Aldosterone suppression on contralateral adrenal during adrenal vein sampling does not predict blood pressure response after adrenalectomy.

CONTEXT: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. OBJECTIVE: The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. SETTING: The study was carried out in eight different referral centers in Italy, Germany, and Japan. PATIENTS: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. RESULTS: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. CONCLUSIONS: For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas.

Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the KCNJ5 gene, which encodes the G-protein-activated inward rectifier K(+) channel 4, GIRK4, account for ≈40% of APAs. Additional somatic APA mutations were identified recently in 2 other genes, ATP1A1 and ATP2B3, encoding Na(+)/K(+)-ATPase 1 and Ca(2+)-ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na(+)/K(+)-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg). CYP11B2 gene expression was higher in APAs harboring ATP1A1 and ATP2B3 mutations compared with those without these or KCNJ5 mutations. Overexpression of Na(+)/K(+)-ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of CYP11B2 gene expression and its transcriptional regulator NR4A2. Structural modeling of the Na(+)/K(+)-ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na(+) activation of phosphorylation and K(+) inhibition of phosphorylation that indicate decreased Na(+) and K(+) binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na(+)/K(+)-ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in CYP11B2 gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.

Visceral adipose tissue: emerging role of gluco- and mineralocorticoid hormones in the setting of cardiometabolic alterations.

Several clinical and experimental lines of evidence have highlighted the detrimental effects of visceral adipose tissue excess on cardiometabolic parameters. Besides, recent findings have shown the effects of gluco-and mineralocorticoid hormones on adipose tissue and have also underscored the interplay existing between such adrenal steroids and their respective receptors in the modulation of adipose tissue biology. While the fundamental role played by glucocorticoids on adipocyte differentiation and storage was already well known, the relevance of the mineralocorticoids in the physiology of the adipose organ is of recent acquisition. The local and systemic renin-angiotensin-aldosterone system (RAAS) acting on adipose tissue seems to contribute to the development of the cardiometabolic phenotype so that its modulation can have deep impact on human health. A better understanding of the pathophysiology of the adipose organ is of crucial importance in order to identify possible therapeutic approaches that can avoid the development of such cardiovascular and metabolic sequelae.

Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists.

Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae.

Blood pressure, thyroid-stimulating hormone, and thyroid disease prevalence in primary aldosteronism and essential hypertension.

BACKGROUND: A positive correlation between thyroid-stimulating hormone (TSH) and blood pressure (BP) has been identified in normotensives and in patients with essential hypertension (EH). This study was designed to evaluate, in primary aldosteronism (PA) and in EH, potential association of BP, TSH, and ultrasonographic changes of the thyroid. METHODS: We studied 188 patients: 92 with PA and 96 matched essential hypertensives. Clinical and ambulatory BP (ABP), and thyroid function were evaluated in all patients. In PA and in a subgroup of EH patients (n = 65) thyroid ultrasonography was performed. RESULTS: In PA patients, diastolic office and diastolic ABP increased across TSH quartiles and multivariate analysis confirmed a positive significant correlation between TSH and diastolic BP, independently of aldosterone levels, body mass index (BMI), duration of hypertension, and age. In EH patients, we found a significant linear increase in systolic and diastolic ABP with increasing TSH. The prevalence of thyroid dysfunctions was similar in PA and EH (15% and 19%, respectively). In PA patients, we found a higher prevalence of ultrasonographic alterations than in EH (66% vs. 46%, P < 0.05). PA patients presenting morphological abnormalities had higher homeostasis model assessment-insulin resistance levels than patients with normal gland at ultrasonography (4.2 ± 1.8 vs. 3.1 ± 0.8 P < 0.05). CONCLUSIONS: We found a positive correlation between TSH and BP both in PA and EH patients. Moreover, in PA patients we observed a high prevalence of thyroid morphological alterations.

The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.

The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2G>C (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2G>C in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression.

Management of primary aldosteronism: its complications and their outcomes after treatment.

Primary aldosteronism is the most common cause of secondary hypertension, accounting for about 10% of all forms of high blood pressure. Life-time pharmacological therapy is the treatment of choice for primary aldosteronism due to idiopathic adrenal hyperplasia (IHA), while adrenalectomy is effective in curing most patients with an aldosterone producing adenoma (APA). Far from being a benign form of hypertension, primary aldosteronism is characterized by the development of cardiovascular renal and metabolic complications, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation and stroke, microalbuminuria, renal cysts as well as metabolic syndrome, glucose impairment and diabetes mellitus. We review recent clinical experience with the above mentioned complications and long-term outcomes of blood pressure normalization and cardiac, renal and gluco-metabolic complications in patients with primary aldosteronism, after medical treatment with mineralocorticoid receptor antagonists and surgical treatment. We conclude that removal of adrenal adenoma results in normalization of the renin-angiotensin-aldosterone system (RAAS) and of kalaemia and improvement of blood pressure levels in all patients. Complete resolution of hypertension is achieved in nearly half of treated patients. Moreover, unilateral adrenalectomy is the best treatment to have the regression of cardiovascular, renal and metabolic complications in patients with APA. On the other hand, targeted medical treatment with aldosterone antagonists improves blood pressure control and appears able to prevent the progression of cardiac and metabolic complications in patients with IHA.

MF59 emulsion is an effective delivery system for a synthetic TLR4 agonist (E6020).

PURPOSE: The effectiveness of vaccines depends on the age and immunocompetence of the vaccinee. Conventional non-adjuvanted influenza vaccines are suboptimal in the elderly and vaccines with improved ability to prevent influenza are required. The TLR4 agonist E6020, either given alone or co-delivered with MF59, was evaluated and compared to MF59 and the TLR9 agonist CpG. Its ability to enhance antibody titres and to modulate the quality of the immune response to a subunit influenza vaccine was investigated. METHODS: Mice were immunized with either antigens alone, with MF59 or with the TLR agonists alone, or with a combination thereof. Serum samples were assayed for IgG antibody titres and hemagglutination inhibition (HI) titres. Th1/Th2 type responses were determined by titrating IgG subclasses in serum samples and by T-cell cytokine responses in splenocytes. RESULTS: MF59 was the best single adjuvant inducing HI and T-cell responses in comparison to all alternatives. The co-delivery of E6020 or CpG with MF59 did not further increase antibody titres however shifted towards a more Th1 based immune response. CONCLUSION: Combining adjuvants like E6020 and MF59 allowed a finer tuning of the immune response towards a particular Th bias, thus have significant implications for the development of improved influenza vaccines.

Small tumor size as favorable prognostic factor after adrenalectomy in Conn's adenoma.

OBJECTIVE: Primary aldosteronism (PA) due to aldosterone-producing adenoma (APA) is the most common curable form of secondary hypertension. DESIGN: In order to evaluate blood pressure outcome after adrenalectomy for APA and to identify new favorable prognostic factors, data from 42 consecutive APA patients who underwent adrenalectomy were collected from 2005 to 2007. METHODS: Renin-angiotensin-aldosterone system (upright and postsaline infusion test), serum and urinary electrolytes, office and ambulatory blood pressure monitoring were evaluated at baseline and after a follow-up of 2.7+/-2.2 years. Drug history and adenoma size at morphological evaluation were also collected. RESULTS: Multiple regression analysis showed that, before surgery, patients with a small adenoma (diameter <20 mm) displayed higher postsaline aldosterone values (P=0.0001), and lower serum potassium levels (P=0.020), than patients with adenoma >20 mm. Before surgery, mineralocorticoid receptor (MR) antagonists were used in patients with small APA in greater percentage than patients with bigger adenomas (64 vs 30% respectively, P=0.037). At follow-up, blood pressure normalized in 63% of the subjects. Recovered patients had a shorter duration of hypertension (P=0.038), and a smaller adenoma size (P=0.035). Receiver operating characteristic curves showed that a duration of hypertension

Diagnosis and management of primary aldosteronism.

PURPOSE OF REVIEW: To illustrate the steps for clinical management of primary aldosteronism from screening evaluation to surgical and/or medical treatment. RECENT FINDINGS: It is now widely accepted that primary aldosteronism represents the most common form of endocrine hypertension and its early diagnosis is crucial for hypertensive patients who can be cured by the surgical removal of an aldosterone-secreting adenoma or benefit from a specific medical treatment with mineralocorticoid receptor antagonists. Recent evidence indicates that hyperaldosteronism is indeed associated with detrimental consequences on cardiovascular system, renal function and glucose metabolism. SUMMARY: The diagnostic protocol for primary aldosteronism requires multistep evaluation and should begin with a screening test, followed when appropriate, by confirmatory test and functional and anatomical evaluation. Finally, although it is technically difficult and the cut-off levels for acceptance of the success are not standardized, the subtype forms should be identified using a selective adrenal venous sampling.

Primary aldosteronism: cardiovascular, renal and metabolic implications.

For many years primary aldosteronism was considered a relatively benign form of hypertension. This assumption reflects the primacy accorded to elevated levels of angiotensin in terms of deleterious cardiovascular effects, and the fact that in primary aldosteronism renin and angiotensin levels are low. We now know that primary aldosteronism causes a constellation of cardiovascular, renal and metabolic sequelae which make it far from benign and that these are not merely effects of blood pressure elevation. In primary aldosteronism, tissue damage, on several indices, is higher than in age-, sex- and blood pressure-matched controls, reflecting the ability of inappropriately elevated aldosterone for salt status to produce structural and functional changes over and above those produced by high blood pressure.

Adipose cell-adrenal interactions: current knowledge and future perspectives.

The central role of adipose tissue in the development of cardiovascular and metabolic pathology has been highlighted by the discovery of mediators (adipokines) secreted by adipose tissue and their involvement in the regulation of various biological processes. In light of recent experimental data, cross-talk between adipose tissue and the adrenal gland, particularly via the mineralocorticoid aldosterone, has been proposed. Aldosterone can induce adipogenesis, and human white adipose tissue is reported to release as-yet-uncharacterized factors that stimulate adrenocortical steroidogenesis and aldosterone production. These data could provide new insights into the pathophysiology of obesity-related disorders, including hypertension and aldosterone excess, with further studies necessary for confirming and better defining such adipose-adrenal interactions.

Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study.

OBJECTIVE: Primary aldosteronism (PA) is characterized by the onset of both cardiac and gluco-metabolic alterations. The aim of this study was to evaluate the impact of aldosterone excess on the development of such complications, and the effects of surgical and pharmacological treatment on their long-term outcome. METHODS: We prospectively re-examined 61 patients: 25 with aldosterone-producing adenoma (APA), after surgery, and 36 patients with idiopathic hyperaldosteronism (IHA) on pharmacological treatment. The lipid, fasting and dynamic glucose profiles and the echocardiographic parameters were evaluated at diagnosis and at follow-up. RESULTS: After adrenalectomy all patients had normalization of aldosterone levels and were cured of hypokalaemia, and a resolution of hypertension was achieved in 12 of 25 patients. APA patients showed a significant reduction of both plasma glucose (P=0.017) and insulin levels (P=0.001) after 75 g oral glucose tolerance test. Stabilization of glucose metabolism complications was observed in IHA patients. Multiple regression analysis at diagnosis showed a positive correlation between homeostasis model assessment (HOMA) insulin resistance index and HOMA beta cell and serum aldosterone levels in both APA and IHA. Echocardiographic parameters were improved in both APA and IHA at follow-up and the difference was statistically significant for left ventricular mass index (P=0.017) and interventricular septum thickness (P=0.007) in APA patients. CONCLUSIONS: The removal of aldosterone excess in APA patients induces the regression of both cardiac and gluco-metabolic complications, indicating aldosterone as a main determinant of such alterations. In IHA patients the medical treatment seems to avoid the possible progression of the these alterations that appear to be stable.

Adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome.

OBJECTIVE: To evaluate the expression of 11beta-hydrxysteroid dehydrogenase type 1 (11beta-HSD1) in omental adipose tissue of patients with Cushing's syndrome and simple obesity, compared with normal weight controls. DESIGN AND METHODS: We have performed a case-control study and studied omental adipose tissue from a total of 24 subjects (eight obese subjects, ten patients with Cushing's syndrome due to adrenal adenoma, and six normal weight controls). Body mass index, blood pressure, plasma glucose, plasma insulin, plasma cortisol, urinary free cortisol and post dexamethasone plasma cortisol were measured with standard methods. 11beta-HSD1 mRNA and protein expression were evaluated in real-time PCR and western blot analysis respectively. RESULTS: 11beta-HSD1 mRNA was 13-fold higher in obese subjects compared with controls (P=0.001). No differences were found between Cushing's patients and controls. Western blot analysis supported the mRNA expression results. CONCLUSIONS: Our data show the involvement of 11beta-HSD1 enzyme invisceral obesity, which is more evident in severely obese patients than in Cushing's syndrome patients. The lack of increase of 11beta-HSD1 expression in Cushing's syndrome could suggest downregulation of the enzyme as a result of long-term overstimulation.

Cytoskeleton rearrangement induced by tetraspanin engagement modulates the activation of T and NK cells.

The hepatitis C virus (HCV) binds to human cells through the interaction of its envelope glycoprotein E2 with the tetraspanin CD81. We have previously reported that engagement of CD81 has opposite effects on T and NK cell function, as it enhances T cell receptor-mediated T cell activation and inhibits CD16- or IL-12-mediated NK cell activation. We further investigated this dichotomy and found that another tetraspanin, CD82, induces the same opposing effects on human primary T and NK cells. Activation by other unrelated stimuli such as NKG2D- and beta-1 integrin is also reduced by CD81 ligation on NK cells. CD81 engagement by monoclonal antibody or HCV-E2 enhances zeta and Erk phosphorylation in T cells and reduces them in NK cells, reflecting the opposite functional outcomes. CD81 engagement induces dramatic morphological changes and local F-actin accumulation in both NK and T cells, indicating rearrangement of the actin cytoskeleton. Pharmacological inhibition of actin polymerization reduces T cell activation, whereas it greatly enhances NK cell activation. Importantly, treatment with actin blockers abolishes the inhibitory effect of CD81 ligation on NK cells. We propose that tetraspanin engagement leads to comparable cytoskeleton reorganization in T and NK cells, which in turn results in opposite functional outcomes.

Analysis of screening and confirmatory tests in the diagnosis of primary aldosteronism: need for a standardized protocol.

BACKGROUND: The upright serum aldosterone/upright plasma renin activity ratio (ARR) has been recommended as a screening tool for the diagnosis of primary aldosteronism. OBJECTIVE: We reviewed the data collected from hypertensive patients in order to define retrospectively the cut-off values and evaluate the reliability of the ARR and of the saline infusion test in the diagnosis of primary aldosteronism. PATIENTS: In 157 patients referred to our unit with a suspicion of primary aldosteronism, 61 of whom had confirmed primary aldosteronism [26 aldosterone-producing adenoma (APA); 35 idiopathic hyperaldosteronism], the supine and upright ARR, and the ARR after the administration of captopril and losartan were calculated, and the results of the saline infusion test were analysed. RESULTS: Choosing 40 as the cut-off value, the upright ARR had 100% sensitivity and 84.4% specificity. The post-captopril and post-losartan ARR were slightly more specific, but at the cost of a lower sensitivity. A cut-off value of 7 ng/dl for serum aldosterone at the end of the saline infusion in patients with an upright ARR of 40, gave 100% specificity and a positive predictive value. Furthermore, APA patients showed increased mean levels of aldosterone/cortisol ratio after the saline infusion test. CONCLUSION: Our data reinforce the superiority of a standardized upright ARR as a screening test in the diagnosis of primary aldosteronism, identifying 40 as an ideal cut-off value. Saline infusion represents a useful test to confirm such a diagnosis, with a serum aldosterone level of 7 ng/dl as a satisfactory cut-off value. Some more information is obtained when the aldosterone/cortisol ratio is considered.

Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension.

BACKGROUND: The HSD11B2 gene, encoding the kidney isoenzyme 11beta-hydroxysteroid dehydrogenase, is a candidate for essential hypertension. We previously showed that the frequency of shorter alleles of a CA repeat polymorphism in the first intron of 11beta-HSD2 gene was significantly higher among salt-sensitive than salt-resistant individuals with hypertension. The aim of the study was to analyze the HSD11B2 gene to assess whether some of its variants might be involved in hypertension. METHODS: Exons 2, 3, 4, and 5 were screened by polymerase chain reaction-single-strand conformation polymorphism analysis in 292 hypertensive patients and 163 control subjects. The samples with variant electrophoretic patterns at single-strand conformation polymorphism were re-analyzed using an automated DNA sequencer. A case-control study was then performed by comparing genotype frequencies in hypertensive and normotensive subjects. RESULTS: Analysis of the HSD11B2 showed that in hypertensive patients there is a higher prevalence of two associated polymorphisms, Thr156/Thr(C468A) in exon 2 (ex2) and Glu178/Glu(G534A) in exon 3 (ex3), than in normotensive subjects (9% v 2.4%). This association did not correlate with salt sensitivity. C468A alone correlates significantly with hypertension (9%) and was identified only in 3% of control subjects (P < .05), whereas G534A was identified also in about 7% of normotensive subjects. The urinary free cortisol/urinary free cortisone ratio (UFF/UFE) was significantly higher in hypertensive patients compared with control subjects (P < .01). CONCLUSIONS: Two different polymorphisms of the HSD11B2 gene were observed. The association of both polymorphisms was significantly higher in hypertensive subjects than in control subjects. Its role should be further investigated, but it could be related to other mutations in the promoter region of HSD11B2 or to the modulation of 11beta-HSD2 mRNA processing in hypertensive subjects.

Reduced nitric oxide levels in acromegaly: cardiovascular implications.

Acromegaly is characterized by major cardiovascular alterations. Although the underlying mechanisms of these vascular modifications have not been elucidated, recent studies have focused on endothelial dysfunction. Nitric oxide (NO) may contribute to increased vascular resistance, reduced platelet aggregation, inhibition of smooth muscle cell proliferation, and reduction of lipoxygenase activity. At present, no data on NO production in acromegalics are available. The aim of this study was to evaluate the effect of high levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) present in acromegaly on NO pathway to investigate the role played by this molecule in the cardiovascular changes experienced by these patients. We studied 13 acromegalics and 12 sex- and age-matched normotensive controls. Platelet NO levels were measured in the supernatant of lysed platelets. Endothelial NO synthase (eNOS) was determined by Western blot analysis of platelets. NO concentrations were significantly reduced in patients (p<0.0001). There were no differences between male and female patients, nor were platelet NO levels and the presence/absence of hypertension related in acromegalics; by contrast, NO concentrations inversely correlated with GH (p=0.03) and IGF-1 (p=0.04) levels, and with disease duration (p=0.04). eNOS protein concentrations were significantly reduced in the platelets of patients compared with controls (p<0.0001). This study demonstrates for the first time a strong reduction in platelet NO concentrations in acromegalic patients due to reduced eNOS expression. Moreover the inverse correlation of NO levels with GH, IGF-1 and disease duration suggests that reduced levels of platelet NO linked to GH excess may contribute to the vascular alterations affecting patients with acromegaly.

[Endocrinology of aldosterone]. / Endocrinologia dell'aldosterone.

Aldosterone is the major mineralocorticoid hormone produced by the zona glomerulosa of the adrenal cortex. Aldosterone secretion is mainly regulated by the renin-angiotensin system, and to a minor extent by serum concentration of potassium, sodium, adrenocorticotropic hormone. and dopamine. This hormone, as well as other adrenal corticosteroids, exert many of its physiological actions through modulation of gene expression. It binds cytosolic receptors that translocate to the nucleus in a ligand-dependent manner and induces transcription of specific genes that encode for proteins involved in the cardiovascular homeostasis. Such proteins act regulating vascular tone, sympathetic nervous system activity, and hydroelectrolyte transport in epithelial tissues. Classical aldosterone target tissues are kidney, colon, sweat and salivary glands. Apart from the genomic effects, which imply a direct action on DNA, rapid non-genomic actions of aldosterone have been recently described in both epithelial and non-epithelial tissues and structures such as heart, vasculature, and kidney. At these sites aldosterone contributes to the development of cardiac fibrosis, myocardial hypertrophy, heart failure and arrhythmias; other deleterious effects exerted by aldosterone include vascular remodeling, endothelial dysfunction, perivascular inflammation, renal fibrosis, and progressive renal failure. Finally, recent evidence has focused on the possible implications of aldosterone excess on metabolic alterations, as described in patients with primary aldosteronism. On these premises lies the pathogenetic role of aldosterone in the development of cardiovascular diseases and the rationale for the use of mineralocorticoid receptor antagonists in the primary and secondary prevention of the complications related to these diseases.