0.001, P = 0.004, P = 0.018; respectively), and a lower value of FMD and 25-hydroxyvitamin D (25-OH-VitD) (P = 0.037, P = 0.019; respectively) with a higher prevalence of non-dipper pattern at Ambulatory Blood Pressure Monitoring (ABPM) (65% vs 40%, P < 0.05) at an early stage of the disease.In this study, we showed a high prevalence of PA in ADPKD patients, associated to higher LVMI, HOMA-IR, Hcy, lower FMD, and 25-OH-VitD, considered as surrogate markers of atherosclerosis, compared to ADPKD patients with normal PAC values. Our

  4. Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease

    PubMed Central

    Lai, Silvia; Petramala, Luigi; Mastroluca, Daniela; Petraglia, Emanuela; Di Gaeta, Alessandro; Indino, Elena; Panebianco, Valeria; Ciccariello, Mauro; Shahabadi, Hossein H.; Galani, Alessandro; Letizia, Claudio; D’Angelo, Anna Rita

    2016-01-01

    Abstract Hypertension is commonly associated with autosomal dominant polycystic kidney disease (ADPKD), often discovered before the onset of renal failure, albeit the pathogenetic mechanisms are not well elucidated. Hyperaldosteronism in ADPKD may contribute to the development of insulin resistance and endothelial dysfunction, and progression of cardiorenal disease. The aim of study was to evaluate the prevalence of primary aldosteronism (PA) in ADPKD patients and identify some surrogate biomarkers of cardiovascular risk. We have enrolled 27 hypertensive ADPKD patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, evaluating the renin–angiotensin–aldosterone system (RAAS), inflammatory indexes, nutritional status, homocysteine (Hcy), homeostasis model assessment-insulin resistance (HOMA-IR), mineral metabolism, microalbuminuria, and surrogate markers of atherosclerosis [carotid intima media thickness (cIMT), ankle/brachial index (ABI), flow mediated dilation (FMD), renal resistive index (RRI) and left ventricular mass index (LVMI)]. Furthermore, we have carried out the morpho-functional magnetic resonance imaging (MRI) with high-field 3 T Magnetom Avanto. We have divided patients into group A, with normal plasma aldosterone concentration (PAC) and group B with PA, present in 9 (33%) of overall ADPKD patients. Respect to group A, group B showed a significant higher mean value of LVMI, HOMA-IR and Hcy (P = 0.001, P = 0.004, P = 0.018; respectively), and a lower value of FMD and 25-hydroxyvitamin D (25-OH-VitD) (P = 0.037, P = 0.019; respectively) with a higher prevalence of non-dipper pattern at Ambulatory Blood Pressure Monitoring (ABPM) (65% vs 40%, P < 0.05) at an early stage of the disease. In this study, we showed a high prevalence of PA in ADPKD patients, associated to higher LVMI, HOMA-IR, Hcy, lower FMD, and 25-OH-VitD, considered as surrogate markers of atherosclerosis, compared to ADPKD patients with normal

  5. Renin angiotensin aldosterone system altered in resistant hypertension in Sub-Saharan African diabetes patients without evidence of primary hyperaldosteronism

    PubMed Central

    Edinga-Melenge, Bertille Elodie; Ama Moor, Vicky J; Nansseu, Jobert Richie N; Nguetse Djoumessi, Romance; Mengnjo, Michel K; Katte, Jean-Claude; Noubiap, Jean Jacques N

    2017-01-01

    Background The renin-angiotensin-aldosterone system may be altered in patients with resistant hypertension. This study aimed to evaluate the relation between renin-angiotensin-aldosterone system activity and resistant hypertension in Cameroonian diabetes patients with resistant hypertension. Methods We carried out a case-control study including 19 diabetes patients with resistant hypertension and 19 diabetes patients with controlled hypertension matched to cases according to age, sex and duration of hypertension since diagnosis. After collection of data, fasting blood was collected for measurement of sodium, potassium, chloride, active renin and plasma aldosterone of which the aldosterone-renin ratio was derived to assess the activity of renin-angiotensin-aldosterone system. Then, each participant received 2000 ml infusion of saline solution after which plasma aldosterone was re-assayed. Results Potassium levels were lower among cases compared to controls (mean: (4.10 ± 0.63 mmol/l vs. 4.47 ± 0.58 mmol/l), though nonsignificant (p = 0.065). Active renin, plasma aldosterone both before and after the dynamic test and aldosterone-renin ratio were comparable between cases and controls (all p values > 0.05). Plasma aldosterone significantly decreased after the dynamic test in both groups (p < 0.001), but no participant exhibited a post-test value>280 pmol/l. We found a significant negative correlation between potassium ion and plasma aldosterone (ρ = −0.324; p = 0.047), the other correlations being weak and unsignificant. Conclusion Although this study failed to show an association between RH and primary hyperaldosteronism in our context, there was a hyperactivity of renin-angiotensin-aldosterone system. Moreover, this study confirms the importance of potassium dosage when screening the renin-angiotensin-aldosterone system. PMID:28321294

  6. [Subclinical endothelial inflammation markers in a family with type I familial hyperaldosteronism caused by a de novo mutation].

    PubMed

    Stehr, Carlos B; Carvajal, Cristian A; Lacourt, Patricia; Alcaíno, Hernán; Mellado, Rosemarie; Cattani, Andreína; Mosso, Lorena M; Lavandera, Sergio; Fardella, Carlos E

    2008-09-01

    Type I familial hyperaldosteronism is caused by the presence of a chimaeric gene CYPl 1B1/CYP11BZ which encodes an enzyme with aldosterone synthetase activity regulated by adrenocorticotrophic hormone (ACTH). Therefore, in patients with FH I is possible to normalize the aldosterone levels with glucocorticoid treatment. Recently it has been shown that aldosterone plays a role in the production of endothelial oxidative stress and subclinical inflammation. To evaluate subclinical endothelial inflammation markers, like Metalloproteinase 9 (MMP-9) and ultrasensitive C reactive protein (usPCR), before and after glucocorticoid treatment in family members with FH-I caused by a de novo mutation. We report three subjects with FH-I in a single family (proband, father and sister). We confirmed the presence of a chimaeric CYPl 1B1/CYP11B2 gene by long-PCR in all of them. Paternal grandparents were unaffected by the mutation. The proband was a 13-year-old boy with hypertension stage 2 (in agree to The Joint National Committee VII, JNC-VII), with an aldosterone/plasma rennin activity ratio equal to 161. A DNA paternity test confirmed the parental relationship between the grandparents and father with the index case. MMP-9 and usPCR levels were determined by gelatin zymography and nephelometry, respectively. All affected subjects had approximately a 50% increase in MMP-9 levels. Only the father had an elevated usPCR. The endothelial inflammation markers returned to normal range after glucocorticoid treatment. We report a family carrying a FH-I caused by a de novo mutation. The elevation of endothelial inflammation markers in these patients and its normalization after glucocorticoid treatment provides new insight about the possible deleterious effect of aldosterone on the endothelium.

  7. Genetics Home Reference: familial hyperaldosteronism

    MedlinePlus

    ... which means that it transports positively charged atoms (ions) of potassium into and out of cells. In the adrenal glands,the flow of ions through potassium channels produced from the KCNJ5 gene ...

  8. Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism.

    PubMed

    Nishimoto, Koshiro; Seki, Tsugio; Kurihara, Isao; Yokota, Kenichi; Omura, Masao; Nishikawa, Tetsuo; Shibata, Hirotaka; Kosaka, Takeo; Oya, Mototsugu; Suematsu, Makoto; Mukai, Kuniaki

    2016-01-01

    We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs). Some APCCs were recently found to carry aldosterone-producing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion. A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. Genomic DNA samples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322_Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin. A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.

  9. [Endosonography -- an additional diagnostic possibility in the differentiation between the two common types of primary hyperaldosteronism].

    PubMed

    Roggenland, Daniela; Schneider, Stephan; Klein, Harald H; Kann, Peter H

    2006-01-15

    Primary aldosteronism is an important and one of the few potentially curable forms of secondary hypertension. The distinction between aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IHA) may be difficult, but establishing the correct diagnosis is essential because surgery is only effective in patients with adrenal adenoma. The case of a 65-year-old man with long-term hypertension due to an APA is reported. The routine laboratory tests displayed an elevated plasma aldosterone/renin quotient as well as an elevated 24-h urinary excretion of aldosterone and its metabolites. The serum aldosterone concentration did not decrease normally in the saline suppression test. The posture testing demonstrated an increase in aldosterone. These facts might lead to the conclusion of an IHA. Magnetic resonance imaging (MRI) of the adrenal glands revealed no abnormalities. Because of the unusual combination of laboratory findings and radiologic results an endosonographic examination of the adrenal glands was performed which yielded a unilateral adrenal adenoma. With establishing this diagnosis, curative surgery became possible. This case demonstrates that in the differential diagnosis of primary aldosteronism, endosonography is more important than previously discussed. It may be helpful in the differentiation of an unusual constellation of laboratory and radiologic findings.

  10. Increased renal alpha-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape.

    PubMed

    Tiwari, Swasti; Packer, Randall K; Hu, Xinqun; Sugimura, Yoshihisa; Verbalis, Joseph G; Ecelbarger, Carolyn A

    2006-07-01

    Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the alpha-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of gamma-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076-F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207-217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-D-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-beta-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, alpha- and gamma-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and gamma-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, alpha- or gamma-ENaC or increased MAP associated with "escape."

  11. Hyperaldosteronism and altered expression of an SGK1-dependent sodium transporter in ZDF rats leads to salt dependence of blood pressure.

    PubMed

    Resch, Markus; Bergler, Tobias; Fredersdorf, Sabine; Griese, Daniel P; Weil, Joachim; Kreuzer, Peter; Brunner, Sabine; Riegger, Günter A J; Luchner, Andreas; Endemann, Dierk H

    2010-10-01

    This study was designed to test whether altered aldosterone-related sodium handling leads to salt-sensitive blood pressure in diabetes and thus may exaggerate end-organ damage. Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes, and Zucker lean (ZL) rats, as euglycemic controls, were divided into groups receiving normal (0.28%) (ZDF+N, ZL+N) and high-salt (5.5%) diets (ZDF+S, ZL+S) for 10 weeks. Renal mRNA expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) and sodium transporters (for example, the epithelial sodium channel-α, ENaCα) were measured by quantitative reverse transcriptase-PCR. Vascular hypertrophy (media-to-lumen ratio, M/L) in mesenteric resistance arteries was assessed using a pressurized myograph. Systolic blood pressure (SBP) was significantly higher in ZDF+S vs. ZDF+N (146 ± 2 vs. 133 ± 3 mm Hg; P<0.05), whereas there was no difference between ZL+S and ZL+N (151 ± 3 vs. 147 ± 3 mm Hg). Plasma sodium concentration was higher in ZDF+S vs. ZDF+N, whereas there was no difference between ZL+S and ZL+N. Plasma aldosterone concentration (PAC) was higher in ZDF+N as compared with ZL+N (191 ± 23 vs. 95 ± 35 pg ml(-1); P<0.05). PAC decreased to zero in ZL+S, which was not the case in ZDF+S (0 ± 0 vs. 37 ± 2 pg ml(-1)). Salt loading decreased the mRNA expression of SGK1 in euglycemic controls (ZL+S 0.58 ± 0.2 vs. ZL+N 1.05 ± 0.05; P=0.05), whereas it significantly increased SGK1 expression in diabetic rats (ZDF+S 1.75 ± 0.15 vs. ZDF+N 0.92 ± 0.07; P<0.01). ENaCα mRNA expression paralleled these changes. The M/L of mesenteric resistance arteries was not different between ZDF+N and ZL+N. High salt significantly increased the M/L in ZDF+S vs. ZDF+N, but not in ZL+S vs. ZL+N. Systolic blood pressure in this model of type 2 diabetes mellitus is salt sensitive, leading to marked vascular remodeling. The underlying pathophysiological mechanism may be inappropriately high levels of aldosterone and up-regulation of SGK1-dependent renal sodium transport by ENaCα, leading to net increased sodium retention.

  12. High prevalence of thyroid ultrasonographic abnormalities in primary aldosteronism.

    PubMed

    Armanini, Decio; Nacamulli, Davide; Scaroni, Carla; Lumachi, Franco; Selice, Riccardo; Fiore, Cristina; Favia, Gennaro; Mantero, Franco

    2003-11-01

    The study was performed to evaluate the prevalence of thyroid abnormalities detected by ultrasonography and, in particular, of multinodular nontoxic goiter in primary aldosteronism. We analyzed 80 consecutive of patients with primary hyperaldosteronism (40 with unilateral adenoma and 40 with idiopathic hyperaldosteronism) and 80 normotensive healthy controls, comparable for age, sex, iodine intake, and geographical area. Blood pressure, thyroid palpation, thyroid function, and ultrasonography were evaluated. The prevalence of ultrasonographic thyroid abnormalities was 60% in primary aldosteronism and 27% in controls (p < 0.0001). There was a statistically significant difference in prevalence of these abnormalities in unilateral adenoma and idiopathic hyperaldosteronism with respect to controls (p < 0.05 and p < 0.0001, respectively). The prevalence of multinodular nontoxic goiter in idiopathic hyperaldosteronism was higher than in controls (p < 0.001) and, in particular, in female patients. From these data it seems to be worth considering the existence of primary hyperaldosteronism in patients with multinodular goiter and hypertension.

  13. Juxtaglomerular cell tumor: MR findings.

    PubMed

    Agrawal, R; Jafri, S Z; Gibson, D P; Bis, K G; Ali-Reza

    1995-01-01

    Juxtaglomerular (JG) cell tumor is a rare benign neoplasm of the kidney that typically presents with hypertension, secondary hyperaldosteronism, hypocalcemia, and hyperreninism. We describe a case of JG cell tumor diagnosed with MRI.

  14. Aldosterone blood test

    MedlinePlus

    ... hypotension) Aldosterone is a hormone released by the adrenal glands . It helps the body regulate blood pressure. Aldosterone ... may be due to Bartter syndrome (extremely rare) Adrenal glands release too much aldosterone hormone ( primary hyperaldosteronism - usually ...

  15. Sodium - blood

    MedlinePlus

    ... naproxen Lower than normal sodium level is called hyponatremia. It may be due to: Use of medicines ... overview Hepatorenal syndrome Hyperaldosteronism - primary and secondary Hypopituitarism Hypothyroidism Ions Low sodium level Nephrotic syndrome Sweating Review ...

  16. What Are Some Types of Adrenal Gland Disorders?

    MedlinePlus

    ... FOIA Jobs at NICHD Meetings, Conferences & Events Partnering & Donating to the NICHD Staff Directory Skip sharing on ... cause: Cushing's syndrome , by producing cortisol so that body levels get too high Primary hyperaldosteronism, by creating ...

  17. A curious case of paralysis.

    PubMed

    Fox, Caroline

    2016-03-01

    Primary hyperaldosteronism is found in up to 13% of patients with hypertension. This article describes a patient with hypokalemia, hypertension, and periodic paralysis that were caused by primary hyperaldosteronism. Plasma aldosterone concentration to plasma renin activity ratio is a common screening test, and adrenal vein sampling can be performed to determine which gland is overproducing aldosterone. Treatment with mineralocorticoid receptor antagonists or adrenalectomy gives similar reductions in BP.

  18. [Clinical case of the month. Renovascular arterial hypertension complicated by diabetes insipidus: report of a case and review of the literature].

    PubMed

    Feloni, S; Radermacher, L; Remy, C; Jousten, J; Corman, V

    2013-01-01

    Mrs. A, a 62 year old patient with a history of hypertension, polyuria and polydipsia is hospitalized after a malaise. A severe hypokalemia, which is the cause of the polyuria and polydipsia, is discovered. The presence of hypertension and hypokalemia arises suspicion of a primary hyperaldosteronism and the plasma levels of renin and aldosterone are measured. Elevated aldosterone levels are combined with high plasma renin concentrations which permits to rule out primary hyperaldosteronism. Further explorations reveal a subocclusive ostial stenosis of the right renal artery. A treatment by sartan is instaured, which allows arterial pressure control and kalemia normalization. Chronic hypokalemia can be the cause of tubular nephropathy manifested by nephrogenic diabetes insipidus.

  19. Use of computed tomography in diagnosing the cause of primary aldosteronism

    SciTech Connect

    White, E.A.; Schambelan, M.; Rost, C.R.; Biglieri, E.G.; Moss, A.A.; Korobkin, M.

    1980-12-25

    Computed tomography (CT) was performed in 22 consecutive patients with primary aldosteronism to evaluate the usefulness of this technique in diagnosing and locating aldosterone-producing adenomas. Sixteen patients had severe hypokalemia, hyperaldosteronism, and elevated plasma levels of 18-hydroxycorticosterone suggestive of an adenoma. In 12 of these 16, a unilateral adrenal mass was demonstrated clearly, and in all 11 who had surgery an adenoma was confirmed. In the other four patients in this group, one adrenal gland was normal and the other was either not seen adequately or had minor abnormalities that could not be definitely classified; and adenoma was found in the poorly visualized gland in each of the two patients who had surgery. The remaining six patients, who had milder biochemical abnormalities suggestive of idiopathic hyperaldosteronism, had bilateral adrenal enlargement or normal-appearing glands on scan and were not surgically explored.

  20. Laparoscopic Single Site Adrenalectomy Using a Conventional Laparoscope and Instrumentation

    PubMed Central

    Colon, Modesto J; LeMasters, Patrick; Newell, Phillipa; Divino, Celia; Weber, Kaare J.

    2011-01-01

    Background and Objectives: We present a case of Laparoendoscopic Single Site Surgery (LESS) left adrenalectomy performed with a conventional laparoscope and instruments. Methods: A 45-year-old male was diagnosed with hyperaldosteronism. Computed tomography detected a left adrenal nodule. Bilateral adrenal vein sampling was consistent with a left-sided source for hyperaldosteronism. Results: Total operative time for LESS left adrenalectomy was 120 minutes. The surgery was performed with conventional instruments, a standard 5-mm laparoscope, and a SILS port, with no additional incisions or trocars needed. No complications occurred, and the patient reported an uneventful recovery. Conclusions: LESS adrenalectomy is a feasible procedure. Although articulating instruments and laparoscopes may offer advantages, LESS adrenalectomy can be done without these. PMID:21902983

  1. Familial or genetic primary aldosteronism and Gordon syndrome.

    PubMed

    Stowasser, Michael; Pimenta, Eduardo; Gordon, Richard D

    2011-06-01

    Salt-sensitive forms of hypertension have received considerable renewed attention in recent years. This article focuses on 2 main forms of salt-sensitive hypertension (familial or genetic primary aldosteronism [PA] and Gordon syndrome) and the current state of knowledge regarding their genetic bases. The glucocorticoid-remediable form of familial PA (familial hyperaldosteronism type I) is dealt with only briefly because it is covered in depth elsewhere.

  2. Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study

    PubMed Central

    Maron, Bradley A.; Opotowsky, Alexander R.; Landzberg, Michael J.; Loscalzo, Joseph; Waxman, Aaron B.; Leopold, Jane A.

    2013-01-01

    Aims Elevated levels of the mineralocorticoid hormone aldosterone are recognized as a modifiable contributor to the pathophysiology of select cardiovascular diseases due to left heart failure. In pulmonary arterial hypertension (PAH), pulmonary vascular remodelling induces right ventricular dysfunction and heart failure in the absence of left ventricular (LV) dysfunction. Hyperaldosteronism has emerged as a promoter of pulmonary vascular disease in experimental animal models of PAH; however, the extent to which hyperaldosteronism is associated with PAH in patients is unknown. Thus, the central aim of the current study is to determine if hyperaldosteronism is an unrecognized component of the PAH clinical syndrome. Methods and results Plasma aldosterone levels and invasive cardiopulmonary haemodynamic measurements were obtained for 25 patients referred for evaluation of unexplained dyspnoea or pulmonary hypertension. Compared with controls (n = 5), patients with PAH (n = 18) demonstrated significantly increased plasma aldosterone levels (1200.4 ± 423.9 vs. 5959.1 ± 2817.9 pg/mL, P < 0.02), mean pulmonary artery pressure (21.4 ± 5.0 vs. 45.5 ± 10.4 mmHg, P < 0.002), and pulmonary vascular resistance (PVR) (1.41 ± 0.6 vs. 7.3 ± 3.8 Wood units, P < 0.003) without differences in LV ejection fraction or pulmonary capillary wedge pressure between groups. Among patients not prescribed PAH-specific pharmacotherapy prior to cardiac catheterization, a subgroup of the cohort with severe pulmonary hypertension, aldosterone levels correlated positively with PVR (r = 0.72, P < 0.02) and transpulmonary gradient (r = 0.69, P < 0.02), but correlated inversely with cardiac output (r = –0.79, P < 0.005). Conclusions These data demonstrate a novel cardiopulmonary haemodynamic profile associated with hyperaldosteronism in patients: diminished cardiac output due to pulmonary vascular disease in the absence of LV heart failure. PMID:23111998

  3. Effects of cabergoline in a pituitary adenoma secreting follicle-stimulating hormone.

    PubMed Central

    Leese, G.; Jeffreys, R.; Vora, J.

    1997-01-01

    A patient with a pituitary adenoma secreting follicle-stimulating hormone with co-existent primary hyperaldosteronism is described. After his second transsphenoidal surgery, the patient developed a Staphylococcus aureus pituitary abscess. Symptoms improved after abscess drainage. Subsequent cabergoline therapy arrested the deterioration of symptoms. and decreased serum follicle-stimulating hormone concentrations. Cabergoline may be a useful treatment for aggressively growing non-prolactin-secreting pituitary adenomas. PMID:9307745

  4. Severity of Obstructive Sleep Apnea is Related to Aldosterone Status in Subjects with Resistant Hypertension

    PubMed Central

    Gonzaga, Carolina C.; Gaddam, Krishna K.; Ahmed, Mustafa I.; Pimenta, Eduardo; Thomas, S. Justin; Harding, Susan M.; Oparil, Suzanne; Cofield, Stacey S.; Calhoun, David A.

    2010-01-01

    Background: We previously described a significant correlation between plasma aldosterone concentration (PAC) and severity of obstructive sleep apnea (OSA) in patients with resistant hypertension. This investigation examines the relationship between aldosterone status and OSA in patients with resistant hypertensive—with and without hyperaldosteronism. Methods and Results: One hundred and nine consecutive patients with resistant hypertension were prospectively evaluated with plasma renin activity (PRA), PAC, 24-hour urinary aldosterone excretion (UAldo), and polysomnography. Hyperaldosteronism (PRA < 1 ng·mL-1·h-1 and UAldo ≥ 12 μg/24-h) prevalence was 28% and OSA prevalence was 77%. In patients with hyperaldosteronism, OSA prevalence was 84%, compared with 74% in hypertensive patients with normal aldosterone levels. There were no significant differences in body mass index or neck circumference between aldosterone groups. PAC and UAldo were both significantly correlated with apnea-hypopnea index (AHI) in the high-aldosterone group (ρ = 0.568, p = 0.0009; ρ = 0.533, p = 0.002, respectively). UAldo correlated weakly with apnea-hypopnea index in the normal-aldosterone group, but there was no significant correlation between PAC and AHI in the normal-aldosterone group (ρ = 0.224, p = 0.049; ρ = 0.015, p = 0.898, respectively). Conclusions: Our analysis of patients with resistant hypertension confirms a markedly high prevalence of OSA in this group. Furthermore, severity of OSA was greater in those patients with hyperaldosteronism and related to the degree of aldosterone excess. The correlation between OSA severity and aldosterone supports the hypothesis that aldosterone excess contributes to greater severity of OSA. Citation: Gonzaga CC; Gaddam KK; Ahmed MI; Pimenta E; Thomas SJ; Harding SM; Oparil S; Cofield SS; Calhoun DA. Severity of obstructive sleep apnea is related to aldosterone status in subjects with resistant hypertension. J Clin Sleep Med 2010

  5. Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma from Bilateral Diseases in Primary Aldosteronism Patients

    PubMed Central

    Satoh, Fumitoshi; Morimoto, Ryo; Ono, Yoshikiyo; Iwakura, Yoshitsugu; Omata, Kei; Kudo, Masataka; Takase, Kei; Seiji, Kazumasa; Sasamoto, Hidehiko; Honma, Seijiro; Okuyama, Mitsunobu; Yamashita, Kouwa; Gomez-Sanchez, Celso E.; Rainey, William E.; Arai, Yoichi; Sasano, Hironobu; Nakamura, Yasuhiro; Ito, Sadayoshi

    2015-01-01

    Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral diseases in primary aldosteronism. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism in 234 patients with primary aldosteronism, including CT-detectable aldosteronoma (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected and the accuracy of diagnosis was clinically and histopathologically confirmed. 18-oxocortisol and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. ROC analysis of 18-oxocortisol discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cutoff value of 4.7ng/dL, compared to that based upon 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18-oxocortisol levels above 6.1ng/dL and/or of aldosterone above 32.7ng/dL were found in 95 of 113 aldosteronoma patients (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18-oxocortisol levels below 1.2ng/dL, the lowest in aldosteronoma, were found 52 out of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that eight of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of 18-oxocortisol and aldosterone were 4.8 and 24.5ng/dL, respectively, both below their cutoff levels indicated above. The peripheral plasma 18-oxocortisol concentrations served not only to differentiate aldosteronoma, but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma. PMID:25776074

  6. Unrecognized secondary causes of hypertension in patients with hypertensive urgency/emergency: prevalence and co-prevalence.

    PubMed

    Börgel, Jan; Springer, Stephanie; Ghafoor, Jasmin; Arndt, Daniel; Duchna, Hans-Werner; Barthel, Andreas; Werner, Sibylle; Van Helden, Josef; Hanefeld, Christoph; Neubauer, Horst; Bulut, Daniel; Mügge, Andreas

    2010-08-01

    Hypertensive urgency/emergency occurs frequently, yet no prospective data on common secondary causes, including sleep apnea (SA), renal artery stenosis (RAS), and hyperaldosteronism, are available. Patients presenting to the emergency room for over 1 year with systolic blood pressure > or =180 mmHg and/or diastolic blood pressure > or =100 mmHg and typical symptoms were included. RAS was diagnosed by direct duplex/Doppler ultrasound of the renal artery, resistance index, and imaging. The aldosterone/renin ratio (ARR) was determined from morning blood samples taken with the patients supine after > or =2 h of rest. A positive ARR (>50) was followed by saline infusion to exclude primary hyperaldosteronism. SA was evaluated by nasal breathing flow screening; when positive [apnea/hypopnea index (AHI) >5/h], complete polysomnography was performed. Of 161 patients (age, 66.0 +/- 13.1 years; BMI, 28.6 +/- 5.1 kg), 131 had previously identified hypertension (duration, 12.7 +/- 11.5 years; 1.9 +/- 1.5 antihypertensive medications). SA was found in 114 (70.8%) patients [18% mild (AHI: 5-15/h), 26.8% moderate (15.1-30/h), and 24.2% severe (>30/h)]. Aldosterone levels exceeded 160 pg/ml in 22 of 23 patients with hyperaldosteronism; 4 had primary and 12 had secondary hyperaldosteronism. Thirteen (8.1%) patients had RAS. Three secondary causes were found in 1 patient (0.6%), > or =2 in 25 (15.5%), and > or =1 in 124 patients (77.0%). Of 150 detected secondary causes, only 5 were recognized previously. Secondary causes of hypertension are common and predominantly unrecognized in patients with hypertensive urgency/emergency. Co-prevalence of secondary causes occurs in about 15% and should be considered before therapeutic intervention.

  7. Liquorice Health Check, Oro-Dental Implications, and a Case Report

    PubMed Central

    Touyz, Louis Z. G.

    2009-01-01

    Liquorice has an active substance, Glycyrrhizin which inhibits the conversion of precursor cortisol to cortisone by inhibiting the enzyme 11-betahydroxysteroid dehydrogenase. When imbibed, liquorice acts like hyperaldosteronism which presents with typical symptoms including high blood pressure, low blood potassium, and muscle pain and weakness. This article appraises physiological and pharmacological effects on health of liquorice, critiques products containing liquorice, describes a typical case report of liquorice-induced hypertension, and appraises oral effects from consumption of liquorice products. PMID:19707475

  8. Relation of plasma aldosterone concentration to diuretic treatment in patients with severe heart disease.

    PubMed Central

    Knight, R K; Miall, P A; Hawkins, L A; Dacombe, J; Edwards, C R; Hamer, J

    1979-01-01

    To assess the relation of hyperaldosteronism and potassium depletion to the intensity of diuretic therapy we have measured plasma aldosterone by radioimmunoassay and total exchangeable potassium by radioisotope dilution in 24 patients when they were stable at the end of their preparation for cardiac operation. Some patients required intensive frusemide therapy to reach an optimal state for operation and many showed hyperaldosteronism. Plasma aldosterone was significantly related to daily dose of frusemide (r=0.77). Depletion of total exchangeable potassium expressed in terms of predicted weight was significantly related to plasma aldosterone (r= -0.64). The reduction in total exchangeable potassium is interpreted as chiefly related to loss of lean tissue mass from the wasting that leads to cardiac cachexia, but evidence is presented on the basis of measurements of extracellular fluid volume as sulphate space (20 patients) of entry of sodium into the cells which may indicate a true cellular potassium loss. Although plasma potassium is usually easily maintained with oral potassium supplements or aldosterone antagonists, we postulate that intensive diuretic therapy in severe heart disease may provoke hyperaldosteronism which accentuates potassium loss and may contribute to wasting and to intracellular potassium depletion in critical tissue, such as myocardium. PMID:508454

  9. Rare oxygen, a rare way to diagnose Conn's syndrome.

    PubMed

    Greven, Wendela L; van Bemmel, Thomas

    2008-12-01

    Background. Symptoms of mountain sickness are due to hypoxia of the brain. The pathogenesis is complex, but acid-base disturbances certainly play a role. When arterial oxygen levels drop, hyperventilation is induced, resulting in a respiratory alkalosis. However, this alkalosis inhibits the hyperventilation necessary for maintaining oxygen pressure. We present a case of a patient with symptoms of mountain sickness at relatively low altitudes, who appeared to have Conn's syndrome (primary hyperaldosteronism). Case. A 61-year-old male with hypokalaemic hypertension presented with symptoms of mountain sickness at relatively low altitudes. Hyperaldosteronism was suspected and laboratory results showed a non-suppressible aldosterone concentration and a mild metabolic alkalosis. A CT scan of the abdomen revealed an adenoma in the left adrenal gland. Treatment of aldosterone blockade by eplerone normalized blood pressure and the symptoms of mountain sickness at low altitudes disappeared completely. Discussion. We suggest that in our patient with hyperaldosteronism, the pre-existing metabolic alkalosis inhibited the central respiratory centre after relatively mild hyperventilation. Therefore, mountain sickness in our patient could occur at a relatively low altitude.

  10. Human congenital long QT syndrome: more than previously thought?

    PubMed

    Attali, Bernard

    2002-06-01

    Mutations in KCNQ1 and KCNE1, the alpha- and beta-subunits of the I(KS) K+ channel, produce the cardiac long QT (LQT) syndrome. These subunits are expressed in heart and inner ear, but also in epithelial tissues such as kidney or intestine where their functional roles have remained elusive. Recent work has shown that KCNE1-deficient mice display chronic hypokalemia and hyperaldosteronism. These results have significant implications for human congenital LQT syndromes because hypokalemia increases the risk of ventricular arrhythmia and cardiac sudden death.

  11. Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies.

    PubMed

    Kamoun, Mahdi; Mnif, Mouna F; Charfi, Nadia; Kacem, Faten H; Naceur, Basma B; Mnif, Fatma; Dammak, Mohamed; Rekik, Nabila; Abid, Mohamed

    2014-01-01

    : Adrenal diseases--including disorders such as Cushing's syndrome, Addison's disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia--are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality. Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis. The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

  12. Adrenal venous sampling in a patient with adrenal Cushing syndrome

    PubMed Central

    Villa-Franco, Carlos Andrés; Román-Gonzalez, Alejandro; Velez-Hoyos, Alejandro; Echeverri-Isaza, Santiago

    2015-01-01

    The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia. PMID:26309345

  13. Adrenal venous sampling in a patient with adrenal Cushing syndrome.

    PubMed

    Builes-Montaño, Carlos Esteban; Villa-Franco, Carlos Andrés; Román-Gonzalez, Alejandro; Velez-Hoyos, Alejandro; Echeverri-Isaza, Santiago

    2015-01-01

    The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia.

  14. Adrenal venous sampling using Dyna-CT--a practical guide.

    PubMed

    Plank, Christina; Wolf, Florian; Langenberger, Herbert; Loewe, Christian; Schoder, Maria; Lammer, Johannes

    2012-09-01

    Primary hyperaldosteronism due to aldosterone secreting adrenal adenomas is an important and potentially curable cause for hypertension. The differentiation between unilateral or bilateral adrenal adenomas is crucial, as unilateral adenomas can easily be cured by surgery whereas bilateral adenomas have to be treated conservatively. Exact diagnosis can be made when unilateral or bilateral hormone production is proven with adrenal vein sampling. We present an effective step-by-step technique how to perform an adrenal vein sampling with a special emphasis on how to reliably catheterize the right adrenal vein using Dyna CT.

  15. [Hormonal evaluation of adrenal incidentalomas].

    PubMed

    Le Loupp, Anne-Gaëlle; Cariou, Bertrand; Drui, Delphine; Graveline, Nolwenn; Masson, Damien; Bach-Ngohou, Kalyane

    2014-01-01

    Imaging technological advances and widespread use of abdominal imaging have led to the identification of an increasing number of adrenal incidentalomas in the last decades. Causes of these adrenal masses are multiple, but the most common etiology is the non-functional adenoma. Although in most cases, these masses are benign and non-functional, clinicians have to perform biochemical testing for subclinical cushing's syndrome, pheochromocytoma or primary hyperaldosteronism. This screening is essential for their etiological diagnosis and therapeutic management. We report in this article the biological approach to detect secretory activity of adrenal incidentalomas and the diagnostic accuracy of the biochemical tests used.

  16. Aldosterone and cortisol co-secreting bifunctional adrenal cortical carcinoma: A rare event.

    PubMed

    Chowdhury, Puskar Shyam; Nayak, Prasant; Gurumurthy, Srinivasan; David, Deepak

    2014-07-01

    Adrenocortical carcinoma (ACC) co-secreting aldosterone and cortisol is extremely rare. We report the case of a 37-yearold female who presented with paresis and facial puffiness. Evaluation revealed hypertension, hyperglycemia, severe hypokalemia and hyperaldosteronemia with elevated plasma aldosterone to renin ratio (ARR). Urinary free cortisol estimation showed elevated levels. Computed tomography scan revealed a right adrenal mass. Radical adrenalectomy specimen revealed ACC (T3N1). Post-operatively, the patient became normotensive and euglycemic with normalization of urinary cortisol and ARR. This case highlights the need for a complete evaluation in patients of hyperaldosteronism if overlapping symptoms of hypercortisolism are encountered, to avoid post-operative adrenal crisis.

  17. Bartter's syndrome in pregnancy: a case report and review.

    PubMed

    O'Sullivan, E; Monga, M; Graves, W

    1997-01-01

    Bartter's syndrome is a rare autosomal recessive disorder characterized by hypokalemia, hyperaldosteronism, sodium wasting, normal blood pressure, hypochloremic alkalosis, and hyperplasia of the juxtaglomerular apparatus. We present a 21-year-old African-American nulliparous patient who was referred to our clinic at 9 weeks' gestation with a history of Bartter's syndrome. Her antenatal course was complicated by muscle cramps, which required increasing potassium supplementation. She developed hypomagnesemia in the third trimester of pregnancy, which necessitated magnesium therapy. She delivered an unaffected infant at term. Bartter's syndrome, although extremely rare in pregnancy, requires prompt recognition and careful management, as it may have significant maternal and neonatal implications.

  18. Bartter's syndrome in pregnancy: a case report and review.

    PubMed

    Li, I C; To, W W

    2000-04-01

    Bartter's syndrome is a rare renal tubular disorder, involving juxtaglomerular cells hyperplasia, characterized by normotensive hyper-reninism and secondary hyperaldosteronism, marked renal loss of potassium and profound hypokalaemia. Both clinical and biochemical features are heterogeneous, ranging from the incidental finding in an asymptomatic patient to marked clinical features of hypokalaemia. Inheritance is likely to be an autosomal recessive. We present a case of Bartter's syndrome complicating pregnancy in a Chinese woman. We documented an increasing demand for potassium supplement during pregnancy which stabilized by mid-trimester. The absence of pregnancy complications such as polyhydramnios indicated that the fetus was unlikely to be affected by the condition.

  19. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  20. Aldosterone and progesterone-secreting adrenocortical adenocarcinoma in a cat with a concurrent meningioma

    PubMed Central

    Leshinsky, Jana; Beatty, Julia A; Fawcett, Anne; Voss, Katja; Makara, Mariano; Krockenberger, Mark B; Barrs, Vanessa R

    2016-01-01

    Case summary A 12-year-old, male neutered domestic shorthair cat was referred for investigation of suspected hyperaldosteronism due to persistent hypokalaemia, hindlimb ataxia, weakness of 1 month’s duration and a left adrenal mass that was detected on abdominal ultrasound. Neurological examination findings at referral were suggestive of a concurrent left forebrain lesion. Hyperaldosteronism and concurrent hyperprogesteronism were confirmed on endocrine testing. On computed tomography (CT) of the abdomen and thorax there was no evidence of local vascular invasion by the adrenal mass or of metastatic disease. CT and magnetic resonance imaging featured a large, focal rim-enhancing extra-axial left forebrain lesion consistent with a meningioma. Surgical excision of the forebrain mass was followed by adrenalectomy 2 weeks later. The tumours were classified on histopathology as a psammomatous meningioma and an adrenocortical adenocarcinoma, respectively. Immunohistochemical staining of the meningioma confirmed the presence of progesterone receptors. The cat remains well 2 years later. Relevance and novel information In humans, elevated serum progesterone levels have been associated with rapid growth of meningiomas due to the presence of progesterone receptors on the tumour. This is the first report of a cat with a progesterone and aldosterone-secreting adrenocortical adenocarcinoma and a concurrent meningioma. Clinicians should be aware of the potential effect of elevated progesterone on meningiomas in cats. PMID:28491405

  1. Pathophysiology, diagnosis, and treatment of mineralocorticoid disorders.

    PubMed

    Magill, Steven B

    2014-07-01

    The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.

  2. Contemporary approach to preoperative preparation of patients with adrenal cortex hormones dysfunction.

    PubMed

    Kalezić, Nevena; Malenković, Vesna; Zivaljević, Vladan; Sabljak, Vera; Diklić, Aleksandar; Ivan, Paunović

    2011-01-01

    Preoperative preparation of the patients with adrenal cortex dysfunction is based on the careful preoperative evaluation of the type and the severity of the disturbance. The dysfunction involving adrenal glands may be: insufficiency (severe, mild, expressed) and hyperfunction (hypercorticism and/or hyperaldosteronism). If we speak about the patients with limited adrenal reserve (Addison's disease, therapeutic glucocorticoid application etc.) they need necessary corticosteroid supplementation, during preoperative preparation, as well as, during complete perioperative period. Doses needed for the substitution are adjusted according to the severity of adrenal insufficiency and according to the extent of the planned surgical procedure. Patients with Cushing's syndrome (or other form of hypercorticism), as well as, patients with Conn's syndrome (or other forms of hyperaldosteronism), do have numerous organ dysfunctions, that are significant in preoperative preparation, anesthesia and for the outcome of the surgical treatment. Common feature for both of the above syndromes is hydroelectrolyte disbalance, with hypokalemia, metabolic alkalosis and hypertension. Disturbances related to the adrenal cortex hyperfunction must be corrected preoperatively, in order to avoid complications. When we speak about hypokalemia it must be promptly corrected even before urgent/vital surgical procedure because it may cause severe intraoperative cardiac arrhythmia.

  3. Ultrasonographic appearance of adrenal glands in healthy and sick cats.

    PubMed

    Combes, Anaïs; Pey, Pascaline; Paepe, Dominique; Rosenberg, Dan; Daminet, Sylvie; Putcuyps, Ingrid; Bedu, Anne-Sophie; Duchateau, Luc; de Fornel-Thibaud, Pauline; Benchekroun, Ghita; Saunders, Jimmy H

    2013-06-01

    The first part of the study aimed to describe prospectively the ultrasonographic features of the adrenal glands in 94 healthy cats and 51 chronically sick cats. It confirmed the feasibility of ultrasonography of adrenal glands in healthy and chronically sick cats, which were not statistically different. The typical hypoechoic appearance of the gland surrounded by hyperechoic fat made it recognisable. A sagittal plane of the gland, not in line with the aorta, may be necessary to obtain the largest adrenal measurements. The reference intervals of adrenal measurements were inferred from the values obtained in the healthy and chronically sick cats (mean ± 0.96 SD): adrenal length was 8.9-12.5 mm; cranial height was 3.0-4.8 mm; caudal height was 3.0-4.5 mm. The second part of the study consisted of a retrospective analysis of the ultrasonographic examination of the adrenal glands in cats with adrenal diseases (six had hyperaldosteronism and four had pituitary-dependent hyperadrenocorticism) and a descriptive comparison with the reference features obtained in the control groups from the prospective study. Cats with hyperaldosteronism presented with unilateral severely enlarged adrenal glands. However, a normal contralateral gland did not preclude a contralateral infiltration in benign or malignant adrenal neoplasms. The ultrasonographic appearance of the adrenal glands could not differentiate benign and malignant lesions. The ultrasonographic appearance of pituitary-dependent hyperadrenocorticism was mainly a symmetrical adrenal enlargement; however, a substantial number of cases were within the reference intervals of adrenal size.

  4. Bilateral Adrenocortical Masses Producing Aldosterone and Cortisol Independently

    PubMed Central

    Lee, Seung-Eun; Lee, You-Bin; Seok, Hyeri; Shin, In Seub; Eun, Yeong Hee; Kim, Jung-Han; Oh, Young Lyun

    2015-01-01

    A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol-producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses. PMID:26248855

  5. Outcomes of drug-based and surgical treatments for primary aldosteronism.

    PubMed

    Steichen, Olivier; Lorthioir, Aurelien; Zinzindohoue, Franck; Plouin, Pierre-François; Amar, Laurence

    2015-05-01

    Treatments for primary aldosteronism (PA) aim to correct or prevent the deleterious consequences of hyperaldosteronism: hypertension, hypokalemia, and direct target organ damage. Patients with unilateral PA considered fit for surgery can undergo laparoscopic adrenalectomy, which significantly decreases blood pressure (BP) and medications in most cases and cures hypertension in about 40%. Mineralocorticoid receptor antagonists (MRA) are used to treat patients with bilateral PA and those with unilateral PA if surgery is not possible or not desired. Spironolactone is more potent than eplerenone, but high doses are poorly tolerated in men. MRA can be replaced or complemented with epithelial sodium channel blockers, such as amiloride. Thiazide diuretics and calcium channel blockers are used when the first-line drugs are insufficient to control BP. Dietary sodium restriction should be implemented in all cases because the deleterious consequences of hyperaldosteronism are dependent on salt loading. Several studies comparing the results of surgery and MRA have reported no differences in terms of BP, serum potassium concentration, or cardiovascular and kidney outcomes, although the benefits of treatment tend to be observed sooner with surgery. Patients with PA display relative glomerular hyperfiltration, which is reversed by specific treatment, revealing CKD in 30% of patients. However, further kidney damage is lessened by the treatment of PA.

  6. Diagnostic value of biochemical parameters in the differential diagnosis of an adrenal mass.

    PubMed

    Petersenn, Stephan; Unger, Nicole; Walz, Martin K; Mann, Klaus

    2006-08-01

    In patients with an adrenal mass, hormonally active tumors including pheochromocytomas as well as aldosterone- and cortisol-secreting adenomas need to be considered. Several studies have demonstrated that metanephrines, which are the metabolites of catecholamines, are reliable parameters for the diagnosis of pheochromocytoma. In patients with an adrenal mass, we found plasma metanephrines, measured by a newly available radioimmunoassay, to be highly sensitive and specific for pheochromocytomas, with a better accuracy than any other biochemical parameter. The plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio is an established screening tool for primary hyperaldosteronism. However, determination of active renin concentration (ARC) in contrast to PRA may offer advantages in regard to processing and standardization. We found a PAC to ARC ratio of >62 in patients with PAC levels>200 ng/L to be a reliable screening method for primary hyperaldosteronism in patients with adrenal masses. The screening for hypercortisolism relies on excess urinary cortisol secretion, loss of the physiological feedback during dexamethasone challenge, and loss of the circadian rhythm. Because urinary-free cortisol may not identify subclinical Cushing's syndrome, in which hypercortisolism is still mild, the 1-mg dexamethasone suppression test has been recommended in all patients with incidentally detected masses. Alternatively, late-night cortisol levels in saliva have been found to have a high sensitivity and specificity for the diagnosis of Cushing's syndrome. In summary, in patients with an adrenal mass, hormonally active adrenal tumors can be excluded with high certainty using a few highly reliable biochemical parameters.

  7. Effects of aldosterone on insulin sensitivity and secretion.

    PubMed

    Luther, James M

    2014-12-01

    Dr. Conn originally reported an increased risk of diabetes in patients with hyperaldosteronism in the 1950s, although the mechanism remains unclear. Aldosterone-induced hypokalemia was initially described to impair glucose tolerance by impairing insulin secretion. Correction of hypokalemia by potassium supplementation only partially restored insulin secretion and glucose tolerance, however. Aldosterone also impairs glucose-stimulated insulin secretion in isolated pancreatic islets via reactive oxygen species in a mineralocorticoid receptor-independent manner. Aldosterone-induced mineralocorticoid receptor activation also impairs insulin sensitivity in adipocytes and skeletal muscle. Aldosterone may produce insulin resistance secondarily by altering potassium, increasing inflammatory cytokines, and reducing beneficial adipokines such as adiponectin. Renin-angiotensin system antagonists reduce circulating aldosterone concentrations and also the risk of type 2 diabetes in clinical trials. These data suggest that primary and secondary hyperaldosteronism may contribute to worsening glucose tolerance by impairing insulin sensitivity or insulin secretion in humans. Future studies should define the effects of MR antagonists and aldosterone on insulin secretion and sensitivity in humans.

  8. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.

    PubMed

    Reungjui, S; Hu, H; Mu, W; Roncal, C A; Croker, B P; Patel, J M; Nakagawa, T; Srinivas, T; Byer, K; Simoni, J; Wesson, D; Sitprija, V; Johnson, R J

    2007-12-01

    Hydrochlorothiazide (HCTZ) is used to manage hypertension and heart failure; however, its side effects include mild hypokalemia, metabolic abnormalities, and volume depletion, which might have deleterious effects on renal and endothelial function. We studied whether HCTZ cause renal injury and/or altered vasoreactivity and if these changes are hypokalemia-dependent. Rats were given a normal diet or a diet moderately low in potassium K+ with or without HCTZ. Animals fed either a low K+ diet alone or HCTZ developed mild hypokalemia. There was no significant difference in systolic blood pressure in the different treatment groups. All three groups with hypokalemia had mild proteinuria; low K(+)-HCTZ rats had reduced creatinine clearance. HCTZ-treated rats displayed hypomagnesemia, hypertriglyceridemia, hyperglycemia, insulin resistance, and hyperaldosteronism. No renal injury was observed in the groups without HCTZ; however, increased kidney weight, glomerular ischemia, medullary injury, and cortical oxidative stress were seen with HCTZ treatment. Endothelium-dependent vasorelaxation was reduced in all hypokalemic groups and correlated with reduced serum K+, serum, and urine nitric oxide. Our results show that HCTZ is associated with greater renal injury for the same degree of hypokalemia as the low K+ diet, suggesting that factors such as chronic ischemia and hyperaldosteronism due to volume depletion may be responsible agents. We also found impaired endothelium-dependent vasorelaxation was linked to mild hypokalemia.

  9. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?

    PubMed

    Grasso, Valeria; Colombo, Carlo; Favalli, Valeria; Galderisi, Alfonso; Rabbone, Ivana; Gombos, Sara; Bonora, Enzo; Massa, Ornella; Meschi, Franco; Cerutti, Franco; Iafusco, Dario; Bonfanti, Riccardo; Monciotti, Carla; Barbetti, Fabrizio

    2013-12-01

    Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter's syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.

  10. A decreased metabolic clearance rate of aldosterone in benign essential hypertension

    PubMed Central

    Nowaczynski, W.; Kuchel, O.; Genest, J.

    1971-01-01

    Aldosterone secretion rate, metabolic clearance rate, and/or plasma concentration were determined in 16 patients with benign, uncomplicated essential hypertension and compared with those of control subjects. The mean metabolic clearance rate of aldosterone in 10 patients was significantly (P < 0.001) lower (mean 867 liters of plasma/day per m2 ±270 SD) than in a group of 7 healthy subjects (mean 1480 liters/day per m2 ±265 SD). Secretion rates in 13 patients (including the 10 already mentioned) tended to be low (83 ±43 vs. 109 ±54 μg/day) and plasma concentrations tended to be high (13.6 ±4.6 vs. 7.5 ±4.8 ng/100 ml), but neither of these differences was statistically significant. The lower metabolic clearance rate could account for elevated plasma concentrations of aldosterone even when the secretion rate is normal or low. Measurement of secretion rate or urinary excretion only is therefore insufficient to establish the presence and/or mode of evolution of hyperaldosteronism. Failure of the aldosterone secretion to adapt fully to a decreased aldosterone metabolic clearance rate (MCR) could explain the state of relative hyperaldosteronism in patients with benign essential hypertension, even when the secretion rate and the urinary excretion rate are in the normal range. PMID:5116208

  11. Genetic analyses of the chimeric CYP11B1/CYP11B2 gene in a Korean family with glucocorticoid-remediable aldosteronism.

    PubMed

    Lee, Ihn Suk; Kim, Seul Young; Jang, Hye Won; Kim, Min Kyeong; Lee, Ju Hee; Lee, Yun Hyeong; Jo, Young Suk

    2010-09-01

    Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

  12. [Hypertension due to persistent hypokalemia: a complex case].

    PubMed

    Abad Cardiel, María; Ruisánchez Muñumel, Juan Vicente; Martell Claros, Nieves

    2009-11-01

    High grade of suspect must be present to diagnose some of the multiple causes of secondary blood hypertension. In the literature, there are reports that describe the coincidence of 2 different aetiologies of secondary hypertension in one patient, but both of endocrine origin. This one is the first time that a case with simultaneity of fibromuscular dysplasia and hyperaldosteronism in the same patient is described. This is the case of a 40-year-sold hypertensive patient, with a normal previous study of secondary hypertension, which after presenting HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count) during a pregnancy with foetal death was studied again to rule out a secondary aetiology for her hypertension. After various studies were performed the patient was diagnosed as having two secondary causes for her hypertension: primary hyperaldosteronism and fibromuscular dysplasia, and after a guided treatment, optimal control for blood pressure was attainted. With this clinical case we show the importance of the clinical suspicion and the need for perseverance in the diagnoses of secondary blood hypertension, and also the exclusivity of this case.

  13. Understanding primary aldosteronism: impact of next generation sequencing and expression profiling

    PubMed Central

    Monticone, Silvia; Else, Tobias; Mulatero, Paolo; Williams, Tracy A.; Rainey, William E.

    2014-01-01

    Primary aldosteronism (PA) encompasses a broad, heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most common form of secondary hypertension and associated with a higher rate of cardiovascular complications, compared to essential hypertension. Despite significant progress in the diagnosis and management of PA, until recently the molecular mechanisms leading to inappropriate aldosterone production were largely unknown. The introduction of next-generation sequencing has had a profound impact on the field of human genetics and has given new insight in the molecular determinants that lead to both sporadic and familial forms of PA. Here we review the recent progress towards understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA. PMID:25240470

  14. [Arterial hypertension secondary to endocrine disorders].

    PubMed

    Minder, Anna; Zulewski, Henryk

    2015-06-01

    Endocrine hypertension offers a potentially curative therapy if the underlying cause is identified and treated accordingly. In contrast to the high prevalence of arterial hypertension especially in the elderly, the classical endocrine causes remain a rare entity. Among patients with arterial hypertension the prevalence of Cushing's syndrome or pheochromocytoma is less than 1%. Primary hyperaldosteronism is more frequent with a reported prevalence of up to 9%. In order to avoid unnecessary, costly and potentially harmful evaluations and therapies due to the limited sensitivity and specificity of the critical endocrine tests it is mandatory to limit the exploration for endocrine causes to preselected patients with high pretest probability for an endocrine disorder. Younger age at manifestation of arterial hypertension or drug resistant hypertension together with other clinical signs of an endocrine disorder should raise the suspicion and prompt the appropriate evaluation.

  15. A case of Liddle's syndrome; unusual presentation with hypertensive encephalopathy.

    PubMed

    Kota, Sunil Kumar; Kota, Siva Krishna; Panda, Sandip; Modi, Kirtikumar D

    2014-07-01

    Liddle's syndrome is a rare cause of secondary hypertension. Identification of this disorder is important because treatment differs from other forms of hypertension. We report an interesting case of a 35-year-old lady, a known diabetic and hypertensive patient, who presented with features of hypertensive encephalopathy. The family history was unremarkable. Past treatment with various combinations of antihypertensive medications including spironolactone, all at high doses, failed to control her blood pressure. Upon evaluation, the patient had hypokalemic alkalosis, low 24-h urine potassium and suppressed plasma renin activity. Although these findings were similar to hyperaldosteronism, plasma aldosterone was lower than the normal range. Blood pressure decreased markedly after administration of amiloride. Along with hyporeninemic hypo-aldosteronism, the non-responsiveness to spironolactone and good response to amiloride established the diagnosis of Liddle's syndrome.

  16. [New insights into the pathophysiology of oedema in nephrotic syndrome].

    PubMed

    Rondon-Berrios, H

    2011-01-01

    Oedema is a common clinical manifestation of nephrotic syndrome. However, the pathophysiological mechanism of sodium retention in nephrotic syndrome has been intensely debated for decades. Several clinical and experimental observations argue against the classic or "underfill" hypothesis of oedema formation in nephrotic syndrome. In many patients, oedema formation in nephrotic syndrome is due to the kidney being intrinsically unable to excrete salt and is unrelated to systemic factors (i.e. hypoalbuminaemia, decreased “effective” arterial blood volume, and secondary hyperaldosteronism). The cortical collecting duct is the nephron site of sodium retention in nephrotic syndrome. Activation of the epithelial sodium channel in the cortical collecting duct is responsible for sodium retention in nephrotic syndrome. In nephrotic syndrome, a defective glomerular filtration barrier allows the passage of proteolytic enzymes or their precursors, which have the ability to activate the epithelial sodium channel, thereby causing the the subsequent sodium retention and oedema.

  17. The influence of pituitary, adrenal, and parathyroid hormones on hemostasis and thrombosis.

    PubMed

    Squizzato, Alessandro; Van Zaane, Bregje; Gerdes, Victor E A; Büller, Harry R

    2011-02-01

    Endocrine disorders can influence the hemostatic balance. Abnormal coagulation test results have been observed in patients with abnormal hormone levels. The present review updates the available evidence on the influence of pituitary, adrenal, and parathyroid hormones on the coagulation and the fibrinolytic system, and their possible clinical implications. The literature supports a possible relevant clinical effect of the imbalance between coagulation and fibrinolysis on thrombotic events in endogenous Cushing's syndrome. An effect on markers of coagulation and fibrinolysis has been shown for hyperprolactinemia, growth hormone excess or deficiency, exogenous hypercortisolism, pheochromocytoma, primary hyperaldosteronism, and hyperparathyroidism. However, the clinical relevance is still unproven. Until definitive evidence is available, clinicians should be aware of the possibility that endocrine disorders may be risk factors for thrombotic events.

  18. [Hypernatremia in head-injured patients: friend or foe?].

    PubMed

    Payen, J-F; Bouzat, P; Francony, G; Ichai, C

    2014-06-01

    Hypernatremia is defined by a serum sodium concentration of more than 145 mmol/L and reflects a disturbance of the regulation between water and sodium. The high incidence of hypernatremia in patients with severe brain injury is due various causes including poor thirst, diabetes insipidus, iatrogenic sodium administration, and primary hyperaldosteronism. Hypernatremia in the intensive care unit is independently associated with increased mortality and complications rates. Because of the rapid brain adaptation to extracellular hypertonicity, sustained hypernatremia exposes the patient to an exacerbation of brain edema during attempt to normalize natremia. Like serum glucose, serum sodium concentration must be tightly monitored in the intensive care unit. Copyright © 2014 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

  19. [Pathophysiology of hypertension: what's new?].

    PubMed

    Büchner, Nikolaus; Vonend, Oliver; Rump, Lars Christian

    2006-06-01

    The pathophysiology of primary hypertension is still unresolved and appears more complex than ever. It is beyond the scope of this article to review all new scientific developments in this field. On clinical grounds, hypertension is divided into primary and secondary forms. Here, the authors discuss the pathophysiology of hypertension associated with three common disease entities showing a large overlap with primary hypertension: chronic kidney disease (CKD), obstructive sleep apnea (OSA), and hyperaldosteronism. Especially in CKD and OSA, the activation of the sympathetic nervous system plays a crucial role. It is the authors' belief that hypertension due to these three diseases is more common than previously appreciated and may account for about 20% of the hypertensive population. The knowledge of the underlying pathophysiology allows early diagnosis and guides optimal treatment of these hypertensive patients.

  20. Laparoscopic Resection of Symptomatic Gastric Diverticula

    PubMed Central

    Zelisko, Andrea; Rodriguez, John; El-Hayek, Kevin

    2014-01-01

    Gastric diverticula are rare and usually asymptomatic. This report, however, describes two examples of symptomatic gastric diverticula successfully treated by laparoscopic resection. Both patients were male and in their sixth decade of life. One patient was relatively healthy with no past medical history, whereas the other patient had chronic pain issues and at presentation was also undergoing evaluation for hyperaldosteronism. The patients presented with gastrointestinal symptoms, including nausea, emesis, abdominal pain, and change in bowel function. In both cases, a gastric diverticulum was identified by CT scan, and precise anatomic position was determined by upper endoscopy. After discussion with the treating teams, including a gastroenterologist and surgeon, surgical treatment and resection was elected. Successful laparoscopic removal was accomplished in both patients, and they were discharged home after tolerating liquid diets. Both patients reported resolution of their abdominal symptoms at follow-up. PMID:24680154

  1. Consequences of morbid obesity on the kidney. Where are we going?

    PubMed Central

    2016-01-01

    Obesity and morbid obesity are modifiable risk factors for the development and progression of kidney disease. Obesity has reached epidemic proportions and is currently an important health problem in Europe, so it is necessary to develop therapeutic and preventive strategies. The obesity-related glomerulopathy has been defined as a secondary form of focal segmental glomerulosclerosis, and its most characteristic feature is glomerulomegaly. The renal evolution of patients with obesity-related glomerulopathy (ORG) who have not been treated is unfavourable. However, morbidly obese patients with ORG that underwent bariatric surgery and drastic weight loss had a better outcome. Many inflammatory factors have been implicated in the pathogenic mechanism of renal disease in obesity. Hypoadiponectinaemia, hyperleptinaemia and hyperaldosteronism have been associated with glomerular injury in obese patients. The application of modern techniques has provided important insights that increase the current understanding of ORG. However, further investigation is needed. PMID:27994854

  2. Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?

    PubMed Central

    Striessnig, Jörg; Ortner, Nadine J.; Pinggera, Alexandra

    2015-01-01

    Inhibition of voltage-gated L-type calcium channels by organic calcium channel blockers is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac ischemia. Since decades these antihypertensives (such as the dihydropyridines amlodipine, felodipine or nifedipine) belong to the most widely prescribed drugs 
world-wide. Their tolerability is excellent because at therapeutic doses their pharmacological effects in humans are limited to the cardiovascular system. During the last years substantial progress has been made to reveal the physiological role of different L-type calcium channel isoforms in many other tissues, including the brain, endocrine and sensory cells. 
Moreover, there is accumulating evidence about their involvement in various human diseases, such as Parkinson's disease, neuropsychiatric disorders and hyperaldosteronism. In this review we discuss the pathogenetic role of L-type calcium channels, potential new indications for existing or isoform-selective compounds and strategies to minimize potential side effects. PMID:25966690

  3. [Hypertension in the course of primary aldosteronism during pregnancy].

    PubMed

    Wyskida, Magdalena; Wyskida, Katarzyna; Olszanecka-Glinianowicz, Magdalena; Maruniak-Chudek, Iwona; Sikora, Jerzy; Chudek, Jerzy

    2015-02-15

    Hypertension is one of the most common cardiovascular diseases during pregnancy. Primary hyperaldosteronism (PHA) is the most frequent endocrinological, secondary cause of hypertension, rarely diagnosed in pregnant women. In the available literature about 50 cases of PHA in pregnant women have been described. PHA is often a cause of resistant hypertension. PHA can cause life-threatening complications both for the pregnant woman and the fetus. Diagnosis of PHA in pregnancy is difficult due to the antagonistic effect of progesterone on aldosterone, physiological increase of aldosterone release during gestation and frequent normokalaemic clinical course. Typical pharmacological treatment of PHA is limited due to the anti‑androgenic effect of spironolactone, lack of data concerning the safety of eplerenone and limited access to amiloride in Poland. Surgical treatment is a therapeutic option only in early pregnancy. This paper presents the current state of knowledge on diagnostic methods and treatment of PHA in pregnant women and a systematic review of cases described in the literature.

  4. Update on diagnosis and treatment of resistant hypertension.

    PubMed

    Pimenta, Eduardo

    2011-07-01

    Resistant hypertension is an increasingly common medical problem, and patients with this condition are at a high risk of cardiovascular events. The prevalence of resistant hypertension is unknown, but data from clinical trials suggest that 20% to 30% of hypertensive individuals may be resistant to antihypertensive treatment. The evaluation of these patients is focused on identifying true resistant hypertension and contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. More established approaches, such as low dietary salt and mineralocorticoid receptor blockers, and new technologies, such as carotid stimulation and renal denervation, have been used in the management of patients with resistant hypertension.

  5. Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

    PubMed Central

    Beggah, Ahmed T.; Escoubet, Brigitte; Puttini, Stefania; Cailmail, Stephane; Delage, Vanessa; Ouvrard-Pascaud, Antoine; Bocchi, Brigitte; Peuchmaur, Michel; Delcayre, Claude; Farman, Nicolette; Jaisser, Frederic

    2002-01-01

    Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the renin–angiotensin–aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2–3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed. PMID:11997477

  6. Resistant hypertension and target organ damage.

    PubMed

    Muiesan, Maria Lorenza; Salvetti, Massimo; Rizzoni, Damiano; Paini, Anna; Agabiti-Rosei, Claudia; Aggiusti, Carlo; Agabiti Rosei, Enrico

    2013-06-01

    Cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke and renal failure are related to both the degree and the duration of blood pressure (BP) increase. Resistant hypertension (RH) is associated with a higher risk of CV complications and a higher prevalence of target organ damage (TOD). The relationship between CV disease and TOD can be bidirectional. Elevated BP in RH may cause CV structural and functional alterations, and the development or persistence of left ventricular hypertrophy, aortic stiffness, atherosclerotic plaques, microvascular disease and renal dysfunction, may render hypertension more difficult to control. Specifically, RH is related to several conditions, including obesity, sleep apnea, diabetes, metabolic syndrome and hyperaldosteronism, characterized by an overexpression of humoral and hormonal factors that are involved in the development and maintenance of TOD. Optimal therapeutic strategies, including pharmacological treatment and innovative invasive methodologies, have been shown to achieve adequate BP control and induce the regression of TOD, thereby potentially improving patient prognosis.

  7. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations.

    PubMed

    Teo, Ada E D; Garg, Sumedha; Shaikh, Lalarukh Haris; Zhou, Junhua; Karet Frankl, Fiona E; Gurnell, Mark; Happerfield, Lisa; Marker, Alison; Bienz, Mariann; Azizan, Elena A B; Brown, Morris J

    2015-10-08

    Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type. (Funded by grants from the National Institute for Health Research Cambridge Biomedical Research Centre and others.).

  8. [Gitelman's Syndrome: from diagnosis to follow-up during pregnancy].

    PubMed

    Ribeiro, Rafael Brito Foureaux; da Silveira Junior, Sérgio Antônio Dias; Silva, Cristiane Calaça Borges; Gontijo, Gisele Rodrigues

    2015-01-01

    Gitelman's Syndrome (GS) is a rare autosomal recessive salt-wasting nephropathy, classically characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and low blood pressure. Fatigue, muscle weakness and muscle paralysis are common symptoms. Besides the typical electrolyte disturbances, others laboratory findings include hyperreninemia and secondary hyperaldosteronism. Bilateral nephrocalcinosis may occur. The treatment consists of potassium replacement and use of aldosterone antagonists. The best approach to pregnant women with GS is yet to be defined. However, we emphasize the need for ions supplementation, weight control as a clinical tool for assessing the water balance, and frequent monitoring of the fetus and amniotic fluid levels. The surgical risk associated with cesarean section in a patient with GS is not yet defined. Despite the risks related to symptomatic episodes of hypokalemia/hypomagnesemia, GS has a good prognosis when treated properly. Pregnancy imposes the need for more intensive control of the disease, but has a good prognosis for the mother and neonate.

  9. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations

    PubMed Central

    Teo, Ada E.D.; Garg, Sumedha; Shaikh, Lalarukh Haris; Zhou, Junhua; Frankl, Fiona E. Karet; Gurnell, Mark; Happerfield, Lisa; Marker, Alison; Bienz, Mariann; Azizan, Elena A.B.; Brown, Morris J.

    2015-01-01

    SUMMARY Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal–gonadal precursor cell type. PMID:26397949

  10. Subchronic treatment with aldosterone induces depression-like behaviours and gene expression changes relevant to major depressive disorder.

    PubMed

    Hlavacova, Natasa; Wes, Paul D; Ondrejcakova, Maria; Flynn, Marianne E; Poundstone, Patricia K; Babic, Stanislav; Murck, Harald; Jezova, Daniela

    2012-03-01

    The potential role of aldosterone in the pathophysiology of depression is unclear. The aim of this study was to test the hypothesis that prolonged elevation of circulating aldosterone induces depression-like behaviour accompanied by disease-relevant changes in gene expression in the hippocampus. Subchronic (2-wk) treatment with aldosterone (2 μg/100 g body weight per day) or vehicle via subcutaneous osmotic minipumps was used to induce hyperaldosteronism in male rats. All rats (n = 20/treatment group) underwent a modified sucrose preference test. Half of the animals from each treatment group were exposed to the forced swim test (FST), which served both as a tool to assess depression-like behaviour and as a stress stimulus. Affymetrix microarray analysis was used to screen the entire rat genome for gene expression changes in the hippocampus. Aldosterone treatment induced an anhedonic state manifested by decreased sucrose preference. In the FST, depressogenic action of aldosterone was manifested by decreased latency to immobility and increased time spent immobile. Aldosterone treatment resulted in transcriptional changes of genes in the hippocampus involved in inflammation, glutamatergic activity, and synaptic and neuritic remodelling. Furthermore, aldosterone-regulated genes substantially overlapped with genes affected by stress in the FST. This study demonstrates the existence of a causal relationship between the hyperaldosteronism and depressive behaviour. In addition, aldosterone treatment induced changes in gene expression that may be relevant to the aetiology of major depressive disorder. Subchronic treatment with aldosterone represents a new animal model of depression, which may contribute to the development of novel targets for the treatment of depression.

  11. Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis in Mice.

    PubMed

    Vergaro, Giuseppe; Prud'homme, Mathilde; Fazal, Loubina; Merval, Regine; Passino, Claudio; Emdin, Michele; Samuel, Jane-Lise; Cohen Solal, Alain; Delcayre, Claude

    2016-03-01

    Galectin-3 (Gal-3) is involved in inflammation, fibrogenesis, and cardiac remodeling. Previous evidence shows that Gal-3 interacts with aldosterone in promoting macrophage infiltration and vascular fibrosis and that Gal-3 genetic and pharmacological inhibition prevents remodeling in a pressure-overload animal model of heart failure. We aimed to explore the contribution of Gal-3 and aldosterone in mechanisms leading to heart failure in a murine model. Male mice with cardiac-specific hyperaldosteronism underwent isoproterenol subcutaneous injections, to be then randomized to receive placebo, a Gal-3 inhibitor (modified citrus pectin [MCP]), an aldosterone antagonist (potassium canrenoate), or MCP+canrenoate for 14 days. Isoproterenol induced a rapid and persistent decrease in left ventricular fractional shortening (-20% at day 14); this was markedly improved by treatment with either MCP or canrenoate (both P<0.001 versus placebo). MCP and canrenoate also reduced cardiac hypertrophy and fibrosis and the expression of genes involved in fibrogenesis (Coll-1 and Coll-3) and macrophage infiltration (CD-68 and MCP-1). After isoproterenol, Gal-3 gene expression (P<0.05 versus placebo) and protein levels (-61% and -69% versus placebo) were decreased by both canrenoate and MCP. The combined use of antagonists of Gal-3 and aldosterone resulted in more pronounced effects on cardiac hypertrophy, inflammation, and fibrosis, when compared with either MCP or canrenoate alone. Inhibition of Gal-3 and aldosterone can reverse isoproterenol-induced left ventricular dysfunction, by reducing myocardial inflammation and fibrogenesis. Gal-3 likely participates in mechanisms of aldosterone-mediated myocardial damage in a heart failure murine model with cardiac hyperaldosteronism. Gal-3 inhibition may represent a new promising therapeutic option in heart failure.

  12. [Primary aldosteronism and pregnancy: report of 2 cases].

    PubMed

    Germain, Alfredo M; Kottman, Cristián; Valdés, Gloria

    2002-12-01

    Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism.

  13. NLRP3 Inflammasome Mediates Aldosterone-Induced Vascular Damage.

    PubMed

    Bruder-Nascimento, Thiago; Ferreira, Nathanne S; Zanotto, Camila Z; Ramalho, Fernanda; Pequeno, Isabela O; Olivon, Vania C; Neves, Karla B; Alves-Lopes, Rheure; Campos, Eduardo; Silva, Carlos Alberto A; Fazan, Rubens; Carlos, Daniela; Mestriner, Fabiola L; Prado, Douglas; Pereira, Felipe V; Braga, Tarcio; Luiz, Joao Paulo M; Cau, Stefany B; Elias, Paula C; Moreira, Ayrton C; Câmara, Niels O; Zamboni, Dario S; Alves-Filho, Jose Carlos; Tostes, Rita C

    2016-12-06

    Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3(-/-)), caspase-1 knockout (Casp-1(-/-)), and interleukin-1 receptor knockout (IL-1R(-/-)) mice treated with vehicle or aldosterone (600 µg·kg(-1)·d(-1) for 14 days through osmotic mini-pump) while receiving 1% saline to drink. Here, we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Long-term infusion of aldosterone in mice resulted in elevation of plasma interleukin-1β levels and vascular abnormalities. Mice lacking the IL-1R or the inflammasome components NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In vitro, aldosterone stimulated NLRP3-dependent interleukin-1β secretion by bone marrow-derived macrophages by activating nuclear factor-κB signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1, and mature interleukin-1β in human peripheral blood mononuclear cells. Hypertensive patients with hyperaldosteronism or normal levels of aldosterone exhibited increased activity of NLRP3 inflammasome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. Together, these data demonstrate that NLRP3 inflammasome, through activation of IL-1R, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels

  14. Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

    PubMed Central

    Schwab, Dietmar; Delporte, Marie-Laure; Palermo, Giuseppe; Amrein, Kurt; Mohr, Susanne; De Vera Mudry, Maria Cristina; Brown, Morris J.; Ferber, Philippe

    2017-01-01

    Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone is produced in the adrenal by aldosterone synthase (AS, encoded by the gene CYP11B2). AS shares 93% homology to 11β-hydroxylase (encoded by the gene CYP11B1), responsible for cortisol production. This homology has hitherto impeded the development of a drug, which selectively suppresses aldosterone but not cortisol production, as a new treatment for primary hyperaldosteronism. We now report the development of RO6836191 as a potent (Ki 13 nmol/L) competitive inhibitor of AS, with in vitro selectivity >100-fold over 11β-hydroxylase. In cynomolgus monkeys challenged with synthetic adrenocorticotropic hormone, single doses of RO6836191 inhibited aldosterone synthesis without affecting the adrenocorticotropic hormone–induced rise in cortisol. In repeat-dose toxicity studies in monkeys, RO6836191 reproduced the adrenal changes of the AS−/− mouse: expansion of the zona glomerulosa; increased expression of AS (or disrupted green fluorescent protein gene in the AS−/− mouse); hypertrophy, proliferation, and apoptosis of zona glomerulosa cells. These changes in the monkey were partially reversible and partially preventable by electrolyte supplementation and treatment with an angiotensin-converting enzyme inhibitor. In healthy subjects, single doses of RO6836191, across a 360-fold dose range, reduced plasma and urine aldosterone levels with maximum suppression at a dose of 10 mg, but unchanged cortisol, on adrenocorticotropic hormone challenge, up to 360 mg, and increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol only at or >90 mg. In conclusion, RO6836191 demonstrates that it is possible to suppress aldosterone production completely in humans without affecting cortisol production. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01995383. PMID:27872236

  15. DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-Hydroxycortisol. Is there clinical utility of these steroids?

    PubMed

    Lenders, Jacques; Williams, Tracy A; Reincke, Martin; Gomez-Sanchez, Celso E

    2017-09-13

    Since the early nineteen eighties 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effective in vivo. In healthy subjects the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.

  16. Aldosterone Inhibits the Fetal Program and Increases Hypertrophy in the Heart of Hypertensive Mice

    PubMed Central

    Azibani, Feriel; Devaux, Yvan; Coutance, Guillaume; Schlossarek, Saskia; Polidano, Evelyne; Fazal, Loubina; Merval, Regine; Carrier, Lucie; Solal, Alain Cohen; Chatziantoniou, Christos; Launay, Jean-Marie; Samuel, Jane-Lise; Delcayre, Claude

    2012-01-01

    Background Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of “fetal” gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear. Methodology/Principal Findings RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (−75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects. Conclusions/Significance Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of

  17. Racial differences in sensitivity of blood pressure to aldosterone.

    PubMed

    Tu, Wanzhu; Eckert, George J; Hannon, Tamara S; Liu, Hai; Pratt, Linda M; Wagner, Mary Anne; Dimeglio, Linda A; Jung, Jeesun; Pratt, J Howard

    2014-06-01

    Blacks in comparison with whites are at risk for a more serious form of hypertension with high rates of complications. Greater sodium retention is thought to underlie the blood pressure (BP)-determining physiology of blacks, but specific mechanisms have not been identified. In a prospective observational study of BP, 226 black children and 314 white children (mean age, 10.6 years) were enrolled initially. Assessments were repeated in 85 blacks and 136 whites after reaching adulthood (mean age, 31 years). The relationship of BP to plasma aldosterone concentration in the context of the prevailing level of plasma renin activity was studied in blacks and whites. In a secondary interventional study, 9-α fludrocortisone was administered for 2 weeks to healthy adult blacks and whites to simulate hyperaldosteronism. BP responses in the 2 race groups were then compared. Although black children had lower levels of plasma renin activity and plasma aldosterone, their BP was positively associated with the plasma aldosterone concentration, an effect that increased as plasma renin activity decreased (P=0.004). Data from black adults yielded similar results. No similar relationship was observed in whites. In the interventional study, 9-α fludrocortisone increased BP in blacks but not in whites. In conclusion, aldosterone sensitivity is a significant determinant of BP in young blacks. Although its role in establishing the risk of hypertension is not known, it could be as relevant as the actual level of aldosterone.

  18. Work up of incidental adrenal mass: state of the art.

    PubMed

    Bada, Maida; Castellan, Pietro; Tamburro, Fabiola R; Berardinelli, Francesco; Neri, Fabio; Cindolo, Luca; Schips, Luigi

    2016-11-18

    Due to the increasing use of radiological investigations, the detection of incidental adrenal masses has become even more frequent. Therefore, it is crucial to identify the nature of the adrenal mass in order to decide the type of treatment that should be undertaken. Toward this goal, biochemical tests are useful in order to assess catecholamines levels for the presence of a pheochromocytoma or cortisol excess in case of Cushing's syndrome. Furthermore, the dexamethasone suppression test and late-night salivary cortisol may be useful in measuring plasma cortisol, respectively, in the blood and urine. Hyperaldosteronism could be suspected in the presence of arterial hypertension. With regard to imaging modalities, the contrast washout and Hounsfield units estimation might play a role as indicators on computed tomography. In terms of treatment, a surgical approach is most suitable for a hyperfunctioning adrenal mass irrespective of size, and for nonfunctioning masses >4 cm. For indeterminate smaller lesions, with washout >50%, <10 Hounsfield Unit, nonfunctioning, benign-appearing, undergoing a follow-up in regular intervals is more appropriate in order to estimate mass growth. This paper summarizes recent findings on the management of incidental adrenal masses, with a special focus on the use of imaging, surgical management and follow-up modalities in improving patient outcomes.

  19. Endocrine hypertension: An overview on the current etiopathogenesis and management options

    PubMed Central

    Thomas, Reena M; Ruel, Ewa; Shantavasinkul, Prapimporn Ch; Corsino, Leonor

    2015-01-01

    Endocrine causes of secondary hypertension include primary aldosteronism, pheochromocytoma, cushing’s syndrome, hyperparathyroidism and hypo- and hyperthyroidism. They comprise of the 5%–10% of the causes of secondary hypertension. Primary hyperaldosteronism, the most common of the endocrine cause of hypertension often presents with resistant or difficult to control hypertension associated with either normo-or hypokalemia. Pheochromocytoma, the great mimicker of many conditions, is associated with high morbidity and mortality if left untreated. A complete history including pertinent family history, physical examination along with a high index of suspicion with focused biochemical and radiological evaluation is important to diagnose and effectively treat these conditions. The cost effective targeted genetic screening for current known mutations associated with pheochromocytoma are important for early diagnosis and management in family members. The current review focuses on the most recent evidence regarding causes, clinical features, methods of diagnosis, and management of these conditions. A multidisciplinary approach involving internists, endocrinologists and surgeons is recommended in optimal management of these conditions. PMID:26413481

  20. Evaluation and management of the patient with difficult-to-control or resistant hypertension.

    PubMed

    Viera, Anthony J; Hinderliter, Alan L

    2009-05-15

    High blood pressure is often difficult to control. Resistant hypertension is blood pressure above goal despite adherence to a combination of at least three antihypertensive medications of different classes, optimally dosed and usually including a diuretic. The approach to blood pressure that is apparently difficult to control begins with an assessment of the patient's adherence to the management plan, including lifestyle modifications and medications. White-coat hypertension may need to be ruled out. Suboptimal therapy is the most common reason for failure to reach the blood pressure goal. Once-daily fixed-dose combination pills may improve control through the synergism of antihypertensive agents from different classes and improved adherence. Truly drug-resistant hypertension is commonly caused by chronic kidney disease, obstructive sleep apnea, or hyperaldosteronism, all of which can lead to fluid retention. Higher doses of diuretics (or a change to a loop diuretic) are usually needed. Other strategies include adding an alpha blocker, alpha-beta blocker, clonidine, or an aldosterone antagonist (e.g., spironolactone). Particularly in patients with diabetes or renal disease, combining a long-acting nondihydropyridine with a dihydropyridine calcium channel . blocker can also be considered. Obesity, heavy alcohol intake, high levels of dietary sodium, and interfering substances (especially nonsteroidal anti-inflammatory drugs) contribute to hypertension that is resistant or difficult to control.

  1. Altered potassium homeostasis in cirrhosis of the liver and Crohn's disease

    SciTech Connect

    Schober, O.; Bossaller, C.

    1984-01-01

    In the course of patients (pts) with cirrhosis of the liver (Ci) and Crohn's disease (CD) frequently noticed arrhythmias of the heart, weakness and adynamic ileus suggest alterations in the potassium (K) homeostasis. It is the purpose of the study to assess the role of Na/sup +/-K/sup +/ pump mechanism in intracellular and extracellular K homeostasis. Relative total body potassium (TBK), serum potassium (K-S), and the number of red blood cell ouabain binding sites (n-ATPase) was studied in 21 pts with Ci, 31 pts with CD and in 31 controls (C), all were not on digitalis. TBK was measured by equilibrium binding of H-3-ouabain. A significant reduction in TBK was accompanied by normal serum potassium levels, whereas the number of Na-K pumps is increased. The results support the suggestion that changes in TBK may regulate the synthesis of Na-K pump molecules. Secondary hyperaldosteronism and diarrhea e.g. may be responsible for chronic potassium depletion. The need for a nutritional support is discussed.

  2. Drug induced hypertension--An unappreciated cause of secondary hypertension.

    PubMed

    Grossman, Alon; Messerli, Franz H; Grossman, Ehud

    2015-09-15

    Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

  3. Channelopathies

    PubMed Central

    Kim, June-Bum

    2014-01-01

    Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases. PMID:24578711

  4. Role of aldosterone in the remnant kidney model in the rat.

    PubMed Central

    Greene, E L; Kren, S; Hostetter, T H

    1996-01-01

    The renin-angiotensin-aldosterone system (RAAS) participates in the injury sustained by the remnant kidney. Our studies assessed the importance of aldosterone in that model and the response of aldosterone to drugs interfering with the RAAS. Initially, four groups of rats were studied: SHAM-operated rats, untreated remnant rats (REM), REM rats treated with losartan and enalapril (REM AIIA), and REM AIIA rats infused with exogenous aldosterone (REM AIIA + ALDO). The last group was maintained with aldosterone levels comparable to those in untreated REM rats by constant infusion of exogenous aldosterone. REM rats had larger adrenal glands and a > 10-fold elevation in plasma aldosterone compared to SHAM. REM AIIA rats demonstrated significant suppression of the hyperaldosteronism as well as marked attenuation of proteinuria, hypertension, and glomerulosclerosis compared to REM. REM AIIA + ALDO rats manifested greater proteinuria, hypertension, and glomerulosclerosis than REM AIIA rats. Indeed, by 4 wk of observation all of these features of the experimental disease were similar in magnitude in REM AIIA + ALDO and untreated REM. In separate REM rats spironolactone administration did not reduce glomerular sclerosis but did transiently reduce proteinuria, lowered arterial pressure, and lessened cardiac hypertrophy. In summary, aldosterone contributes to hypertension and renal injury in the remnant kidney model. PMID:8770880

  5. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

    PubMed Central

    Leopold, Jane A.; Dam, Aamir; Maron, Bradley A.; Scribner, Anne W.; Liao, Ronglih; Handy, Diane E.; Stanton, Robert C.; Pitt, Bertram; Loscalzo, Joseph

    2013-01-01

    Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanism by which aldosterone promotes endothelial dysfunction remains unknown. Glucose-6-phosphate dehydrogenase (G6pd), the principal source of Nadph, modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO•). In these studies, we show that aldosterone (10−9-10−7 mol/l) decreases endothelial G6pd expression and activity in vitro resulting in increased oxidant stress and decreased cGMP levels similar to what is observed in G6pd-deficient cells. Aldosterone decreases G6pd expression by protein kinase A activation to increase expression of Crem, which interferes with Creb binding to the G6pd promoter. In vivo, infusion of aldosterone decreases vascular G6pd expression and impairs vascular reactivity. These effects are abrogated by spironolactone or vascular gene transfer of G6pd. These studies demonstrate that aldosterone induces a G6pd-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6pd activity. PMID:17273168

  6. Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension.

    PubMed

    Leung, Alexander A; Nerenberg, Kara; Daskalopoulou, Stella S; McBrien, Kerry; Zarnke, Kelly B; Dasgupta, Kaberi; Cloutier, Lyne; Gelfer, Mark; Lamarre-Cliche, Maxime; Milot, Alain; Bolli, Peter; Tremblay, Guy; McLean, Donna; Tobe, Sheldon W; Ruzicka, Marcel; Burns, Kevin D; Vallée, Michel; Prasad, G V Ramesh; Lebel, Marcel; Feldman, Ross D; Selby, Peter; Pipe, Andrew; Schiffrin, Ernesto L; McFarlane, Philip A; Oh, Paul; Hegele, Robert A; Khara, Milan; Wilson, Thomas W; Penner, S Brian; Burgess, Ellen; Herman, Robert J; Bacon, Simon L; Rabkin, Simon W; Gilbert, Richard E; Campbell, Tavis S; Grover, Steven; Honos, George; Lindsay, Patrice; Hill, Michael D; Coutts, Shelagh B; Gubitz, Gord; Campbell, Norman R C; Moe, Gordon W; Howlett, Jonathan G; Boulanger, Jean-Martin; Prebtani, Ally; Larochelle, Pierre; Leiter, Lawrence A; Jones, Charlotte; Ogilvie, Richard I; Woo, Vincent; Kaczorowski, Janusz; Trudeau, Luc; Petrella, Robert J; Hiremath, Swapnil; Drouin, Denis; Lavoie, Kim L; Hamet, Pavel; Fodor, George; Grégoire, Jean C; Lewanczuk, Richard; Dresser, George K; Sharma, Mukul; Reid, Debra; Lear, Scott A; Moullec, Gregory; Gupta, Milan; Magee, Laura A; Logan, Alexander G; Harris, Kevin C; Dionne, Janis; Fournier, Anne; Benoit, Geneviève; Feber, Janusz; Poirier, Luc; Padwal, Raj S; Rabi, Doreen M

    2016-05-01

    Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force provides annually updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present 4 new recommendations, as well as revisions to 2 previous recommendations. In the diagnosis and assessment of hypertension, automated office blood pressure, taken without patient-health provider interaction, is now recommended as the preferred method of measuring in-office blood pressure. Also, although a serum lipid panel remains part of the routine laboratory testing for patients with hypertension, fasting and nonfasting collections are now considered acceptable. For individuals with secondary hypertension arising from primary hyperaldosteronism, adrenal vein sampling is recommended for those who are candidates for potential adrenalectomy. With respect to the treatment of hypertension, a new recommendation that has been added is for increasing dietary potassium to reduce blood pressure in those who are not at high risk for hyperkalemia. Furthermore, in selected high-risk patients, intensive blood pressure reduction to a target systolic blood pressure ≤ 120 mm Hg should be considered to decrease the risk of cardiovascular events. Finally, in hypertensive individuals with uncomplicated, stable angina pectoris, either a β-blocker or calcium channel blocker may be considered for initial therapy. The specific evidence and rationale underlying each of these recommendations are discussed. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will continue to provide annual updates.

  7. Novel Therapeutic Strategies for Reducing Right Heart Failure Associated Mortality in Fibrotic Lung Diseases

    PubMed Central

    Adegunsoye, Ayodeji; Levy, Matthew; Oyenuga, Olusegun

    2015-01-01

    Fibrotic lung diseases carry a significant mortality burden worldwide. A large proportion of these deaths are due to right heart failure and pulmonary hypertension. Underlying contributory factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-β, and elevated systemic NO levels. Specific therapies targeting pulmonary hypertension include calcium channel blockers, endothelin (ET-1) receptor antagonists, prostacyclin analogs, phosphodiesterase type 5 (PDE5) inhibitors, and rho-kinase (ROCK) inhibitors. Newer antifibrotic and anti-inflammatory agents may exert beneficial effects on heart failure in idiopathic pulmonary fibrosis. Furthermore, right ventricle-targeted therapies, aimed at mitigating the effects of functional right ventricular failure, include β-adrenoceptor (β-AR) blockers, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, modulators of metabolism, and 5-hydroxytryptamine-2B (5-HT2B) receptor antagonists. Newer nonpharmacologic modalities for right ventricular support are increasingly being implemented. Early, effective, and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life. PMID:26583148

  8. Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome.

    PubMed

    Hadj-Rabia, Smail; Brideau, Gaelle; Al-Sarraj, Yasser; Maroun, Rachid C; Figueres, Marie-Lucile; Leclerc-Mercier, Stéphanie; Olinger, Eric; Baron, Stéphanie; Chaussain, Catherine; Nochy, Dominique; Taha, Rowaida Z; Knebelmann, Bertrand; Joshi, Vandana; Curmi, Patrick A; Kambouris, Marios; Vargas-Poussou, Rosa; Bodemer, Christine; Devuyst, Olivier; Houillier Md PhD, Pascal; El-Shanti, Hatem

    2017-08-03

    PurposeWe aimed to identify the genetic cause to a clinical syndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX syndrome), and to comprehensively delineate the phenotype.MethodsWe performed homozygosity mapping, whole-genome sequencing, gene sequencing, expression studies, functional tests, protein bioinformatics, and histological characterization in two unrelated families with HELIX syndrome.ResultsWe identified biallelic missense mutations (c.386C>T, p.S131L and c.2T>C, p.M1T) in CLDN10B in six patients from two unrelated families. CLDN10B encodes Claudin-10b, an integral tight junction (TJ) membrane-spanning protein expressed in the kidney, skin, and salivary glands. All patients had hypohidrosis, renal loss of NaCl with secondary hyperaldosteronism and hypokalemia, as well as hypolacrymia, ichthyosis, xerostomia, and severe enamel wear. Functional testing revealed that patients had a decreased NaCl absorption in the thick ascending limb of the loop of Henle and a severely decreased secretion of saliva. Both mutations resulted in reduced or absent Claudin-10 at the plasma membrane of epithelial cells.ConclusionCLDN10 mutations cause a dysfunction in TJs in several tissues and, subsequently, abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity.GENETICS in MEDICINE advance online publication, 3 August 2017; doi:10.1038/gim.2017.71.

  9. Medical management of adrenal disease: a narrative review.

    PubMed

    Michalakis, K; Ilias, I

    2009-07-01

    Adrenal diseases comprise for a variety of medical endocrine issues, ranging from partial or complete gland insufficiency, to several kinds of adrenal hyperfunction, either of congenital or neoplastic etiology. For hypofunction of the adrenals (partial or complete) the treatment of choice is medical; the mainstay of treatment is hydrocortisone. Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess. Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated, however this may not be always feasible or effective. For Cushing's syndrome ketoconazole controls cortisol's hypersecretion, whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension. For neoplastic adrenomedullary disease surgery is the treatment of choice; medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and /or recurrence (mainly metyrosine). For malignant adrenocortical disease, surgical removal remains the indicated treatment, but if the potential for surgical intervention is limited due to tumor extension, medical treatment can alleviate symptoms of hormone hypersecretion; mitotane in selected patients has good results.

  10. Adrenal Venous Sampling: Where Is the Aldosterone Disappearing to?

    SciTech Connect

    Solar, Miroslav; Ceral, Jiri; Krajina, Antonin; Ballon, Marek; Malirova, Eva; Brodak, Milos; Cap, Jan

    2010-08-15

    Adrenal venous sampling (AVS) is generally considered to be the gold standard in distinguishing unilateral and bilateral aldosterone hypersecretion in primary hyperaldosteronism. However, during AVS, we noticed a considerable variability in aldosterone concentrations among samples thought to have come from the right adrenal glands. Some aldosterone concentrations in these samples were even lower than in samples from the inferior vena cava. We hypothesized that the samples with low aldosterone levels were unintentionally taken not from the right adrenal gland, but from hepatic veins. Therefore, we sought to analyze the impact of unintentional cannulation of hepatic veins on AVS. Thirty consecutive patients referred for AVS were enrolled. Hepatic vein sampling was implemented in our standardized AVS protocol. The data were collected and analyzed prospectively. AVS was successful in 27 patients (90%), and hepatic vein cannulation was successful in all procedures performed. Cortisol concentrations were not significantly different between the hepatic vein and inferior vena cava samples, but aldosterone concentrations from hepatic venous blood (median, 17 pmol/l; range, 40-860 pmol/l) were markedly lower than in samples from the inferior vena cava (median, 860 pmol/l; range, 460-4510 pmol/l). The observed difference was statistically significant (P < 0.001). Aldosterone concentrations in the hepatic veins are significantly lower than in venous blood taken from the inferior vena cava. This finding is important for AVS because hepatic veins can easily be mistaken for adrenal veins as a result of their close anatomic proximity.

  11. Genetics of mineralocorticoid excess: an update for clinicians.

    PubMed

    Zennaro, Maria-Christina; Rickard, Amanda Jane; Boulkroun, Sheerazed

    2013-07-01

    Aldosterone plays a major role in the regulation of sodium and potassium homeostasis and blood pressure. More recently, aldosterone has emerged as a key hormone mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism (PA), the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. PA represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid-remediable aldosteronism, one of the three Mendelian forms of PA, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone-producing adenoma (APA) and in familial hyperaldosteronism type 3. Moreover, recent findings have shown somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of APAs. This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population and the genetics of familial and sporadic PA. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production are also discussed. Finally, we outline the cardiovascular, renal, and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation.

  12. Hyperplasia in glands with hormone excess.

    PubMed

    Marx, Stephen J

    2016-01-01

    Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.

  13. The Role of Aldosterone in Obesity-Related Hypertension

    PubMed Central

    Kawarazaki, Wakako

    2016-01-01

    Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin–angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension. PMID:26927805

  14. Mineralocorticoid hypertension

    PubMed Central

    Gupta, Vishal

    2011-01-01

    Hypertension affects about 10 – 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism – Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy. PMID:22145132

  15. Ultrasonographical examination of feline adrenal glands: intra- and inter-observer variability.

    PubMed

    Combes, Anaïs; Stock, Emmelie; Van der Vekens, Elke; Duchateau, Luc; Van Ryssen, Bernadette; Saunders, Jimmy H

    2014-12-01

    Interpretation of ultrasonographical measurements requires an understanding of the source and the magnitude of variation. A substantial part of the variation can be attributed to the observer, the equipment or the animal. The aim of this study was to evaluate which adrenal gland measurement is the least variable within and between observers. Three experienced ultrasonographers examined six cats at three different times on the same day, more than 1 h apart, according to a strict scanning protocol. Seven ultrasonographical measurements were performed on each adrenal gland (maximal length on sagittal images, maximal height at the cranial and caudal poles on sagittal and transverse images, and maximal width of the cranial and caudal poles on transverse images). Height measurements in both planes showed the lowest variability within and between observers compared with length and width measurements. Descriptive ultrasonographical features, such as echogenicity of the gland, presence of hyperechoic spots or layering assessment, demonstrated satisfactory-to-good intra- and inter-observer agreement, whereas the shape assessment showed very poor inter-observer agreement. The results of this study describe a reliable scanning protocol that can be the basis for future adrenal ultrasonographical examinations for cats suspected of adrenal disease (eg, hyperaldosteronism, hyperadrenocorticism, sex hormone-producing tumours). © ISFM and AAFP 2014.

  16. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis.

    PubMed

    Li, Ping; Sun, Fei; Cao, Huang-Ming; Ma, Qin-Yun; Pan, Chun-Ming; Ma, Jun-Hua; Zhang, Xiao-Na; Jiang, He; Song, Huai-Dong; Chen, Ming-Dao

    2009-12-25

    Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.

  17. Salt-losing nephropathy associated with inappropriate secretion of atrial natriuretic peptide--a new clinical syndrome.

    PubMed

    Rodríguez-Soriano, J; Vallo, A

    1997-10-01

    A state of normokalemic renal sodium wasting associated with an apparently inappropriate secretion of atrial natriuretic peptide (ANP) has not been previously recognized. We here report an 11-year-old boy who presented with a chronic "salt-losing" nephropathy manifested by normonatremic or mildly hyponatremic extracellular fluid volume depletion, hypodipsia, absence of salt appetite, normokalemic metabolic alkalosis, hyper-reninemic hyperaldosteronism, hypertrophy of the juxtaglomerular apparatus, and highly conserved capacities for concentrating diluting the urine. Plasma ANP values were paradoxically elevated (between 10 and 47 fmol/ml), despite the coexistence of intravascular volume depletion and increased plasma levels of renin and aldosterone. Although the patient had some clinical similarities to Bartter's syndrome, fractional sodium chloride (NaCl) reabsorption during hypotonic saline diuresis was normal and no clinical amelioration was observed while on indomethacin therapy. Neither a tumor nor cardiac or cerebral abnormalities, which could be responsible for the increased ANP secretion, were detected. These clinical, biochemical, and histological features have not been previously described together and may represent a new clinical syndrome. The pathophysiology of this entity remains unknown, but an attractive, although unproven, hypothesis is that the renal defect in NaCl reabsorption in this patient could be related to an inappropriate and unregulated secretion of ANP.

  18. Association of adrenal medullar and cortical nodular hyperplasia: a report of two cases with clinical and morpho-functional considerations.

    PubMed

    Valdés, Gloria; Roessler, Eric; Salazar, Iván; Rosenberg, Helmar; Fardella, Carlos; Martínez, Pedro; Velasco, Alfredo; Velasco, Soledad; Orellana, Pilar

    2006-12-01

    Arterial hypertension of adrenal etiology is mainly attributed to primary hyperaldosteronism. However, subtle expressions of hyperadrenergic or glucocorticoid excess can also generate arterial hypertension. The present report describes two hypertensive patients cataloged as resistant essential hypertensives, in whom adrenal masses were found incidentally, who highlight the need to recognize these tenuous clinical or laboratory presentations. Case 1 was a 50-yr-old female with hyperadrenergic hypertension associated to a left adrenal node, normal cortisol and aldosterone:renin ratio, marginally increased urinary normetanephrine, and a positive 131I MIBG radioisotope scan. Adrenalectomy normalized blood pressure and urinary metanephrines. Pathology showed a hyperplastic adrenal medulla associated to a multinodular cortical hyperplasia. Case 2 was a 62- yr-old female with progressive hypertension, a slight Cushing phenotype, non-suppressible hypercortisolism, normal urinary metanephrines, and bilateral adrenal nodes. Bilateral adrenalectomy and subsequent replacement normalized blood pressure and phenotypic stigmata. Pathology demonstrated bilateral cortical multinodular hyperplasia and medullary hyperplasia. The clinical study in both patients was negative for MEN. The apparently rare association of cortical and medullary lesions presented by both patients is probably overlooked in routine pathology exams, but should be meticulously searched since the crosstalk between the adrenal cortex and medulla may prompt dual abnormalities.

  19. Role of voltage-gated calcium channels in the regulation of aldosterone production from zona glomerulosa cells of the adrenal cortex.

    PubMed

    Barrett, Paula Q; Guagliardo, Nick A; Klein, Peter M; Hu, Changlong; Breault, David T; Beenhakker, Mark P

    2016-10-15

    Zona glomerulosa cells (ZG) of the adrenal gland constantly integrate fluctuating ionic, hormonal and paracrine signals to control the synthesis and secretion of aldosterone. These signals modulate Ca(2+) levels, which provide the critical second messenger to drive steroid hormone production. Angiotensin II is a hormone known to modulate the activity of voltage-dependent L- and T-type Ca(2+) channels that are expressed on the plasma membrane of ZG cells in many species. Because the ZG cell maintains a resting membrane voltage of approximately -85 mV and has been considered electrically silent, low voltage-activated T-type Ca(2+) channels are assumed to provide the primary Ca(2+) signal that drives aldosterone production. However, this view has recently been challenged by human genetic studies identifying somatic gain-of-function mutations in L-type CaV 1.3 channels in aldosterone-producing adenomas of patients with primary hyperaldosteronism. We provide a review of these assumptions and challenges, and update our understanding of the state of the ZG cell in a layer in which native cellular associations are preserved. This updated view of Ca(2+) signalling in ZG cells provides a unifying mechanism that explains how transiently activating CaV 3.2 channels can generate a significant and recurring Ca(2+) signal, and how CaV 1.3 channels may contribute to the Ca(2+) signal that drives aldosterone production.

  20. Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents.

    PubMed

    Tamargo, Juan; Segura, Julian; Ruilope, Luis M

    2014-04-01

    Diuretics enhance the renal excretion of Na(+) and water due to a direct action at different tubular sites of the nephron where solute re-absorption occurs. This paper focuses on the mechanism of action, pharmacodynamics, antihypertensive effects, adverse effects, interactions and contraindications of loop diuretics and potassium-sparing agents (including mineralocorticoid receptor antagonists (MRAs) and epithelial Na(+) channel blockers). Loop diuretics are less effective than thiazide diuretics in lowering blood pressure, so that their major use is in edematous patients with congestive heart failure (HF), cirrhosis with ascites and nephritic edema. MRAs represent a major advance in the treatment of resistant hypertension, primary and secondary hyperaldosteronism and in patients with systolic HF to reduce the risks of hospitalization and of premature death. Potassium-sparing diuretics when coadministered with diuretics (thiazides and loop diuretics) working at more proximal nephron locations reduce the risk of hypokalemia and hypomagnesemia and the risk of cardiac arrhythmias. At the end of the article, the basis for the combination of diuretics with other antihypertensive drugs to achieve blood pressure targets is presented.

  1. Baseline Demographic and Clinical Characteristics of Patients with Adrenal Incidentaloma from a Single Center in China: A Survey

    PubMed Central

    Yang, Guoqing; Zhao, Ling; Gu, Weijun; Lv, Zhaohui; Lu, Juming; Mu, Yiming

    2017-01-01

    Aim To investigate the clinical and endocrinological characteristics of patients with adrenal incidentaloma (AI). Materials and Methods This retrospective study enrolled 1941 AI patients hospitalized at the Department of Endocrinology, Chinese PLA General Hospital, Beijing, China, between January 1997 and December 2016. The patient gender, age at visits, imaging features, functional status, and histological results were analyzed. Results Of the 1941 patients, 984 (50.70%) were men. The median age was 52 years (interquartile range: 44–69 years). 140 cases had bilateral AI. Endocrine evaluation showed that 1411 (72.69%) patients had nonfunctional tumor, 152 (7.83%) had subclinical Cushing syndrome (SCS), and 82 (4.33%) had primary hyperaldosteronism. A total of 925 patients underwent operation for removal of 496 cortical adenomas (53.62%), 15 adrenal cortical carcinomas (1.62%), and 172 pheochromocytomas (18.59%). The bilateral group had a higher proportion of SCS (18.57% versus 7.10%, P < 0.001, P = 0.006). A mass size of 46 mm was of great value in distinguishing malignant tumors from the benign tumors, with sensitivity of 88.2% and specificity of 95.5%. Conclusions We reported the baseline demographic and clinical characteristics of patients with AI in a large series from a single center in China. PMID:28848603

  2. Hypertension secondary to renin-secreting juxtaglomerular cell tumor: case report and review of 38 cases.

    PubMed

    McVicar, M; Carman, C; Chandra, M; Abbi, R J; Teichberg, S; Kahn, E

    1993-08-01

    A 15-year-old girl with severe high renin hypertension caused by a juxtaglomerular cell tumor (JCT) was successfully treated with the calcium channel blocker nifedipine until surgical removal effected a permanent cure. This case was incorporated into a review of the 37 cases previously published. Comparison of the children and adolescents with the adult population showed that the features of JCT were similar in the two groups except for the average duration of symptoms prior to diagnosis (pediatric group 2.6 years vs. 6.0 years for the adult group). Analysis of all 38 cases demonstrated the following: 1. Teenagers constituted the largest single population with JCT (39%) and approximately two-thirds of the entire population were female. 2. Many patients failed to show persistent hypokalemia despite high plasma renin activity and secondary hyperaldosteronism. 3. Renal angiography was initially negative in more than half the cases. 4. Renal vein renin failed to show lateralization to the affected kidney in 52% of the cases. 5. Computerized tomography demonstrated a renal mass in all of the cases in which it was performed, even when other imaging studies were negative. 6. Calcium channel blockers may evolve as the preferred treatment for the high renin hypertension of JCT.

  3. ACTH stimulation test and computed tomography are useful for differentiating the subtype of primary aldosteronism.

    PubMed

    Moriya, Ayako; Yamamoto, Masaaki; Kobayashi, Shunsuke; Nagamine, Tomoko; Takeichi-Hattori, Naomi; Nagao, Mototsugu; Harada, Taro; Tanimura-Inagaki, Kyoko; Onozawa, Shiro; Murata, Satoru; Tamura, Hideki; Fukuda, Izumi; Oikawa, Shinichi; Sugihara, Hitoshi

    2017-01-30

    The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.

  4. Circadian Rhythm of Plasma Aldosterone Concentration in Patients with Primary Aldosteronism

    PubMed Central

    Kem, David C.; Weinberger, Myron H.; Gomez-Sanchez, Celso; Kramer, Norman J.; Lerman, Robert; Furuyama, Shunsuke; Nugent, Charles A.

    1973-01-01

    Plasma aldosterone, cortisol, and renin activity were measured in nine recumbent patients with hyperaldosteronism, including seven with adenomas, one with idiopathic hyperplasia, and one with glucocorticoid suppressible hyperplasia. All had peak values of plasma aldosterone concentration from 3 a.m. to noon and lowest values at 6 p.m. or midnight. This rhythm was similar to the circadian pattern of plasma cortisol in the same patients. When these data were normalized to eliminate the wide variation in ranges of plasma aldosterone and cortisol between individuals, there was an excellent correlation (r = + 0.87, P < 0.005) between the two hormones. In contrast, plasma aldosterone concentrations did not correlate with plasma renin activity before or after normalization of data. Short term suppression of ACTH by administration of dexamethasone eliminated the circadian variation of plasma aldosterone in both patients with hyperplasia and in four of five patients with adenomas, while it markedly altered the rhythm in the fifth. Similar doses of dexamethasone were administered to four normal subjects and did not flatten the circadian rhythm of plasma aldosterone. These data suggest that patients with primary aldosteronism have a circadian rhythm of plasma aldosterone mediated by changes in ACTH. PMID:4353776

  5. A late 17α-hydroxylase deficiency diagnosis that leads to the discovery of a new CYP17 gene mutation.

    PubMed

    Guenego, Agathe; Morel, Yves; Ionesco, Oana; Mallet, Delphine; Priou-Guesdon, Melanie

    2015-02-01

    17α-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia. It leads to a reduced production of cortisol and sex steroids and thus an increase in adrenocorticotrophic hormone and gonadotrophins levels. High adrenocorticotrophic hormone levels result in an accumulation of 17-deoxysteroids, such as deoxycorticosterone and corticosterone. Deoxycorticosterone and corticosterone have an important mineralocorticoid activity. We report the case of a 66-year-old woman who presented with hypertension and symptomatic hypokalaemia. Primary hyperaldosteronism was suspected and a right adrenal mass was removed. After surgery, the patient was referred to the endocrinology department for persistant hypokalaemia. Actually, she presented some signs of hypogonadism (impuberism, primary amenorrhea, infertility). Cortisol and 17OH-progesterone serum levels were low. Deoxycorticosterone and corticosterone were markedly elevated. The hypothesis of 17α-hydroxylase deficiency was considered and confirmed by genetic exploration. A non-sense mutation c.938G>A (p.Trp313X) in exon 5 of the CYP17 gene was found that had never been reported so far to our knowledge. Moreover, the patient's karyotype found a mosaic Turner syndrome. This case is particularly interesting because of the delay of diagnosis. The 17α-hydroxylase deficiency diagnosis is to be considered when hypertension is associated with hypokalaemia and hypogonadism, even in adult patients.

  6. Hypokalemic paralysis in a professional bodybuilder.

    PubMed

    Mayr, Florian B; Domanovits, Hans; Laggner, Anton N

    2012-09-01

    Severe hypokalemia is a potentially life-threatening disorder and is associated with variable degrees of skeletal muscle weakness, even to the point of paralysis. On rare occasions, diaphragmatic paralysis from hypokalemia can lead to respiratory arrest. There may also be decreased motility of smooth muscle, manifesting with ileus or urinary retention. Rarely, severe hypokalemia may result in rhabdomyolysis. Other manifestations of severe hypokalemia include alteration of cardiac tissue excitability and conduction. Hypokalemia can produce electrocardiographic changes such as U waves, T-wave flattening, and arrhythmias, especially if the patient is taking digoxin. Common causes of hypokalemia include extrarenal potassium losses (vomiting and diarrhea) and renal potassium losses (eg, hyperaldosteronism, renal tubular acidosis, severe hyperglycemia, potassium-depleting diuretics) as well as hypokalemia due to potassium shifts (eg, insulin administration, catecholamine excess, familial periodic hypokalemic paralysis, thyrotoxic hypokalemic paralysis). Although the extent of diuretic misuse in professional bodybuilding is unknown, it may be regarded as substantial. Hence, diuretics must always be considered as a cause of hypokalemic paralysis in bodybuilders.

  7. 18-Oxocortisol Measurement in Adrenal Vein Sampling as a Biomarker for Subclassifying Primary Aldosteronism

    PubMed Central

    Nakamura, Yasuhiro; Morimoto, Ryo; Kudo, Masataka; Takase, Kei; Gomez-Sanchez, Celso E.; Honma, Seijiro; Okuyama, Mitsunobu; Yamashita, Kouwa; Rainey, William E.; Sasano, Hironobu; Ito, Sadayoshi

    2011-01-01

    Context: 18-Oxocortisol (18-oxoF) is a derivative of cortisol (F) that is produced by aldosterone synthase (CYP11B2). The potential for this steroid as a biomarker for differentiating patients with aldosterone-producing adenoma (APA) from those with idiopathic hyperaldosteronism (IHA) has not been examined. Objectives: We measured 18-oxoF, aldosterone, and F in plasma from adrenal vein sampling (AVS) of patients with primary aldosteronism. We compared 18-oxoF levels and 18-oxoF/F ratios for their potential to differentiate APA from IHA. Design, Setting, and Subjects: This study measured 18-oxoF, F, and aldosterone in AVS obtained from patients with unilateral APA (14 cases) or bilateral IHA (seven cases, 14 samples total) using liquid chromatography-tandem mass spectrometry and RIA analyses. Results: The levels of 18-oxoF and the ratios of 18-oxoF/F, before and after ACTH stimulation, were significantly higher in blood-draining APA than in those from the contralateral adrenal glands and from adrenal glands with IHA. Conclusions: The 18-oxoF levels and ratios of 18-oxoF/F in AVS samples can be a clinically useful biomarker for differentiating APA from IHA and for determining the localization or lateralization of APA in patients with primary aldosteronism. PMID:21593107

  8. The Role of Aldosterone in Obesity-Related Hypertension.

    PubMed

    Kawarazaki, Wakako; Fujita, Toshiro

    2016-04-01

    Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin-angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension.

  9. Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism.

    PubMed

    Lefebvre, H; Prévost, G; Louiset, E

    2013-11-01

    A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.

  10. Resistant hypertension in office practice: a clinical approach.

    PubMed

    Siyam, Fadi; Brietzke, Stephen A; Sowers, James R

    2010-11-01

    Resistant hypertension is defined as blood pressure uncontrolled to guideline levels despite the use of ≥3 antihypertensive medications. When evaluating patients with resistant hypertension, it is important to consider issues such as blood pressure measurement technique, lifestyle, other comorbid conditions and medications, and the white coat effect. To this point, potential contributing factors include obstructive sleep apnea, excess alcohol intake, and use of blood pressure-elevating medications, such as nonsteroidal anti-inflammatory drugs, sympathomimetics, certain anorexic agents, and oral contraceptives. Secondary causes of hypertension are common in patients with resistant hypertension and appropriate screening tests should be performed as suggested by signs, symptoms, and laboratory abnormalities. In this regard, there is increasing evidence that hyperaldosteronism is common in the resistant hypertensive patient group. Pharmacologic therapy in patients with resistant hypertension is centered on drug combinations that have different mechanisms of action, including diuretics, which are essential in maximizing antihypertensive effects. The role of mineralocorticoid receptor antagonists is expanding, especially in patients with the metabolic syndrome, where aldosterone excess is increasingly recognized as an etiology of resistant hypertension. Finally, when appropriate, specialist referral may be necessary to appropriately assess and treat these patients.

  11. Blood pressure, magnesium and other mineral balance in two rat models of salt-sensitive, induced hypertension: effects of a non-peptide angiotensin II receptor type 1 antagonist.

    PubMed

    Rondón, Lusliany Josefina; Marcano, Eunice; Rodríguez, Fátima; del Castillo, Jesús Rafael

    2014-01-01

    The renin-angiotensin system is critically involved in regulating arterial blood pressure (BP). Inappropriate angiotensin type-1 receptor activation by angiotensin-II (Ang-II) is related to increased arterial BP. Mg has a role in BP; it can affect cardiac electrical activity, myocardial contractility, and vascular tone. To evaluate the relationship between high BP induced by a high sodium (Na) diet and Mg, and other mineral balances, two experimental rat models of salt-sensitive, induced-hypertension were used: Ang-II infused and Dahl salt-sensitive (SS) rats. We found that: 1) Ang-II infusion progressively increased BP, which was accompanied by hypomagnesuria and signs of secondary hyperaldosteronism; 2) an additive effect between Ang-II and a high Na load may have an effect on strontium (Sr), zinc (Zn) and copper (Cu) balances; 3) Dahl SS rats fed a high Na diet had a slow pressor response, accompanied by altered Mg, Na, potassium (K), and phosphate (P) balances; and 4) losartan prevented BP increases induced by Ang II-NaCl, but did not modify mineral balances. In Dahl SS rats, losartan attenuated high BP and ameliorated magnesemia, Na and K balances. Mg metabolism maybe considered a possible defect in this strain of rat that may contribute to hypertension.

  12. Calcium unresponsive hypocalcemic tetany: gitelman syndrome with hypocalcemia.

    PubMed

    Desai, Madhav; Kolla, Praveen Kumar; Reddy, P L Venkata Pakki

    2013-01-01

    Introduction. Gitelman's syndrome (GS) is autosomal recessive renal tubular disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hyperreninemic hyperaldosteronism. It is usually associated with normal serum calcium. We report a patient presented with hypocalcemic tetany, and evaluation showed Gitelman's syndrome with hypocalcemia. Case Report. A 28-year-old woman presented with cramps of the arms, legs, fatigue, and carpal spasms of one week duration. She has history of similar episodes on and off for the past two years. Her blood pressure was 98/66 mmHg. Chvostek's sign and Trousseau's sign were positive. Evaluation showed hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Self-medication, diuretic use, laxative abuse, persistent vomiting, and diarrhoea were ruled out. Urinary prostaglandins and genetic testing could not be done because of nonavailability. To differentiate Gitelman syndrome from Bartter's syndrome (BS), thiazide loading test was done. It showed blunted fractional chloride excretion. GS was confirmed and patient was treated with spironolactone along with magnesium, calcium, and potassium supplementation. Symptomatically, she improved and did not develop episodes of tetany again. Conclusion. In tetany patient along with serum calcium measurement, serum magnesium, serum potassium, and arterial blood gases should be measured. Even though hypocalcemia in Gitelman syndrome is rare, it still can occur.

  13. A novel mutation of CLCNKB in a Korean patient of mixed phenotype of Bartter-Gitelman syndrome

    PubMed Central

    Cho, Hee-Won; Lee, Sang Taek; Cheong, Hae Il

    2016-01-01

    Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation. PMID:28018459

  14. Adrenal incidentaloma in adults - management recommendations by the Polish Society of Endocrinology.

    PubMed

    Bednarczuk, Tomasz; Bolanowski, Marek; Sworczak, Krzysztof; Górnicka, Barbara; Cieszanowski, Andrzej; Otto, Maciej; Ambroziak, Urszula; Pachucki, Janusz; Kubicka, Eliza; Babińska, Anna; Koperski, Łukasz; Januszewicz, Andrzej; Prejbisz, Aleksander; Górska, Maria; Jarząb, Barbara; Hubalewska-Dydejczyk, Alicja; Glinicki, Piotr; Ruchała, Marek; Kasperlik-Załuska, Anna

    2016-01-01

    A wide use of imaging techniques results in more frequent diagnosis of adrenal incidenataloma. To analyse the current state of knowledge on adrenal incidentaloma in adults in order to prepare practical management recommendations. Following a discussion, the Polish Society of Endocrinology expert working group have analysed the available data and summarised the analysis results in the form of recommendations. Unenhanced adrenal computed tomography (CT) may be recommended as an initial assessment examination helpful in the differentiation between adenomas and "non-adenomatous" lesions. In the case of density > 10 Hounsfield units, CT with contrast medium washout assessment or MRI are recommended. However, in all patients with adrenal incidentaloma, hormonal assessment is recommended in order to exclude pheochromocytoma and hypercortisolism, notwithstanding the clinical picture or concomitant diseases. In addition, examination to exclude primary hyperaldosteronism is suggested in patients with diagnosed hypertension or hypokalaemia. Surgical treatment should be recommended in patients with adrenal incidentaloma, where imaging examinations suggest a malignant lesion (oncological indication) or with confirmed hormonal activity (endocrinological indication). The basis of the surgical treatment is laparoscopic adrenalectomy. Patients with suspected pheochromocytoma must be pharmacologically prepared prior to surgery. In patients not qualified for surgery, control examinations (imaging and laboratory tests) should be established individually, taking into consideration such features as the size, image, and growth dynamics of the tumour, clinical symptoms, hormonal tests results, and concomitant diseases.

  15. Reduced 11beta-hydroxysteroid dehydrogenase activity in patients with the nephrotic syndrome.

    PubMed

    Vogt, B; Dick, B; N'Gankam, V; Frey, F J; Frey, B M

    1999-02-01

    Patients with the nephrotic syndrome (NS) exhibit abnormal renal sodium retention which cannot completely explained by a secondary hyperaldosteronism due to reduced renal perfusion. As an alternative mechanism to explain this phenomenon we postulate a cortisol-mediated mineralocorticoid effect as a consequence of a reduced activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). A down-regulation of 11beta-HSD, i.e. of the shuttle of active to inactive glucocorticosteroids, has been shown to cause mineralocorticoid effects. Therefore we investigated the activity of 11beta-HSD by measuring the urinary ratio of (tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone [(THF+5alpha-THF)/THE] by gas-chromatography in 29 NS patients with biopsy-proven glomerulonephritis and 29 healthy control subjects. The ratio of (THF+5alpha-THF)/THE was higher in NS patients (median 1.49, range 0.45-4.07) than in the control subjects (0.98, 0.60-1.36; p<0.01). This ratio was increased as a consequence of a decreased urinary excretion rate of the cortisone metabolite, THE. The present data indicate that a reduced activity of 11beta-HSD is a new mechanism contributing to the exaggerated sodium retention in patients with the NS.

  16. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed Central

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  17. ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3.

    PubMed

    Andrini, Olga; Keck, Mathilde; Briones, Rodolfo; Lourdel, Stéphane; Vargas-Poussou, Rosa; Teulon, Jacques

    2015-06-15

    The mutations in the CLCNKB gene encoding the ClC-Kb chloride channel are responsible for Bartter syndrome type 3, one of the four variants of Bartter syndrome in the genetically based nomenclature. All forms of Bartter syndrome are characterized by hypokalemia, metabolic alkalosis, and secondary hyperaldosteronism, but Bartter syndrome type 3 has the most heterogeneous presentation, extending from severe to very mild. A relatively large number of CLCNKB mutations have been reported, including gene deletions and nonsense or missense mutations. However, only 20 CLCNKB mutations have been functionally analyzed, due to technical difficulties regarding ClC-Kb functional expression in heterologous systems. This review provides an overview of recent progress in the functional consequences of CLCNKB mutations on ClC-Kb chloride channel activity. It has been observed that 1) all ClC-Kb mutants have an impaired expression at the membrane; and 2) a minority of the mutants combines reduced membrane expression with altered pH-dependent channel gating. Although further investigation is needed to fully characterize disease pathogenesis, Bartter syndrome type 3 probably belongs to the large family of conformational diseases, in which the mutations destabilize channel structure, inducing ClC-Kb retention in the endoplasmic reticulum and accelerated channel degradation.

  18. Hypokalemic Paralysis Complicated by Concurrent Hyperthyroidism and Hyperaldosternoism: A Case Report

    PubMed Central

    Hsiao, Yu-Hsin; Fang, Yu-Wei; Leu, Jyh-Gang; Tsai, Ming-Hsien

    2017-01-01

    Patient: Female, 38 Final Diagnosis: Primary hyperaldosteronism Symptoms: Paralysis Medication: — Clinical Procedure: — Specialty: Nephrology Objective: Challenging differential diagnosis Background: Thyrotoxic periodic paralysis (TPP) is commonly observed in patients with acute paralysis and hyperthyroidism. However, there is a possibility of secondary causes of hypokalemia in such a setting. Case Report: Herein, we present the case of a 38-year-old woman with untreated hypertension and hyperthyroidism. She presented with muscle weakness, nausea, vomiting, and diarrhea since one week. The initial diagnosis was TPP. However, biochemistry tests showed hypokalemia with metabolic alkalosis and renal potassium wasting. Moreover, a suppressed plasma renin level and a high plasma aldosterone level were noted, which was suggestive of primary aldosteronism. Abdominal computed tomography confirmed this diagnosis. Conclusions: Therefore, it is imperative to consider other causes of hypokalemia (apart from TPP) in a patient with hyper-thyroidism but with renal potassium wasting and metabolic alkalosis. This can help avoid delay in diagnosis of the underlying disease. PMID:28050008

  19. "Bartter-like" phenotype in Kearns-Sayre syndrome.

    PubMed

    Emma, Francesco; Pizzini, Carla; Tessa, Alessandra; Di Giandomenico, Silvia; Onetti-Muda, Andrea; Santorelli, Filippo M; Bertini, Enrico; Rizzoni, Gianfranco

    2006-03-01

    Kearns-Sayre syndrome (KSS) is a mitochondrial disease caused by large deletions in mitochondrial DNA (mtDNA). In most patients the disease is characterized by mtDNA heteroplasmy, where a mixture of wild-type and mutated mtDNA co-exist within cells in variable proportion, modulating the severity of the phenotype in different tissues. We report on the case of a 14-year-old child with classical symptoms of KSS and a renal phenotype characterized by hypokalaemic alkalosis, hypomagnesaemia, hyperreninaemia, hyperaldosteronism and nephrocalcinosis, resembling Bartter syndrome. Analysis of mtDNA demonstrated an 8,661 bp deletion involving eight mitochondrial genes. Uneven degrees of mtDNA heteroplasmy were demonstrated in several tissues, ranging from 24% to 60% of deleted/total mtDNA. Variable degrees of expression of mitochondrial enzymes were also found in biopsy specimens of renal and skeletal muscle by histocytochemistry. In particular, preserved cytochrome c oxidase was observed in tubular structures within medullary rays. It is proposed that a "Bartter-like" phenotype can arise in some patients with KSS as a result of heteroplasmy. In these cases aldosterone-responsive tubular structures have been spared during renal embryogenesis, allowing for the development of hypokalaemic alkalosis in response to salt and water losses from the more damaged tubular segments.

  20. Novel Therapeutic Strategies for Reducing Right Heart Failure Associated Mortality in Fibrotic Lung Diseases.

    PubMed

    Adegunsoye, Ayodeji; Levy, Matthew; Oyenuga, Olusegun

    2015-01-01

    Fibrotic lung diseases carry a significant mortality burden worldwide. A large proportion of these deaths are due to right heart failure and pulmonary hypertension. Underlying contributory factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-β, and elevated systemic NO levels. Specific therapies targeting pulmonary hypertension include calcium channel blockers, endothelin (ET-1) receptor antagonists, prostacyclin analogs, phosphodiesterase type 5 (PDE5) inhibitors, and rho-kinase (ROCK) inhibitors. Newer antifibrotic and anti-inflammatory agents may exert beneficial effects on heart failure in idiopathic pulmonary fibrosis. Furthermore, right ventricle-targeted therapies, aimed at mitigating the effects of functional right ventricular failure, include β-adrenoceptor (β-AR) blockers, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, modulators of metabolism, and 5-hydroxytryptamine-2B (5-HT2B) receptor antagonists. Newer nonpharmacologic modalities for right ventricular support are increasingly being implemented. Early, effective, and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life.

  1. Regulation of aldosterone secretion by Cav1.3

    PubMed Central

    Xie, Catherine B.; Haris Shaikh, Lalarukh; Garg, Sumedha; Tanriver, Gizem; Teo, Ada E. D.; Zhou, Junhua; Maniero, Carmela; Zhao, Wanfeng; Kang, Soosung; Silverman, Richard B.; Azizan, Elena A. B.; Brown, Morris J.

    2016-01-01

    Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, CaV1.2, over CaV1.3. In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 μM of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 μM). Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3. PMID:27098837

  2. Case Report: A case report of acromegaly associated with primary aldosteronism

    PubMed Central

    Matrozova, Joanna; Vandeva, Silvia; Zacharieva, Sabina

    2014-01-01

    We describe a patient with a rare combination of acromegaly and primary aldosteronism. A 37 year-old female patient was diagnosed with acromegaly on the basis of typical clinical, hormonal and image characteristics. She presented also with one of the most common co-morbidities – arterial hypertension. The patient has been regularly followed-up and after three surgical interventions, irradiation and adjuvant treatment with a dopamine agonist, acromegaly was finally controlled in 2008 (20 years after diagnosis). Arterial hypertension however, remained a therapeutic problem even after prescription of four antihypertensive drugs. She had normal biochemical parameters, except for low potassium levels 3.2 (3.5-5.6) mmol/l. This raised the suspicion of primary hyperaldosteronism, confirmed by a high aldosterone to plasma rennin activity ratio, high aldosterone level after a Captopril challenge test and visualization of a 35 mm left adrenal nodule on a CT scan. After an operation, the patient recovered from hypokalemia and antihypertensive therapy was reduced to a small dose of a Ca blocker. Co-morbid arterial hypertension is common in acromegaly, though it is rare for this to be caused by Conn’s adenoma. The association of Conn’s adenoma with acromegaly has been interpreted in two lines: as a component of multiple endocrine neoplasia type (MEN1) syndrome or as a direct mitogenic effect of hyperactivated GH-IGF1 axis. PMID:25210615

  3. Aldosterone, Parathyroid Hormone, and the Use of Renin-Angiotensin-Aldosterone System Inhibitors: The Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Brown, Jenifer; de Boer, Ian H.; Robinson-Cohen, Cassianne; Siscovick, David S.; Kestenbaum, Bryan; Allison, Matthew

    2015-01-01

    Context: Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed. Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort. Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements. Outcome: Serum PTH concentration. Results: Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = −2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication. Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration

  4. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  5. HUMAN INTERVENTIONS TO CHARACTERIZE NOVEL RELATIONSHIPS BETWEEN THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND PARATHYROID HORMONE

    PubMed Central

    Brown, Jenifer M.; Williams, Jonathan S.; Luther, James M.; Garg, Rajesh; Garza, Amanda E.; Pojoga, Luminita H.; Ruan, Daniel T.; Williams, Gordon H.; Adler, Gail K.; Vaidya, Anand

    2014-01-01

    Observational studies in primary hyperaldosteronism (PA) suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiologic relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without PA. PTH was measured before and after: Study 1) low-dose angiotensin II [AngII] infusion (1 ng/kg/min) and captopril administration (25 mg × 1); Study 2) high-dose AngII infusion (3 ng/kg/min); Study 3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg/hr) and vehicle; and Study 4) blinded randomization to spironolactone (50mg/daily) or placebo for 6 weeks. Infusion of AngII at 1 ng/kg/min acutely increased aldosterone (+148%) and PTH (+10.3%), while AngII at 3 ng/kg/min induced larger incremental changes in aldosterone (+241%) and PTH (+36%) (P<0.01). Captopril acutely decreased aldosterone (−12%) and PTH (−9.7%) (P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy over 6 weeks modestly lowered PTH when compared to placebo (P<0.05). In vitro studies revealed the presence of AngII type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without PA: the acute modulation of PTH by the RAAS appears to be mediated by AngII, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted. PMID:24191286

  6. Effect of aldosterone-producing adenoma on endothelial function and Rho-associated kinase activity in patients with primary aldosteronism.

    PubMed

    Matsumoto, Takeshi; Oki, Kenji; Kajikawa, Masato; Nakashima, Ayumu; Maruhashi, Tatsuya; Iwamoto, Yumiko; Iwamoto, Akimichi; Oda, Nozomu; Hidaka, Takayuki; Kihara, Yasuki; Kohno, Nobuoki; Chayama, Kazuaki; Goto, Chikara; Aibara, Yoshiki; Noma, Kensuke; Liao, James K; Higashi, Yukihito

    2015-04-01

    The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure-matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P<0.05, respectively), whereas there was no significant difference in FMD between the IHA and EHT groups. There was no significant difference in nitroglycerine-induced vasodilation in the 3 groups. ROCK activity was higher in the APA group than in the IHA and EHT groups (1.29±0.57 versus 1.00±0.46 and 0.81±0.36l; P<0.05, respectively), whereas there was no significant difference in ROCK activity between the IHA and EHT groups. FMD correlated with age (r=-0.31; P<0.01), plasma aldosterone concentration (r=-0.35; P<0.01), and aldosterone:renin ratio (r=-0.34; P<0.01). ROCK activity correlated with age (r=-0.24; P=0.04), plasma aldosterone concentration (r=0.33; P<0.01), and aldosterone:renin ratio (r=0.46; P<0.01). After adrenalectomy, FMD and ROCK activity were restored in patients with APA. APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EHT. APA may have a higher risk of future cardiovascular events.

  7. Role of the T-type calcium channel CaV3.2 in the chronotropic action of corticosteroids in isolated rat ventricular myocytes.

    PubMed

    Maturana, Andrés; Lenglet, Sébastien; Python, Magaly; Kuroda, Shun'ichi; Rossier, Michel F

    2009-08-01

    The mineralocorticoid receptor is involved in the development of several cardiac dysfunctions, including lethal ventricular arrhythmias associated with heart failure or hyperaldosteronism, but the molecular mechanisms responsible for these effects remain to be clarified. Reexpression of low voltage-activated T-type calcium channels in ventricular myocytes together with other fetal genes during cardiac pathologies could confer automaticity to these cells and would represent a pro-arrhythmogenic condition if occurring in vivo. In the present study, we demonstrated that in isolated neonatal rat ventricular myocytes, corticosteroids selectively induced the expression of a particular isoform of T channel, Ca(V)3.2/alpha1H. This response was accompanied by an increase of the Ca(V)3.2 T-type current, identified with the patch clamp technique by its sensitivity to nickel, and a concomitant acceleration of the myocyte spontaneous contractions. Silencing Ca(V)3.2 expression markedly reduced the chronotropic response to steroids. Moreover, modulation of the frequency of cell contractions by different redox agents was independent of channel expression but involved a direct regulation of channel activity. Although oxidants increased both Ca(V)3.2 current amplitude and beating frequency, they decreased L-type channel activity. Reducing agents had the opposite effect on these parameters. In conclusion, the acceleration of ventricular myocyte spontaneous contractions induced by corticosteroids in vitro appears dependent on the expression of the Ca(V)3.2 T channel isoform and modulated by the redox potential of the cells. These results provide a molecular model that could explain the high incidence of arrhythmias observed in patients upon combination of inappropriate activation of the mineralocorticoid receptor and oxidative stress.

  8. Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor

    PubMed Central

    2017-01-01

    Abstract Significance: Soluble guanylyl cyclase (sGC), which produces the second messenger cyclic guanosine 3′, 5′-monophosphate (cGMP), is at the crossroads of nitric oxide (NO) signaling: sGC catalytic activity is both stimulated by NO binding to the heme and inhibited by NO modification of its cysteine (Cys) thiols (S-nitrosation). Modulation of sGC activity by thiol oxidation makes sGC a therapeutic target for pathologies originating from oxidative or nitrosative stress. sGC has an unusually high percentage of Cys for a cytosolic protein, the majority solvent exposed and therefore accessible modulatory targets for biological and pathophysiological signaling. Recent Advances: Thiol oxidation of sGC contributes to the development of cardiovascular diseases by decreasing NO-dependent cGMP production and thereby vascular reactivity. This thiol-based resistance to NO (e.g., increase in peripheral resistance) is observed in hypertension and hyperaldosteronism. Critical Issues: Some roles of specific Cys thiols have been identified in vitro. So far, it has not been possible to pinpoint the roles of specific Cys of sGC in vivo and to investigate the molecular mechanisms in an animal model. Future Directions: The role of Cys as redox sensors, intermediates of activation, and mediators of change in sGC conformation, activity, and dimerization remains largely unexplored. To understand modulation of sGC activity, it is critical to investigate the roles of specific oxidative thiol modifications that are formed during these processes. Where the redox state of sGC thiols contribute to pathologies (vascular resistance and sGC desensitization by NO donors), it becomes crucial to design therapeutic strategies to restore sGC to its normal, physiological thiol redox state. Antioxid. Redox Signal. 26, 137–149. PMID:26906466

  9. Aldosterone Increases Oxidant Stress to Impair Guanylyl Cyclase Activity by Cysteinyl Thiol Oxidation in Vascular Smooth Muscle Cells*S⃞

    PubMed Central

    Maron, Bradley A.; Zhang, Ying-Yi; Handy, Diane E.; Beuve, Annie; Tang, Shiow-Shih; Loscalzo, Joseph; Leopold, Jane A.

    2009-01-01

    Hyperaldosteronism is associated with impaired endothelium-dependent vascular reactivity owing to increased reactive oxygen species and decreased bioavailable nitric oxide (NO·); however, the effects of aldosterone on vasodilatory signaling pathways in vascular smooth muscle cells (VSMC) remain unknown. Soluble guanylyl cyclase (GC) is a heterodimer that is activated by NO· to convert cytosolic GTP to cGMP, a second messenger required for normal VSMC relaxation. Here, we show that aldosterone (10-9-10-7 mol/liter) diminishes GC activity by activating NADPH oxidase in bovine aortic VSMC to increase reactive oxygen species levels and induce oxidative posttranslational modification(s) of Cys-122, a β1-subunit cysteinyl residue demonstrated previously to modulate NO· sensing by GC. In VSMC treated with aldosterone, Western immunoblotting detected evidence of GC β1-subunit disulfide bonding, whereas mass spectrometry analysis of a homologous peptide containing the Cys-122-bearing sequence exposed to conditions of increased oxidant stress confirmed cysteinyl sulfinic acid (m/z 435), sulfonic acid (m/z 443), and disulfide (m/z 836) bond formation. The functional effect of these modifications was examined by transfecting COS-7 cells with wild-type GC or mutant GC containing an alanine substitution at Cys-122 (C122A). Exposure to aldosterone or hydrogen peroxide (H2O2) significantly decreased cGMP levels in cells expressing wild-type GC. In contrast, aldosterone or H2O2 did not influence cGMP levels in cells expressing the mutant C122A GC, confirming that oxidative modification of Cys-122 specifically impairs GC activity. These findings demonstrate that pathophysiologically relevant concentrations of aldosterone increase oxidant stress to convert GC to an NO·-insensitive state, resulting in disruption of normal vasodilatory signaling pathways in VSMC. PMID:19141618

  10. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    PubMed Central

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  11. Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension

    PubMed Central

    Maron, Bradley A.; Zhang, Ying-Yi; White, Kevin; Chan, Stephen Y.; Handy, Diane E.; Mahoney, Christopher E.; Loscalzo, Joseph; Leopold, Jane A.

    2012-01-01

    Background Pulmonary arterial hypertension (PAH) is characterized, in part, by decreased endothelial nitric oxide (NO•) production and elevated levels of endothelin-1. Endothelin-1 is known to stimulate endothelial nitric oxide synthase (eNOS) via the endothelin-B receptor (ETB), suggesting that this signaling pathway is perturbed in PAH. Endothelin-1 also stimulates adrenal aldosterone synthesis; in systemic blood vessels, hyperaldosteronism induces vascular dysfunction by increasing endothelial reactive oxygen species (ROS) generation and decreasing NO• levels. We hypothesized that aldosterone modulates PAH by disrupting ETB-eNOS signaling through a mechanism involving increased pulmonary endothelial oxidant stress. Methods and Results In rats with PAH, elevated endothelin-1 levels were associated with elevated aldosterone levels in plasma and lung tissue and decreased lung NO• metabolites in the absence of left heart failure. In human pulmonary artery endothelial cells (HPAECs), endothelin-1 increased aldosterone levels via PGC-1α/steroidogenesis factor-1-dependent upregulation of aldosterone synthase. Aldosterone also increased ROS production, which oxidatively modified cysteinyl thiols in the eNOS-activating region of ETB to decrease endothelin-1-stimulated eNOS activity. Substitution of ETB-Cys405 with alanine improved ETB-dependent NO• synthesis under conditions of oxidant stress, confirming that Cys405 is a redox sensitive thiol that is necessary for ETB-eNOS signaling. In HPAECs, mineralocorticoid receptor antagonism with spironolactone decreased aldosterone-mediated ROS generation and restored ETB-dependent NO• production. Spironolactone or eplerenone prevented or reversed pulmonary vascular remodeling and improved cardiopulmonary hemodynamics in two animal models of PAH in vivo. Conclusions Our findings demonstrate that aldosterone modulates an ETB cysteinyl thiol redox switch to decrease pulmonary endothelium-derived NO• and promote PAH

  12. Analysis of insulin sensitivity in adipose tissue of patients with primary aldosteronism.

    PubMed

    Urbanet, Riccardo; Pilon, Catia; Calcagno, Alessandra; Peschechera, Alessandro; Hubert, Edwige-Ludiwyne; Giacchetti, Gilberta; Gomez-Sanchez, Celso; Mulatero, Paolo; Toffanin, Mariacristina; Sonino, Nicoletta; Zennaro, Maria-Christina; Giorgino, Francesco; Vettor, Roberto; Fallo, Francesco

    2010-08-01

    The objective of the study was to assess the effect of high aldosterone levels on insulin sensitivity of adipose tissue in humans. Visceral adipose tissue (VAT) was obtained from patients with aldosterone-producing adenoma (APA; n=14) and, as controls, nonfunctioning adenoma (NFA; n=14) undergoing laparoscopic adrenalectomy. Homeostasis model assessment index was higher and potassium was lower in APA than NFA (P<0.05). Immunohistochemistry, Western blotting, and real-time PCR were used to detect and quantify mineralocorticoid receptor (MR) expression. Transcript levels of peroxisome proliferative-activated receptor-gamma, insulin receptor, glucose transporter 4, insulin receptor substrate-1 and -2, leptin, adiponectin, IL-6, monocyte chemoattractant protein-1, glucocorticoid receptor (GR)-alpha, 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1, and HSD11B2 were quantified. The effect of increasing aldosterone concentrations on 2-deoxy-[3H]d-glucose uptake was tested in human sc abdominal adipocytes. Expression of MR was demonstrated in VAT, with no difference between APA and NFA as to mRNA levels of MR, GRalpha, HSD11B1, and glucose metabolism and inflammation factors. In cultured adipocytes, basal and insulin-stimulated glucose uptake were unaffected by 1-100 nM (normal/hyperaldosteronism) and impaired only by much higher, up to 10 microM, aldosterone concentrations. The impairment was prevented by RU486 but not by eplerenone. Gene expression of insulin signaling/inflammatory molecules was similar in VAT of APA and NFA patients, not supporting an effect of aldosterone excess on insulin sensitivity of adipose tissues. Only at pharmacological concentrations and through GR activation, aldosterone reduced glucose uptake in adipocytes. Insulin resistance in primary aldosteronism might occur in compartments other than fat and/or depend on concurrent environmental factors.

  13. Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells Both In Vitro and In Vivo

    PubMed Central

    Oteiza, Patricia I.; Link, Samuel; Hey, Valentin; Stopper, Helga; Schupp, Nicole

    2014-01-01

    Abstract Aims: An increased kidney cancer risk was found in hypertensive patients, who frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. The capacity of kidney cells to up-regulate transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2), a key regulator of the cellular antioxidative defense, as a prevention of aldosterone-induced oxidative damage was investigated both in vitro and in vivo. Results: Aldosterone activated Nrf2 and increased the expression of enzymes involved in glutathione (GSH) synthesis and detoxification. This activation depended on the mineralocorticoid receptor (MR) and oxidative stress. In vitro, Nrf2 activation, GSH amounts, and target gene levels decreased after 24 h, while oxidant levels remained high. Nrf2 activation could not protect cells against oxidative DNA damage, as aldosterone-induced double-strand breaks and 7,8-dihydro-8-oxo-guanine (8-oxodG) lesions steadily rose. The Nrf2 activator sulforaphane enhanced the Nrf2 response both in vitro and in vivo, thereby preventing aldosterone-induced DNA damage. In vivo, Nrf2 activation further had beneficial effects on the aldosterone-caused blood pressure increase and loss of kidney function. Innovation: This is the first study showing the activation of Nrf2 by aldosterone. Moreover, the results identify sulforaphane as a substance that is capable of preventing aldosterone-induced damage both in vivo and in vitro. Conclusion: Aldosterone-induced Nrf2 adaptive response cannot neutralize oxidative actions of chronically increased aldosterone, which, therefore could be causally involved in the increased cancer incidence of hypertensive individuals. Enhancing the cellular antioxidative defense with sulforaphane might exhibit beneficial effects. Antioxid. Redox Signal. 21, 2126–2142. PMID:24512358

  14. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis.

    PubMed

    Brilla, C G; Weber, K T

    1992-12-01

    Unlike the non-renin-dependent hypertension associated with infrarenal aorta banding, an abnormal accumulation of fibrillar collagen occurs within the adventitia of intramural coronary arteries and neighboring interstitial space of the left and right ventricles in arterial hypertension associated with primary or secondary hyperaldosteronism. Based on these findings it was suggested that this interstitial and perivascular fibrosis was mediated by mineralocorticoid excess (i.e., elevated plasma aldosterone relative to dietary sodium) and not ventricular loading. To further address the importance of mineralocorticoid excess, we examined the fibrous tissue response after 8 weeks in the following uninephrectomized rat groups receiving a high-sodium diet: D-aldosterone (ALDO) infusion (0.75 micrograms/hr sc, n = 16); deoxycorticosterone acetate (DOCA) administration (100 mg/kg/wk sc, n = 8); and administration of a mineralocorticoid-like substance, glycyrrhizic acid (GA; 1 gm kg/wk sc, n = 8). Compared with ALDO infusion and sodium deprivation (n = 9), untreated controls (n = 14), and uninephrectomized rats with high dietary sodium and no mineralocorticoid administration (n = 15), we found (1) hypertension and left ventricular hypertrophy with all forms of mineralocorticoid excess; (2) a rise in collagen volume fraction with ALDO, and an increase in perivascular collagen with DOCA; and (3) no observance of myocardial fibrosis with GA or experimental controls, including ALDO infusion and sodium deprivation. Thus, in the presence of enhanced sodium intake, chronic administration of ALDO or DOCA are associated with collagen accumulation in the myocardium, whereas with the mineralocorticoid-like compound GA, myocardial fibrosis was not seen.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer

    PubMed Central

    Danila, Daniel C.; Morris, Michael J.; de Bono, Johann S.; Ryan, Charles J.; Denmeade, Samuel R.; Smith, Matthew R.; Taplin, Mary-Ellen; Bubley, Glenn J.; Kheoh, Thian; Haqq, Christopher; Molina, Arturo; Anand, Aseem; Koscuiszka, Michael; Larson, Steve M.; Schwartz, Lawrence H.; Fleisher, Martin; Scher, Howard I.

    2010-01-01

    Purpose Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. Patients and Methods Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was ≥ 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. Results A ≥ 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from ≥ 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. Conclusion AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations. PMID:20159814

  16. [A clinical analysis of reninoma-induced hypertensive crisis associated with reversible posterior encephalopathy syndrome].

    PubMed

    Wu, Hong-hua; Wang, Guang-ya; Ma, Xiao-wei; Guo, Xiao-hui

    2012-01-01

    Reninoma is a rare benign tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia via hypersecretion of renin, while it is extremely rare that reninoma induced hypertensive crisis with reversible posterior encephalopathy syndrome (RPES). To improve the clinical understanding for this disease, we conducted a case-analysis. To analyze the clinical and pathological data of a case of reninoma-induced hypertensive crisis with reversible posterior encephalopathy syndrome, who was admitted to Peking University First Hospital in November, 2007 and follow-up. This was a 16-year old female patient, onset with suddenly spasm with loss of consciousness, while blood pressure stepped up to 210/140 mm Hg (1 mm Hg = 0.133 kPa), and the head magnetic resonance imaging (MRI) revealed "multiple long-T(2) signal", and hypokalemia (2.8 - 3.2 mmol/L), urine protein positive, ultrasound cardiogram revealed left ventricular hypertrophy, laboratory study revealed hyperreninism (38.23 ng·ml(-1)×h(-1), normal range 0.07 - 1.15 ng·ml(-1)×h(-1)) and hyperaldosteronism (660.9 ng/L, normal range 60 - 174 ng/L), abdominal CT-Scan revealed a mass at right kidney, blood pressure achieved safety range and the head MRI was rechecked and revealed "the abnormal long-T(2) signal disappeared". The clinical diagnosis was reninoma induced hypertensive crisis with RPES. The tumor was resected and the pathologic diagnosis was reninoma. The patient remained normotensive in the postoperative period without any medication. Reninoma represents a rare but surgically curable cause of hypertension, thus the clinical suspicion of it is very important in young patients. If the diagnosis is confirmed, positive treatment must be done immediately to improve the prognosis. The most common cause of RPES is hypertension, and the diagnosis depends on the distinctive head MRI. There is always a good prognosis with the decline of blood pressure rapidly.

  17. Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1*

    PubMed Central

    Amazit, Larbi; Le Billan, Florian; Kolkhof, Peter; Lamribet, Khadija; Viengchareun, Say; Fay, Michel R.; Khan, Junaid A.; Hillisch, Alexander; Lombès, Marc; Rafestin-Oblin, Marie-Edith; Fagart, Jérôme

    2015-01-01

    Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist. PMID:26203193

  18. Activation of mTORC1 in collecting ducts causes hyperkalemia.

    PubMed

    Chen, Zhenguo; Dong, Heling; Jia, Chunhong; Song, Qiancheng; Chen, Juan; Zhang, Yue; Lai, Pinglin; Fan, Xiaorong; Zhou, Xuan; Liu, Miao; Lin, Jun; Yang, Cuilan; Li, Ming; Gao, Tianming; Bai, Xiaochun

    2014-03-01

    Mutation of TSC (encoding tuberous sclerosis complex protein) and activation of mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of several renal diseases, such as diabetic nephropathy and polycystic kidney disease. However, the role of mTOR in renal potassium excretion and hyperkalemia is not known. We showed that mice with collecting-duct (CD)-specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) activation in the CD and demonstrated features of pseudohypoaldosteronism, including hyperkalemia, hyperaldosteronism, and metabolic acidosis. mTORC1 activation caused endoplasmic reticulum stress, columnar cell lesions, and dedifferentiation of CD cells with loss of aquaporin-2 and epithelial-mesenchymal transition-like phenotypes. Of note, mTORC1 activation also reduced the expression of serum- and glucocorticoid-inducible kinase 1, a crucial regulator of potassium homeostasis in the kidney, and decreased the expression and/or activity of epithelial sodium channel-α, renal outer medullary potassium channel, and Na(+), K(+)-ATPase in the CD, which probably contributed to the aldosterone resistance and hyperkalemia in these mice. Rapamycin restored these phenotypic changes. Overall, this study identifies a novel function of mTORC1 in regulating potassium homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiation and dysfunction of the CD and causes hyperkalemia. The CDTsc1KO mice provide a novel model for hyperkalemia induced exclusively by dysfunction of the CD.

  19. Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications.

    PubMed

    Salpietro, Vincenzo; Polizzi, Agata; Di Rosa, Gabriella; Romeo, Anna Claudia; Dipasquale, Valeria; Morabito, Paolo; Chirico, Valeria; Arrigo, Teresa; Ruggieri, Martino

    2014-01-01

    Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal

  20. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients.

    PubMed

    Rossi, Gian Paolo; Bernini, Giampaolo; Caliumi, Chiara; Desideri, Giovambattista; Fabris, Bruno; Ferri, Claudio; Ganzaroli, Chiara; Giacchetti, Gilberta; Letizia, Claudio; Maccario, Mauro; Mallamaci, Francesca; Mannelli, Massimo; Mattarello, Mee-Jung; Moretti, Angelica; Palumbo, Gaetana; Parenti, Gabriele; Porteri, Enzo; Semplicini, Andrea; Rizzoni, Damiano; Rossi, Ermanno; Boscaro, Marco; Pessina, Achille Cesare; Mantero, Franco

    2006-12-05

    We prospectively investigated the prevalence of curable forms of primary aldosteronism (PA) in newly diagnosed hypertensive patients. The prevalence of curable forms of PA is currently unknown, although retrospective data suggest that it is not as low as commonly perceived. Consecutive hypertensive patients referred to 14 hypertension centers underwent a diagnostic protocol composed of measurement of Na+ and K+ in serum and 24-h urine, sitting plasma renin activity, and aldosterone at baseline and after 50 mg captopril. The patients with an aldosterone/renin ratio >40 at baseline, and/or >30 after captopril, and/or a probability of PA (by a logistic discriminant function) > or =50% underwent imaging tests and adrenal vein sampling (AVS) or adrenocortical scintigraphy to identify the underlying adrenal pathology. An aldosterone-producing adenoma (APA) was diagnosed in patients who in addition to excess autonomous aldosterone secretion showed: 1) lateralized aldosterone secretion at AVS or adrenocortical scintigraphy, 2) adenoma at surgery and pathology, and 3) a blood pressure decrease after adrenalectomy. Evidence of excess autonomous aldosterone secretion without such criteria led to a diagnosis of idiopathic hyperaldosteronism (IHA). A total of 1,180 patients (age 46 +/- 12 years) were enrolled; a conclusive diagnosis was attained in 1,125 (95.3%). Of these, 54 (4.8%) had an APA and 72 (6.4%) had an IHA. There were more APA (62.5%) and fewer IHA cases (37.5%) at centers where AVS was available (p = 0.002); the opposite occurred where AVS was unavailable. In newly diagnosed hypertensive patients referred to hypertension centers, the prevalence of APA is high (4.8%). The availability of AVS is essential for an accurate identification of the adrenocortical pathologies underlying PA.

  1. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes.

    PubMed

    Queisser, Nina; Happ, Kathrin; Link, Samuel; Jahn, Daniel; Zimnol, Anna; Geier, Andreas; Schupp, Nicole

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague-Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased.

  2. Adrenal Disorders and the Paediatric Brain: Pathophysiological Considerations and Clinical Implications

    PubMed Central

    Polizzi, Agata; Di Rosa, Gabriella; Romeo, Anna Claudia; Dipasquale, Valeria; Chirico, Valeria; Arrigo, Teresa; Ruggieri, Martino

    2014-01-01

    Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal

  3. Comparison of 24-h urinary aldosterone level and random urinary aldosterone-to-creatinine ratio in the diagnosis of primary aldosteronism.

    PubMed

    Wu, Che-Hsiung; Yang, Ya-Wen; Hu, Ya-Hui; Tsai, Yao-Chou; Kuo, Ko-Lin; Lin, Yen-Hung; Hung, Szu-Chun; Wu, Vin-Cent; Wu, Kwan-Dun

    2013-01-01

    Historically, urinary aldosterone level measurement was a commonly employed confirmatory test to detect primary aldosteronism (PA). However, 24-h urine collection is inconvenient and cumbersome. We hypothesized that random urinary aldosterone measurements with correction for creatinine concentration might be comparable to 24-h urinary aldosterone levels (Uald-24 h) in the diagnosis of PA. The non-concurrent prospective study was conducted between June 2006 and March 2008 in patients admitted for confirmation of aldosteronism by salt loading test. A 24-h urine sample, which was collected during hospitalization on the day before saline infusion testing after restoration of serum hypokalemia, was collected from all subjects. Moreover, participants were asked to collect a first bladder voiding random urine sample during clinic visits. Uald-24 h and the random urinary aldosterone-to-creatinine ratio (UACR) were calculated accordingly. A total of 102 PA patients (71 patients diagnosed of aldosterone-producing adenoma, 31 with idiopathic hyperaldosteronism) and 65 patients with EH were enrolled. The receiver operating characteristic curve showed comparable areas under the curves of UACR and Uald-24 h. The Bland-Altman plot showed mean bias but no obvious heteroscedasticity between the two tests. When using random UACR >3.0 ng/mg creatinine as the cutoff value, we obtained a specificity of 90.6% to confirm PA from essential hypertension. Our study reinforce that the diagnostic accuracy of random UACR was comparable to that of Uald-24 h in PA patients. With the quickness and simplicity of the UACR method and its equivalence to Uald-24 h, this assay could be a good alternative diagnostic tool for PA confirmation.

  4. LH, progesterone, and TSH can stimulate aldosterone in vitro: a study on normal adrenal cortex and aldosterone producing adenoma.

    PubMed

    Nicolini, G; Balzan, S; Morelli, L; Iacconi, P; Sabatino, L; Ripoli, A; Fommei, E

    2014-05-01

    Endocrine factors different from ACTH or angiotensin II can stimulate aldosterone secretion and have a role in the pathophysiology of hyperaldosteronism. Aldosterone may increase in luteotropic/progestogenic and in hypothyroid states; LH and, occasionally, TSH receptors have been detected in normal adrenal cortex and aldosterone-producing adenoma. The aim of the study was to compare adrenal contents of LH and TSH receptors between normal cortex and aldosterone-producing adenoma and to evaluate the ability of LH, its product progesterone, and TSH to stimulate aldosterone secretion in vitro from primary adrenocortical cells. Surgical aldosterone-producing adenoma fragments from 19 patients and adrenal cortex fragments from 10 kidney donors were used for Western blotting and cell cultures. LH (n=26), TSH (n=19) and progesterone (n=8) receptor proteins were investigated; LH receptor-mRNA was also tested in 8 samples. Aldosterone responses in vitro to LH, progesterone, and TSH stimulation were assayed. LH and TSH receptors were more expressed in adenoma than normal cortex (p<0.01, p<0.05, respectively); progesterone receptor was observed in 6/8 samples. Aldosterone increased after in vitro stimulation with LH (5/12 adenoma, 1/7 normal cells), progesterone (4/5 adenoma, 5/6 normal cells), and TSH (3/5 adenoma and 3/5 normal cells). LH and TSH receptors were more expressed in aldosterone producing adenoma than normal adrenal cortex. LH, progesterone, and TSH can stimulate aldosterone in vitro. Similar mechanisms could participate in vivo in the aldosterone increase in lutheotropic, progestogenic, or hypothyroid states and may exist in both normal adrenal cortex and adenoma in responsive individuals.

  5. Ultrasonographic measurements of adrenal glands in cats with hyperthyroidism.

    PubMed

    Combes, Anaïs; Vandermeulen, Eva; Duchateau, Luc; Peremans, Kathelijne; Daminet, Sylvie; Saunders, Jimmy

    2012-01-01

    Feline hyperthyroidism is potentially associated with exaggerated responsiveness of the adrenal gland cortex. The adrenal glands of 23 hyperthyroid cats were examined ultrasonographically and compared to the adrenal glands of 30 control cats. Ten hyperthyroid cats had received antithyroid drugs until 2 weeks before sonography, the other 13 were untreated. There was no difference in adrenal gland shape between healthy and hyperthyroid cats: bean-shaped, well-defined, hypoechoic structures surrounded by a hyperechoic halo in 43/60 (71.6%) healthy cats and 34/46 (73.9%) hyperthyroid cats; more ovoid in 13/60 (21.6%) healthy cats and 9/46 (19.6%) hyperthyroid cats while more elongated in 4/60 (6.7%) healthy cats, 3/46 (6.5%) hyperthyroid cats. Hyperechoic foci were present in 9/23 (39.1%) hyperthyroid cats and 2/30 (6.7%) healthy cats. The adrenal glands were significantly larger in hyperthyroid cats, although there was overlap in size range. The mean difference between hyperthyroid cats and healthy cats was 1.6 and 1.7 mm in left and right adrenal gland length, 0.8 and 0.9 mm in left and right cranial adrenal gland height, and 0.4 and 0.9 mm in left and right caudal adrenal gland height. There was no significant difference between the adrenal gland measurements in treated and untreated hyperthyroid cats. The adrenomegaly was most likely associated with the hypersecretion of the adrenal cortex documented in hyperthyroid cats. Hyperthyroidism should be an alternative to hyperadrenocorticism, hyperaldosteronism, and acromegaly in cats with bilateral moderate adrenomegaly.

  6. Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy.

    PubMed

    Li, Hai; Liu, Jianbin; Feng, Xiujuan; Liu, Liehua; Wei, Guohong; Cao, Xiaopei; Li, Yanbing

    2017-09-16

    To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = -0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = -0.251, 95% CI -0.040, -0.464, p = 0.042). Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization.

  7. Effectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials)

    PubMed Central

    Maron, Bradley A.; Waxman, Aaron B.; Opotowsky, Alexander R.; Gillies, Hunter; Blair, Christiana; Aghamohammadzadeh, Reza; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor—mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan D spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings. PMID:23751938

  8. Classification and surgical treatment for 180 cases of adrenocortical hyperplastic disease

    PubMed Central

    Zhang, Yushi; Li, Hanzhong

    2015-01-01

    Objective: To review and discuss the diagnostic and surgical therapeutic methods of adrenocortical hyperplastic disease. Methods: A retrospective analysis was done to 180 adrenocortical hyperplasia patients (74 males, 109 females, aged 6~76 (average 40.1). Studies were done to the relationship between patients’ clinical characteristics, biochemical, endocrinological and imaging examination results, the therapeutic effects. Results: Among all 180 cases, there are 107 Cushing disease (CD), 19 ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 28 adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 4 primary pigmented nodular adrenocortical hyperplasia (PPNAH), and 28 Idiopathic Hyperaldosteronism (IHA). Twenty-four-hour urinary free cortisol (24 h UFC) excretion of CD, EAAH, AIMAH and PPNAH patients were 95.2~535.7 µg (average 287.6 µg), 24.8~808.2 µg (average 307.9 µg), 102.5~3127.0 µg (average 852.5 µg), and 243.8~1124.6 µg (average 564.3 µg). Both low and high-dose dexamethasone suppression tests (DDST) were not suppressed in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. CT thin scanning results of 180 patients all showed enlargements in the affected side adrenal gland. Unilateral adrenalectomies were performed in 102 hypercortisolism cases. Local lesion excisions were done to 21 IHA patients. 57 patients had surgeries in both sides of the adrenal glands (39 bilateral total adrenalectomies, 16 total adrenalectomy in one side andsubtotal adrenalectomy in the other, 2 bilateral subtotal adrenalectomies). 106 (59%) patients were followed up for 4~158 (average 32) months. Conclusion: Unilateral adrenalectomy was the first choice for operable adrenocortical hyperplasia patients. The operation mode for the other adrenal gland should be based on the type of hyperplasia and clinical observation. PMID:26770569

  9. Repeated resections for liver metastasis from primary adrenocortical carcinoma: A case report

    PubMed Central

    Nakano, Ryosuke; Satoh, Daisuke; Nakajima, Hirochika; Yoshimura, Yuri; Miyoshi, Hisanobu; Yoshida, Kazuhiro; Matsukawa, Hiroyoshi; Shiozaki, Shigehiro; Ichimura, Kouichi; Okajima, Masazumi; Ninomiya, Motoki

    2015-01-01

    Introduction Adrenal cortical carcinoma (ACC) is a very rare type of tumor that generally has a poor prognosis. Little has been reported on repeated liver resections with recurrent metastasis still confined to the liver. In this report, we describe a case of functioning ACC in a 65-year-old woman with 2 liver metastases of the ACC (at 1.5 and 4 years) after the right adrenalectomy. Presentation of case A 65-year-old woman was referred to our hospital based on a suspicion of hyperaldosteronism. Abdominal computed tomography revealed a lesion at the right adrenal gland; therefore, we performed right adrenalectomy and subsequently diagnosed the lesion as ACC. However, follow-up computed tomography at 1.5 and 4 years after the right adrenalectomy revealed liver metastasis of ACC; liver resection was performed for both metastases. Discussion Complete surgical resection is the established approach for the treatment of ACC. The prognosis of ACC is usually dismal, and recurrence rates of up to 85% have been reported. However, the appropriate treatment for recurrent ACC is not well established, and the effectiveness of other modalities, such as chemotherapy and radiotherapy, is not proven. Therefore, surgical resection may currently be the most appropriate treatment modality, as the patient achieved a disease-free interval of 2.5 years after the first liver resection. Conclusion In selected patients with recurrent or metastatic ACC, resection is likely to be associated with prolonged survival. However, a full cure is generally not achievable, and a multidisciplinary approach is likely needed to achieve long-term disease-free status and survival. PMID:25765741

  10. Genetic variations in the KCNJ5 gene in primary aldosteronism patients from Xinjiang, China.

    PubMed

    Li, Nan-Fang; Li, Hong-Jian; Zhang, De-Lian; Zhang, Ju-Hong; Yao, Xiao-Guang; Wang, Hong-Mei; Abulikemu, Suofeiya; Zhou, Ke-Ming; Zhang, Xiang-Yang

    2013-01-01

    Primary aldosteronism (PA) is the most common endocrine form of secondary hypertension, and one of the most common subtypes of sporadic PA is aldosterone-producing adenoma (APA). Recently, two somatic mutations of the KCNJ5 gene were implicated in APA, and two germline mutations were associated with familial hyperaldosteronism III. This case-control study was designed to investigate the relationship between genetic variations in the KCNJ5 gene and sporadic PA patients in Xinjiang, China. Five common single nucleotide polymorphisms (SNPs) of the KCNJ5 gene (rs6590357, rs4937391, rs3740835, rs2604204, and rs11221497) were detected in patients with sporadic PA (n = 235) and essential hypertension (EH; n=913) by the TaqMan polymerase chain reaction method. The EH group and the PA group showed significant differences in the distributions of genotypes and alleles of rs4937391 and rs2604204 in total and male subjects (P<0.05), as well as rs3740835 in male subjects (P<0.05). However, only the association between the rs2604204 genotype and male sporadic PA remained significant after Bonferroni's correction (P<0.01). Furthermore, logistic regression analysis demonstrated that the CC genotype of rs2604204 was a risk factor for male patients with sporadic PA, after adjusting for age and body mass index (odds ratio=2.228, 95% CI: 1.300-3.819, P=0.004). The genetic variant rs2604204 of KCNJ5 is associated with sporadic PA in Chinese males, suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in these particular patients.

  11. Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism.

    PubMed

    Sonoyama, Takuhiro; Sone, Masakatsu; Tamura, Naohisa; Honda, Kyoko; Taura, Daisuke; Kojima, Katsutoshi; Fukuda, Yorihide; Kanamoto, Naotetsu; Miura, Masako; Yasoda, Akihiro; Arai, Hiroshi; Itoh, Hiroshi; Nakao, Kazuwa

    2014-12-01

    We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900 h (PAC0900), 2300 h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients. © 2014 The authors.

  12. Body Mass Index Predicts 24-Hour Urinary Aldosterone Levels in Patients With Resistant Hypertension.

    PubMed

    Dudenbostel, Tanja; Ghazi, Lama; Liu, Mingchun; Li, Peng; Oparil, Suzanne; Calhoun, David A

    2016-10-01

    Prospective studies indicate that hyperaldosteronism is found in 20% of patients with resistant hypertension. A small number of observational studies in normotensive and hypertensive patients suggest a correlation between aldosterone levels and obesity while others could not confirm these findings. The correlation between aldosterone levels and body mass index (BMI) in patients with resistant hypertension has not been previously investigated. Our objective was to determine whether BMI is positively correlated with plasma aldosterone concentration, plasma renin activity, aldosterone:renin ratio, and 24-hour urinary aldosterone in black and white patients. We performed a cross-sectional analysis of a large diverse cohort (n=2170) with resistant hypertension. The relationship between plasma aldosterone concentration, plasma renin activity, aldosterone:renin ratio, 24-hour urinary aldosterone, and BMI was investigated for the entire cohort, by sex and race (65.3% white, 40.3% men). We demonstrate that plasma aldosterone concentration and aldosterone:renin ratio were significantly correlated to BMI (P<0.0001) across the first 3 quartiles, but not from the 3rd to 4th quartile of BMI. Plasma renin activity was not correlated with BMI. Twenty-four-hour urinary aldosterone was positively correlated across all quartiles of BMI for the cohort (P<0.0001) and when analyzed by sex (men P<0.0001; women P=0.0013) and race (P<0.05), and stronger for men compared with women (r=0.19, P<0.001 versus r=0.05, P=0.431, P=0.028) regardless of race. In both black and white patients, aldosterone levels were positively correlated to increasing BMI, with the correlation being more pronounced in black and white men. These findings suggest that obesity, particularly the abdominal obesity typical of men, contributes to excess aldosterone in patients with resistant hypertension. © 2016 American Heart Association, Inc.

  13. Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans

    PubMed Central

    Lu, Yingchang; Tao, Ran; Sung, Yun Ju; Manichaikul, Ani; Haessler, Jeff; Fornage, Myriam; Schwander, Karen; Zubair, Niha; Bien, Stephanie; Hindorff, Lucia A.; Guo, Xiuqing; Bielinski, Suzette J.; Ehret, Georg; Kaufman, Joel D.; Rich, Stephen S.; Carlson, Christopher S.; Bottinger, Erwin P.; North, Kari E.; Rao, D. C.; Chakravarti, Aravinda; Barrett, Paula Q.; Loos, Ruth J. F.; Buyske, Steven; Kooperberg, Charles

    2016-01-01

    Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10−9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans—populations that are understudied for hypertension genetic risk factors. PMID:27736895

  14. Differences Between Bilateral Adrenal Incidentalomas and Unilateral Lesions.

    PubMed

    Pasternak, Jesse D; Seib, Carolyn D; Seiser, Natalie; Tyrell, J Blake; Liu, Chienying; Cisco, Robin M; Gosnell, Jessica E; Shen, Wen T; Suh, Insoo; Duh, Quan-Yang

    2015-10-01

    Adrenal incidentalomas are found in 1% to 5% of abdominal cross-sectional imaging studies. Although the workup and management of unilateral lesions are well established, limited information exists for bilateral incidentalomas. To compare the natural history of patients having bilateral incidentalomas with those having unilateral incidentalomas. Retrospective analysis of a prospective database of consecutive patients referred to an academic multidisciplinary adrenal conference. The setting was a tertiary care university hospital among a cohort of 500 patients with adrenal lesions between July 1, 2009, and July 1, 2014. Prevalence, age, imaging characteristics, biochemical workup, any intervention, and final diagnosis. Twenty-three patients with bilateral incidentalomas and 112 patients with unilateral incidentalomas were identified. The mean age at diagnosis of bilateral lesions was 58.7 years. The mean lesion size was 2.4 cm on the right side and 2.8 cm on the left side. Bilateral incidentalomas were associated with a significantly higher prevalence of subclinical Cushing syndrome (21.7% [5 of 23] vs 6.2% [7 of 112]) (P = .009) and a significantly lower prevalence of pheochromocytoma (4.3% [1 of 23] vs 19.6% [22 of 112]) (P = .003) compared with unilateral lesions, while rates of hyperaldosteronism were similar in both groups (4.3% [1 of 23] vs 5.4% [6 of 112]) (P > .99). Only one patient with bilateral incidentalomas underwent unilateral resection. The mean follow-up was 4 years (range, 1.2-13.0 years). There were no occult adrenocortical carcinomas. Bilateral incidentalomas are more likely to be associated with subclinical Cushing syndrome and less likely to be pheochromocytomas. Although patients with bilateral incidentalomas undergo a workup similar to that in patients with unilateral lesions, differences in their natural history warrant a greater index of suspicion for subclinical Cushing syndrome.

  15. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

    PubMed Central

    Ishikawa, Kiyotake; Hadri, Lahouaria; Santos-Gallego, Carlos; Fish, Kenneth; Hammoudi, Nadjib; Chaanine, Antoine; Torquato, Samantha; Naim, Charbel; Ibanez, Borja; Pereda, Daniel; García-Alvarez, Ana; Fuster, Valentin; Sengupta, Partho P.; Leopold, Jane A.; Hajjar, Roger J.

    2014-01-01

    In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca2+-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism. PMID:25158063

  16. Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis.

    PubMed

    Huby, Anne-Cécile; Antonova, Galina; Groenendyk, Jake; Gomez-Sanchez, Celso E; Bollag, Wendy B; Filosa, Jessica A; Belin de Chantemèle, Eric J

    2015-12-01

    In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting

  17. PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues

    PubMed Central

    Felizola, Saulo J. A.; Nakamura, Yasuhiro; Ono, Yoshikiyo; Kitamura, Kanako; Kikuchi, Kumi; Onodera, Yoshiaki; Ise, Kazue; Takase, Kei; Sugawara, Akira; Hattangady, Namita; Rainey, William E.; Satoh, Fumitoshi; Sasano, Hironobu

    2014-01-01

    Purkinje cell protein 4 (PCP4) is a calmodulin (CaM) binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA) but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol producing adenomas (CPA; n=15) and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR (qPCR) of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa (ZG) of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than wild-type (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic and neoplastic human adrenocortical cells. PMID:24403568

  18. Galectin-3 Blockade Reduces Renal Fibrosis in Two Normotensive Experimental Models of Renal Damage

    PubMed Central

    Martinez-Martinez, Ernesto; Ibarrola, Jaime; Calvier, Laurent; Fernandez-Celis, Amaya; Leroy, Celine; Cachofeiro, Victoria; Rossignol, Patrick; Lopez-Andres, Natalia

    2016-01-01

    Background Galectin-3 (Gal-3), a β-galactoside-binding lectin, is increased in kidney injury and its pharmacological blockade reduces renal damage in acute kidney injury, hyperaldosteronism or hypertensive nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in early renal damage associated with obesity and aortic stenosis (AS). Results Gal-3 was upregulated in kidneys from high fat diet (HFD) rats and in animals with partial occlusion of ascending aorta (AS). Urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) and urinary albumin were enhanced in HFD and AS rats. In kidney from obese rats, fibrotic markers (collagen, TFG-β), epithelial-mesenchymal transition molecules (α-smooth muscle actin, E-cadherin), inflammatory mediator (osteopontin) and kidney injury marker (kidney injury molecule-1) were modified. In kidney from AS rats, fibrotic markers (collagen, CTGF), epithelial-mesenchymal transition molecules (fibronectin, α-smooth muscle actin, β-catenin, E-cadherin) and kidney injury markers (NGAL, kidney injury molecule-1) were altered. Histologic observations of obese and AS rat kidneys revealed tubulointerstitial fibrosis. The pharmacological inhibition of Gal-3 with MCP normalized renal Gal-3 levels as well as functional, histological and molecular alterations in obese and AS rats. Conclusions In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation and damage, while these alterations were prevented by Gal-3 blockade. These data suggest that Gal-3 could be a new player in renal molecular, histological and functional alterations at early stages of kidney damage. PMID:27829066

  19. Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease.

    PubMed

    Tomaschitz, Andreas; Ritz, Eberhard; Pieske, Burkert; Rus-Machan, Jutta; Kienreich, Katharina; Verheyen, Nicolas; Gaksch, Martin; Grübler, Martin; Fahrleitner-Pammer, Astrid; Mrak, Peter; Toplak, Hermann; Kraigher-Krainer, Elisabeth; März, Winfried; Pilz, Stefan

    2014-01-01

    Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. © 2013.

  20. Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor.

    PubMed

    Beuve, Annie

    2017-01-20

    Soluble guanylyl cyclase (sGC), which produces the second messenger cyclic guanosine 3', 5'-monophosphate (cGMP), is at the crossroads of nitric oxide (NO) signaling: sGC catalytic activity is both stimulated by NO binding to the heme and inhibited by NO modification of its cysteine (Cys) thiols (S-nitrosation). Modulation of sGC activity by thiol oxidation makes sGC a therapeutic target for pathologies originating from oxidative or nitrosative stress. sGC has an unusually high percentage of Cys for a cytosolic protein, the majority solvent exposed and therefore accessible modulatory targets for biological and pathophysiological signaling. Recent Advances: Thiol oxidation of sGC contributes to the development of cardiovascular diseases by decreasing NO-dependent cGMP production and thereby vascular reactivity. This thiol-based resistance to NO (e.g., increase in peripheral resistance) is observed in hypertension and hyperaldosteronism. Some roles of specific Cys thiols have been identified in vitro. So far, it has not been possible to pinpoint the roles of specific Cys of sGC in vivo and to investigate the molecular mechanisms in an animal model. The role of Cys as redox sensors, intermediates of activation, and mediators of change in sGC conformation, activity, and dimerization remains largely unexplored. To understand modulation of sGC activity, it is critical to investigate the roles of specific oxidative thiol modifications that are formed during these processes. Where the redox state of sGC thiols contribute to pathologies (vascular resistance and sGC desensitization by NO donors), it becomes crucial to design therapeutic strategies to restore sGC to its normal, physiological thiol redox state. Antioxid. Redox Signal. 26, 137-149.

  1. Syndromes that Mimic an Excess of Mineralocorticoids.

    PubMed

    Sabbadin, Chiara; Armanini, Decio

    2016-09-01

    Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of renin and aldosterone. It can be due to endogenous or exogenous substances that mimic the effector mechanisms of aldosterone, leading not only to alterations of electrolytes and hypertension, but also to an increased inflammatory reaction in several tissues. Enzymatic defects of adrenal steroidogenesis (deficiency of 17α-hydroxylase and 11β-hydroxylase), mutations of mineralocorticoid receptor (MR) and alterations of expression or saturation of 11-hydroxysteroid dehydrogenase type 2 (apparent mineralocorticoid excess syndrome, Cushing's syndrome, excessive intake of licorice, grapefruits or carbenoxolone) are the main causes of pseudohyperaldosteronism. In these cases treatment with dexamethasone and/or MR-blockers is useful not only to normalize blood pressure and electrolytes, but also to prevent the deleterious effects of prolonged over-activation of MR in epithelial and non-epithelial tissues. Genetic alterations of the sodium channel (Liddle's syndrome) or of the sodium-chloride co-transporter (Gordon's syndrome) cause abnormal sodium and water reabsorption in the distal renal tubules and hypertension. Treatment with amiloride and thiazide diuretics can respectively reverse the clinical picture and the renin aldosterone system. Finally, many other more common situations can lead to an acquired pseudohyperaldosteronism, like the expansion of volume due to exaggerated water and/or sodium intake, and the use of drugs, as contraceptives, corticosteroids, β-adrenergic agonists and FANS. In conclusion, syndromes or situations that mimic aldosterone excess are not rare and an accurate personal and pharmacological history is mandatory for a correct diagnosis and avoiding unnecessary tests and mistreatments.

  2. Acid-base disturbances in nephrotic syndrome: analysis using the CO2/HCO3 method (traditional Boston model) and the physicochemical method (Stewart model).

    PubMed

    Kasagi, Tomomichi; Imai, Hirokazu; Miura, Naoto; Suzuki, Keisuke; Yoshino, Masabumi; Nobata, Hironobu; Nagai, Takuhito; Banno, Shogo

    2017-03-13

    The Stewart model for analyzing acid-base disturbances emphasizes serum albumin levels, which are ignored in the traditional Boston model. We compared data derived using the Stewart model to those using the Boston model in patients with nephrotic syndrome. Twenty-nine patients with nephrotic syndrome and six patients without urinary protein or acid-base disturbances provided blood and urine samples for analysis that included routine biochemical and arterial blood gas tests, plasma renin activity, and aldosterone. The total concentration of non-volatile weak acids (ATOT), apparent strong ion difference (SIDa), effective strong ion difference (SIDe), and strong ion gap (SIG) were calculated according to the formulas of Agrafiotis in the Stewart model. According to the Boston model, 25 of 29 patients (90%) had alkalemia. Eighteen patients had respiratory alkalosis, 11 had metabolic alkalosis, and 4 had both conditions. Only three patients had hyperreninemic hyperaldosteronism. The Stewart model demonstrated respiratory alkalosis based on decreased PaCO2, metabolic alkalosis based on decreased ATOT, and metabolic acidosis based on decreased SIDa. We could diagnose metabolic alkalosis or acidosis with a normal anion gap after comparing delta ATOT [(14.09 - measured ATOT) or (11.77 - 2.64 × Alb (g/dL))] and delta SIDa [(42.7 - measured SIDa) or (42.7 - (Na + K - Cl)]). We could also identify metabolic acidosis with an increased anion gap using SIG > 7.0 (SIG = 0.9463 × corrected anion gap-8.1956). Patients with nephrotic syndrome had primary respiratory alkalosis, decreased ATOT due to hypoalbuminemia (power to metabolic alkalosis), and decreased levels of SIDa (power to metabolic acidosis). We could detect metabolic acidosis with an increased anion gap by calculating SIG. The Stewart model in combination with the Boston model facilitates the analysis of complex acid-base disturbances in nephrotic syndrome.

  3. Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes

    SciTech Connect

    Queisser, Nina; Happ, Kathrin; Link, Samuel; Jahn, Daniel; Zimnol, Anna; Geier, Andreas; Schupp, Nicole

    2014-11-01

    Mineralocorticoid receptor blockers show antifibrotic potential in hepatic fibrosis. The mechanism of this protective effect is not known yet, although reactive oxygen species seem to play an important role. Here, we investigated the effects of elevated levels of aldosterone (Ald), the primary ligand of the mineralocorticoid receptor, on livers of rats in a hyperaldosteronism model: aldosterone-induced hypertension. Male Sprague–Dawley rats were treated for 4 weeks with aldosterone. To distinguish if damage caused in the liver depended on increased blood pressure or on increased Ald levels, the mineralocorticoid receptor antagonist spironolactone was given in a subtherapeutic dose, not normalizing blood pressure. To investigate the impact of oxidative stress, the antioxidant tempol was administered. Aldosterone induced fibrosis, detected histopathologically, and by expression analysis of the fibrosis marker, α-smooth muscle actin. Further, the mRNA amount of the profibrotic cytokine TGF-β was increased significantly. Fibrosis could be reduced by scavenging reactive oxygen species, and also by blocking the mineralocorticoid receptor. Furthermore, aldosterone treatment caused oxidative stress and DNA double strand breaks in livers, as well as the elevation of DNA repair activity. An increase of the transcription factor Nrf2, the main regulator of the antioxidative response could be observed, and of its target genes heme oxygenase-1 and γ-glutamylcysteine synthetase. All these effects of aldosterone were prevented by spironolactone and tempol. Already after 4 weeks of treatment, aldosteroneinfusion induced fibrosis in the liver. This effect was independent of elevated blood pressure. DNA damage caused by aldosterone might contribute to fibrosis progression when aldosterone is chronically increased. - Highlights: • Aldosterone has direct profibrotic effects on the liver independent of blood pressure. • Fibrosis is mediated by the mineralocorticoid receptor and

  4. Congenital chloride diarrhoea. Clinical analysis of 21 Finnish patients.

    PubMed Central

    Holmberg, C; Perheentupa, J; Launiala, K; Hallman, N

    1977-01-01

    Clinical findings in 21 Finnish children with congenital chloride diarrhoea are reported. Inheritance of this disease by the autosomal recessive mode is established. All children were born 1-8 weeks prematurely. Hydramnios was present in every case and no meconium was observed; intrauterine onset of diarrhoea is thus apparent. In most cases the diarrhoea or passing of large volumes of "urine" was noted on the first day of life and the abdomen was usually large and distended. The neonatla weight loss was abnormally large, and was associated with hypochloraemia and hyponatraemia. Some infants survived the neonatal period without adequate therapy. They presented later with failure to thrive and usually had hypochloraemia, hypokalaemia, and metabolic alkalosis associated with hyperaldosteronism. However, these features may be absent and the diagnosis is based on a history of hydramnios and diarrhoea, and a faecal Cl- concentration which always exceeds 90 mmol/l when fluid and electrolyte deficits have been corrected. Lower faecal Cl- concentrations were seen only in chronic hypochloraemia, which is also associated with achloriduria. Adequate treatment consists of full continuous replacement of the faecal losses of water, NaCl, and KCl. This should be given intravenously in the early neonatal period; later a solution can be taken orally with meals. The dose has to be adjusted to maintain normal serum electrolyte concentrations, normal blood pH, and some chloriduria. This therapy prevents the renal lesions and the retarded growth and psychomotor development which were seen in the children who were diagnosed late and in those who received inadequate replacement therapy. The watery diarrhoea persists and increases slightly with age, though patients learn to live with their disease and to make an adequate social adjustment. Images Fig. 3 Fig. 4 Fig. 7 Fig. 10 PMID:324405

  5. [Hypotension from endocrine origin].

    PubMed

    Vantyghem, Marie-Christine; Douillard, Claire; Balavoine, Anne-Sophie

    2012-11-01

    Hypotension is defined by a low blood pressure either permanently or only in upright posture (orthostatic hypotension). In contrast to hypertension, there is no threshold defining hypotension. The occurrence of symptoms for systolic and diastolic measurements respectively below 90 and 60 mm Hg establishes the diagnosis. Every acute hypotensive event should suggest shock, adrenal failure or an iatrogenic cause. Chronic hypotension from endocrine origin may be linked to adrenal failure from adrenal or central origin, isolated hypoaldosteronism, pseudohypoaldosteronism, pheochromocytoma, neuro-endocrine tumors (carcinoïd syndrome) or diabetic dysautonomia. Hypotension related to hypoaldosteronism associates low blood sodium and above all high blood potassium levels. They are generally classified according to their primary (hyperreninism) or secondary (hyporeninism) adrenal origin. Isolated primary hypoaldosteronisms are rare in adults (intensive care unit, selective injury of the glomerulosa area) and in children (aldosterone synthase deficiency). Isolated secondary hypoaldosteronism is related to mellitus diabetes complicated with dysautonomia, kidney failure, age, iatrogenic factors, and HIV infections. In both cases, they can be associated to glucocorticoid insufficiency from primary adrenal origin (adrenal failure of various origins with hyperreninism, among which congenital 21 hydroxylase deficiency with salt loss) or from central origin (hypopituitarism with hypo-reninism). Pseudohypoaldosteronisms are linked to congenital (type 1 pseudohypoaldosteronism) or acquired states of resistance to aldosterone. Acquired salt losses from enteric (total colectomy with ileostomy) or renal (interstitial nephropathy, Bartter and Gitelman syndromes…) origin might be responsible for hypotension and are associated with hyperreninism-hyperaldosteronism. Hypotension is a rare manifestation of pheochromocytomas, especially during surgical removal when the patient has not been

  6. Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1.

    PubMed

    Amazit, Larbi; Le Billan, Florian; Kolkhof, Peter; Lamribet, Khadija; Viengchareun, Say; Fay, Michel R; Khan, Junaid A; Hillisch, Alexander; Lombès, Marc; Rafestin-Oblin, Marie-Edith; Fagart, Jérôme

    2015-09-04

    Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist. © 2015 by The American Society for Biochemistry and Molecular

  7. Potassium secretion in rat distal colon during dietary potassium loading: role of pH regulated apical potassium channels

    PubMed Central

    Sandle, G; Butterfield, I

    1999-01-01

    +-H+ exchange, which may be a manifestation of the secondary hyperaldosteronism associated with this model of colonic K+ adaptation. 

 Keywords: colon; dietary potassium; pH; potassium channels PMID:9862824

  8. Protective effects of dietary potassium chloride on hemodynamics of Dahl salt-sensitive rats in response to chronic administration of sodium chloride.

    PubMed

    Manger, William M; Simchon, Shlomoh; Stier, Charles T; Loscalzo, Joseph; Jan, Kung-Ming; Jan, Rex; Haddy, Francis

    2003-12-01

    Dietary potassium supplementation decreases blood pressure and prevents strokes in humans, and prevents strokes and renal damage in Dahl salt-sensitive (DSS) rats. To study the effects of various concentrations of dietary potassium chloride (KCl) on the hemodynamics of Dahl salt-resistant (DSR) and DSS rats receiving a 1% sodium chloride (NaCl) diet for 8 months, to determine whether there is an optimal dietary concentration of KCl that minimizes increases in blood pressure and causes least impairment of blood flow in the brain and kidneys. We found a biphasic effect on hemodynamic parameters as a function of dietary KCl in DSS rats of the Rapp strain fed 1% NaCl with increasing dietary KCl (0.7, 2.6, 4 and 8%). After 8 months receiving a diet containing 1% NaCl and 0.7% KCl, DSS rats had mean arterial pressures (MAP), plasma volumes, cardiac outputs and renal and cerebral vascular resistances that were significantly increased compared with those of DSR rats receiving the same diet. With a 2.6% KCl diet, all these parameters were significantly reduced compared with those in DSS rats fed the 0.7% KCl diet and were similar to those in DSR rats fed 2.6% KCl. Total peripheral resistance in DSR and DSS rats was similar on all diets. When KCl was increased to 4 and 8%, MAP, plasma volume, cardiac output and renal vascular resistance progressively increased in DSR and DSS rats, without changing total peripheral resistance. These changes paralleled increases in plasma aldosterone, which resulted from adrenocortical stimulation by the increasing dietary KCl; however, cerebral vascular resistance of DSR and DSS rats decreased significantly with a 4% KCl diet, despite increased aldosterone and sodium retention. Only DSS rats fed a 2.6% KCl diet had hemodynamics similar to those of DSR control rats fed the same diet, and hyperaldosteronism, sodium retention and increased plasma volume did not occur. 'Optimal' dietary KCl (2.6%) prevents hypertension and preserves cerebral and

  9. Dose-dependency of clonidine's effects in ascitic cirrhotic rats: comparison with α1-adrenergic agonist midodrine.

    PubMed

    Sansoè, Giovanni; Aragno, Manuela; Mastrocola, Raffaella; Parola, Maurizio

    2016-02-01

    Sympathetic nervous system (SNS) activation decreases response to diuretics, but both α1-adrenoceptor agonists and sympatholytic α2-adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (α2-agonist) vs. midodrine (α1-agonist) in advanced cirrhosis. Renal function, mean arterial pressure (MAP), and hormonal status were measured in rats with ascitic cirrhosis due to 13-week CCl(4) administration (groups G1-G5), in control rats (Gc), and in rats with ascitic cirrhosis untreated (G6) or treated with daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+) -canrenoate during the 11(th) -13(th) weeks of CCl(4)) (G7). G1-G5 cirrhotic rats received daily, during the 11(th)-13(th) CCl(4) weeks: clonidine 0.3 μg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 μg (G4), and diuretics + midodrine 1 mg/kg b.w. (G5). Cirrhotic rats in G1 or G2 had higher glomerular filtration rate, renal plasma flow and natriuresis than cirrhotic rats treated with diuretics (G7) (all P < 0.05). The addition of clonidine 0.2 μg to diuretics (G2 vs. G7) reduced serum norepinephrine (169 ± 71 ng/L vs. 523 ± 88 ng/L) and plasma renin activity (12 ± 3 ng/ml/h vs. 25 ± 5 ng/ml/h) (all P < 0.05). Midodrine did not improve the renal performance in ascitic rats treated with diuretics. In comparison to absolute cirrhotic controls (G6), MAP was lower in G4 and higher in G5 (all P < 0.05). Low-dose α2-agonists improve natriuresis and reduce SNS function and hyper-aldosteronism without affecting arterial pressure in experimental ascitic cirrhosis treated with diuretics. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

    PubMed Central

    Leibrock, Christina B.; Alesutan, Ioana; Voelkl, Jakob; Pakladok, Tatsiana; Michael, Diana; Schleicher, Erwin; Kamyabi-Moghaddam, Zahra; Quintanilla-Martinez, Leticia; Kuro-o, Makoto

    2015-01-01

    Klotho, a cofactor in suppressing 1,25(OH)2D3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH)2D3, Ca2+, and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescence-associated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH4Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice >12-fold in males and >4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH)2D3, Ca2+, and phosphate. NH4Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH4Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH4Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH4Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH4Cl treatment. In conclusion, NH4Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH4Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling. PMID:25644113

  11. Myocardial Na,K-ATPase: Clinical aspects

    PubMed Central

    Kjeldsen, Keld

    2003-01-01

    The specific binding of digitalis glycosides to Na,K-ATPase is used as a tool for Na,K-ATPase quantification with high accuracy and precision. In myocardial biopsies from patients with heart failure, total Na,K-ATPase concentration is decreased by around 40%; a correlation exists between a decrease in heart function and a decrease in Na,K-ATPase concentration. During digitalization, around 30% of remaining pumps are occupied by digoxin. Myocardial Na,K-ATPase is also influenced by other drugs used for the treatment of heart failure. Thus, potassium loss during diuretic therapy has been found to reduce myocardial Na,K-ATPase, whereas angiotensin-converting enzyme inhibitors may stimulate Na,K pump activity. Furthermore, hyperaldosteronism induced by heart failure has been found to decrease Na,K-ATPase activity. Accordingly, treatment with the aldosterone antagonist, spironolactone, may also influence Na,K-ATPase activity. The importance of Na,K pump modulation with heart disease, inhibition in digitalization and other effects of medication should be considered in the context of sodium, potassium and calcium regulation. It is recommended that digoxin be administered to heart failure patients who, after institution of mortality-reducing therapy, still have heart failure symptoms, and that the therapy be continued if symptoms are revealed or reduced. Digitalis glycosides are the only safe inotropic drugs for oral use that improve hemodynamics in heart failure. An important aspect of myocardial Na,K pump affection in heart disease is its influence on extracellular potassium (Ke) homeostasis. Two important aspects should be considered: potassium handling among myocytes, and effects of potassium entering the extracellular space of the heart via the bloodstream. It should be noted that both of these aspects of Ke homeostasis are affected by regulatory aspects, eg, regulation of the Na,K pump by physiological and pathophysiological conditions, as well as by medical

  12. Hyperadrenalism in childhood and adolescence.

    PubMed Central

    Thomas, C G; Smith, A T; Griffith, J M; Askin, F B

    1984-01-01

    Hyperadrenalism in childhood and adolescence has unique features that influence diagnosis and management. We reviewed our experience with 18 patients, ranging in age from 18 months to 18 years. Nine had bilateral adrenal hyperplasia, eight had adrenal neoplasms, and one had micronodular hyperplasia. Patients with congenital adrenal hyperplasia and hyperaldosteronism were excluded. Six patients with Cushing's disease diagnosed in earlier years were treated by total adrenalectomy and recently two patients underwent transsphenoidal removal of pituitary tumors. Bilateral adrenalectomy was carried out in one patient with micronodular hyperplasia and in a second because of elevated adrenocorticotrophic hormone (ACTH) levels from an undefined source. Eight patients had adrenal neoplasms, including five adenomas and three carcinomas. We found no reliable criteria to differentiate before surgery between adrenal adenomas and adrenal carcinomas. The most recognizable characteristic of malignancy was tumor size, specifically weight greater than 75 gms. Of the three patients with adrenal carcinoma, one expired 20 months after adrenalectomy and 8 months after receiving palliative partial hepatectomy for liver metastasis. Two patients are well with normal growth and development at 11 and 20 years following adrenalectomy. With the exception of one patient who died 6 years after surgery from a glioblastoma multiforme, all patients with adrenal adenomas are well. Eight patients underwent bilateral adrenalectomy for hypercortisolism. Five of the six who have reached their adult stature are significantly stunted. Four of six patients with Cushing's disease, treated by total adrenalectomy, have developed Nelson's syndrome at 2, 6, 10, and 12 years after surgery. Of the two patients undergoing transsphenoidal surgery, one had recurrent disease at 2 years and was treated by pituitary irradiation with recovery. The patients undergoing adrenalectomy for micronodular hyperplasia and ectopic

  13. Nationwide review of hormonally active adrenal tumors highlights high morbidity in pheochromocytoma.

    PubMed

    Parikh, Punam P; Rubio, Gustavo A; Farra, Josefina C; Lew, John I

    2017-07-01

    Adrenal adenomas are benign tumors often discovered incidentally, and >70% are hormonally inactive. The remaining subset may produce excess aldosterone, cortisol, or catecholamine. Perioperative outcomes after adrenalectomy for such "hormonally active" tumors remain unclear. This study examines in-hospital outcomes after unilateral adrenalectomy for hormonally active tumors. A retrospective review was performed using the Nationwide Inpatient Sample (2006-2011) to identify patients undergoing unilateral adrenalectomy for hormonally active or inactive tumors. Malignant adrenal tumors were excluded. Demographics, comorbidities, and postoperative complications were evaluated by univariate analysis, using two-tailed Chi-square and t-tests and multivariate logistic regression. Of 27,312 patients who underwent adrenalectomy, 78% (n = 21,279) had hormonally inactive and 22% (n = 6033) had hormonally active adrenal tumors. Among the latter, 65% (n = 4000) had primary hyperaldosteronism (Conn's syndrome), 33% (n = 1996) had hypercortisolism (Cushing's syndrome), and 1.4% (n = 85) had pheochromocytoma. Patients with pheochromocytoma had higher rate of comorbidities including congestive heart failure, chronic lung disease, and malignant hypertension compared with remaining hormonally active tumors (12% versus 4%, 18% versus 11%, 6% versus 2%; P < 0.01). For patients with pheochromocytoma versus other hormonally active tumors, mean length of stay was 5 versus 3 d and total in-hospital cost was $50,000 versus $41,000 (P < 0.01). On multivariate analysis, pheochromocytoma had an independently higher risk for intraoperative blood transfusion (4.2, 95% confidence interval [CI] 2.4-7.2), postoperative cardiac (7.6, 95% CI 2.8-20.2), and respiratory (1.9, 95% CI 1.0-3.3) complications. Patients with pheochromocytoma have high rates of preoperative comorbidities, postoperative cardiopulmonary complications, and longer and more costly hospitalizations. Such high

  14. The Renin-Angiotensin-Aldosterone system in patients with depression compared to controls – a sleep endocrine study

    PubMed Central

    Murck, Harald; Held, Katja; Ziegenbein, Marc; Künzel, Heike; Koch, Kathrin; Steiger, Axel

    2003-01-01

    gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample. Conclusion Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression. PMID:14585110

  15. The renin-angiotensin-aldosterone system in patients with depression compared to controls--a sleep endocrine study.

    PubMed

    Murck, Harald; Held, Katja; Ziegenbein, Marc; Künzel, Heike; Koch, Kathrin; Steiger, Axel

    2003-10-29

    regulation. No difference in conventional sleep EEG parameters were found in our sample. Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.

  16. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension

    PubMed Central

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E.; Arons, Elena; Zaman, Paula; Polach, Kevin J.; Matar, Majed; Yung, Lai-Ming; Yu, Paul B.; Bowman, Frederick P.; Opotowsky, Alexander R.; Waxman, Aaron B.; Loscalzo, Joseph; Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10−9 to 10−7 M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor–small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro. Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo. Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.—Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery

  17. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample.

    PubMed

    Newton-Cheh, Christopher; Guo, Chao-Yu; Gona, Philimon; Larson, Martin G; Benjamin, Emelia J; Wang, Thomas J; Kathiresan, Sekar; O'Donnell, Christopher J; Musone, Stacy L; Camargo, Amy L; Drake, Jared A; Levy, Daniel; Hirschhorn, Joel N; Vasan, Ramachandran S

    2007-04-01

    Aldosterone:renin ratio (ARR) is used to screen for hyperaldosteronism. Data regarding correlates of ambulatory ARR in the community and its relation to hypertension incidence are limited. We defined clinical correlates of ARR, determined its heritability, tested for association and linkage, and related ARR to blood pressure (BP) progression in nonhypertensive individuals among 3326 individuals from the Framingham Heart Study (53% women; mean age: 59 years). Ambulatory morning ARR (serum aldosterone and plasma renin concentrations) were related to clinical covariates, genetic variation across the REN locus, a 10-cM linkage map, and among nonhypertensive participants (n=1773) to progression of >or=1 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP category (optimal: <120/80 mm Hg, normal: 120 to 129/80 to 84 mm Hg, high normal: 130 to 139/85 to 89 mm Hg, hypertension: >or=140/90 mm Hg), or incident hypertension (systolic BP: >or=140 mm Hg, diastolic BP: >or=90 mm Hg, or use of antihypertensive treatment). ARR was positively associated with age, female sex, untreated hypertension, total/high-density lipoprotein cholesterol ratio, hormone replacement therapy, and beta-blocker use, but negatively associated with angiotensin-converting enzyme inhibitor and diuretic use. ARR was heritable (h(2)=0.40), had modest linkage to chromosome 11p (logarithm of the odds: 1.89), but was not associated with 17 common variants in REN (n=1729). On follow-up (mean: 3 years), 607 nonhypertensive individuals (34.2%) developed BP progression, and 283 (16.0%) developed hypertension. Higher baseline logARR was associated with increased risk of BP progression (odds ratio per SD increment: 1.23; 95% CI: 1.11 to 1.37) and hypertension incidence (odds ratio per SD increment: 1.16; 95% CI: 1.00 to 1.33). ARR is a heritable trait influenced by clinical and genetic factors. There is a continuous gradient of increasing risk

  18. Pre-B Lymphocyte Protein 3 (VPREB3) Expression in the Adrenal Cortex: Precedent for non-Immunological Roles in Normal and Neoplastic Human Tissues.

    PubMed

    Felizola, Saulo J A; Katsu, Koshin; Ise, Kazue; Nakamura, Yasuhiro; Arai, Yoichi; Satoh, Fumitoshi; Sasano, Hironobu

    2015-05-01

    The pre-B lymphocyte protein 3 (VPREB3) is expressed during B cell differentiation and in subsets of mature B lymphocytes and is mainly found in bone marrow and lymphoid tissue germinative centers. So far, its function in B cells remains to be clarified. The messenger RNA (mRNA) of VPREB3 was previously detected in aldosterone-producing adenomas (APA); however, further information about this protein in human adrenocortical cells and tissues is currently unavailable. Therefore, in the present study, we, for the first time, investigate the protein expression of VPREB3 in human adrenocortical tissues. In addition, we approach the previously suggested similarities in expression patterns of aldosterone-producing cells and Purkinje neurons. Immunohistochemical analysis of VPREB3 was performed in 13 nonpathological adrenals (NA), 6 adrenal glands with idiopathic hyperaldosteronism (IHA), 18 APA, 5 cortisol-producing adenomas (CPA), and 5 nonpathological human cerebellum specimens. The mRNA levels of VPREB3, steroidogenic enzymes, and other aldosterone biosynthesis markers were detected in 53 APA samples using real-time RT-PCR (qPCR) and compared to the clinical data of APA patients. In our results, the VPREB3 protein was diffusely detected in APA, partially or weakly detected in CPA, and immunolocalized in the zona glomerulosa of NA and IHA, as well as in the cytoplasm of cerebellar Purkinje cells. In APA, VPREB3 mRNA levels were significantly correlated to plasma aldosterone (P = 0.026; R = 0.30), KCNJ5 mutations (P = 0.0061; mutated 34:19 wild type), CYP11B2 (P < 0.0001; R = 0.65), Purkinje cell protein 4 (PCP4; P < 0.0001; R = 0.53), and voltage-dependent calcium channels CaV1.3 (P = 0.023; R = 0.31) and CaV3.2 (P = 0.0019; R = 0.42). Based on our data, we hypothesize a possible role for VPREB3 in aldosterone biosynthesis, and present ideas for future functional studies.

  19. On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA)

    PubMed Central

    Sebastian, Anthony; McSherry, Elisabeth; Morris, R. Curtis

    1971-01-01

    .55. These results provide evidence that renal potassium wasting in type 2 RTA is physiologically separable from that in type 1 RTA and in part the result of a reduction in the rate at which the proximal tubule reabsorbs bicarbonate and the distal delivery of supernormal amounts of sodium bicarbonate. With an increased stimulus to distal sodium reabsorption, indicated by the finding of hyperaldosteronism, delivery to the distal nephron of supernormal amounts of sodium with the relatively impermeant bicarbonate anion would be expected to increase intraluminal negativity in the distal nephron, and as a consequence, increase potassium secretion and promote renal potassium wasting. PMID:5101297

  20. [The application of captopril challenge test in the diagnosis of primary aldosteronism].

    PubMed

    Chen, S; Zeng, Z P; Song, A L; Zhu, L; Lu, L; Tong, A L; Shi, C; Li, H Z

    2017-06-01

    Objective: To evaluate the value of captopril challenge test (CCT) in the diagnosis of primary aldosteronism (PA). Methods: A total of 674 patients [(45.0±13.7) years, men 341, women 333] admitted to Peking Union Medical College Hospital from 2000 to 2015 were analyzed. Among them, 222 subjects were with essential hypertension (EH), 28 were with pheochromocytoma (PHEO), 246 were with idiopathic hyperaldosteronism (IHA) and 178 were with aldosterone producing adenoma (APA). All patients received CCT. 24 h urine sodium was measured in partial patients. Plasma renin activity (PRA), aldosterone (ALD) were detected. Results: Compared with EH [PRA: before 0.5(0.2, 0.9) μg·L(-1)·h(-1,) after 0.8(0.4, 1.5) μg·L(-1)·h(-1;) ALD: before (393±122) pmol/L, after (360±97) pmol/L] and PHEO [PRA: before 0.3(0.1, 0.9) μg·L(-1)·h(-1,) after 0.4(0.1, 1.6) μg·L(-1)·h(-1;) ALD: before (396±108) pmol/L, after (374±114) pmol/L], lower levels of PRA and higher levels of ALD before and after CCT were observed in PA patients [PRA: before 0.1 (0.1, 0.2) μg·L(-1)·h(-1,) after 0.1 (0.1, 0.2) μg·L(-1)·h(-1;) ALD: before (468±216) pmol/L; after (457±199) pmol/L]. After CCT, the suppression rate of ALD [2.8% (-8.8%, 15.4%) vs 6.6% (-4.3%, 17.6%)] and increasing rate of PRA [0(0, 50%) vs 50%(0, 200%)] in PA patients were lower than those in EH patients. The ALD/PRA ratio (ARR) were higher in PA than that in EH or PHEO patients. In the EH subjects, ALD levels of seated posture were higher than those of recumbent posture both before and after receiving captopril, but with no changes in ARR after CCT. No significant differences in ALD and ARR (before and after receiving captopril) were observed between seated and recumbent position in the PA group. The ARR after CCT tended to decrease in EH subjects with elevated urine-sodium compared with those with normal urine-sodium. No changes could be viewed in ALD and PRA levels between normal urine-sodium and elevated urine

  1. SY 03-3 OVERVIEW OF SOMATIC MUTATIONS AND EPIGENETIC REGULATION OF ALDOSTERONE PRODUCING ADENOMA (APA).

    PubMed

    Umemura, Satoshi

    2016-09-01

    Primary aldosteronism (PA) is a heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most frequent endocrine cause of secondary hypertension and associated with a higher rate of cardiovascular complications, compared with essential hypertension.Here I review the recent progress in understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA.Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with resistant hypertension. A unilateral APA is the most common curable cause of hypertension. Early detection of an APA is important both to cure of hypertension by means of adenoma removal and to prevent the onset of resistant hypertension and the risk of long-term cardiovascular complications, such as left ventricular hypertrophy, coronary artery disease, myocardial infarction, heart failure, and atrial fibrillation. (Hypertens 2013; 62: 331)(1) Novel somatic mutations in APARecent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA. Pathogenic mechanisms of APA by the somatic mutation are as follows.The majority of the GIRK4 APA mutations (KCNJ5) lie in or within the close proximity of the ion selectivity filter of the K+ channel and result in the indiscriminate conductance of Na+ that causes membrane depolarization, Ca2+ influx, and increased aldosterone biosynthesis.Mutations in the Na+/K+- ATPase 1 (ATP1A1) produce a decrease in K+ binding that results in the reduced import of K+ and export of Na+ and also causes cell depolarization. This in turn results in the opening of voltage- gated Ca2+-channels.In contrast, the Ca2+-ATPase mutations (ATP2B3) were proposed to affect the clearance of cytoplasmic calcium ions. The net result of mutations in both ATPases is therefore likely to cause