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The gut microbiome regulates many important host physiological processes associated with cardiovascular health and disease; however, the impact of the gut microbiome on aldosterone is unclear. Investigating whether gut microbiota regulate aldosterone can offer novel insights into how the microbiome affects blood pressure. In this study, we aimed to determine whether gut microbiota regulate host aldosterone. We used enzyme-linked immunosorbent assays (ELISAs) to assess plasma aldosterone and plasma renin activity (PRA) in female and male mice in which gut microbiota are intact, suppressed, or absent. In addition, we examined urinary aldosterone. Our findings demonstrated that when the gut microbiota is suppressed following antibiotic treatment, there is an increase in plasma and urinary aldosterone in both female and male mice. In contrast, an increase in PRA is seen only in males. We also found that when gut microbiota are absent (germ-free mice), plasma aldosterone is significantly increased compared with conventional animals (in both females and males), but PRA is not. Understanding how gut microbiota influence aldosterone levels could provide valuable insights into the development and treatment of hypertension and/or primary aldosteronism. This knowledge may open new avenues for therapeutic interventions, such as probiotics or dietary modifications to help regulate blood pressure via microbiota-based changes to aldosterone. NEW & NOTEWORTHY We explore the role of the gut microbiome in regulating aldosterone, a hormone closely linked to blood pressure and cardiovascular disease. Despite the recognized importance of the gut microbiome in host physiology, the relationship with circulating aldosterone remains largely unexplored. We demonstrate that suppression of gut microbiota leads to increased levels of plasma and urinary aldosterone. These findings underscore the potential of the gut microbiota to influence aldosterone regulation, suggesting new possibilities for treating hypertension.

Introduction: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl-]) was recently proposed as the "chloride (Cl) theory" for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the "Cl theory.", Methods: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones., Results: In the 29 patients, urinary Cl concentrations ([uCl-]) inversely correlated with log (plasma renin activity [PRA]) (r = -0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = -0.50, p = 0.006). The [sCl-]‒[uCl-] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl-]‒[uCl-] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (-77 to ‒5 mEq/L; n = 14), the absorption group (1-84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. -0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001)., Conclusion: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the "Cl theory." A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4-6, 2023., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period. Design: Prospective study Setting: One multi-disciplinary intensive care unit (ICU) Participants: Forty-two critically ill patients Methods: Messenger RNA (mRNA) expression of MR, HSD11B1 , and HSD11B2 , aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls. Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period. Conclusion: Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states., Competing Interests: Disclosure: The authors have not reported any financial or personal conflicts of interest related to this research., (Copyright © 2023 Marshfield Clinic Health System.)

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRR R279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na + channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury. NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na + -retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na + balance and blood pressure.

Primary aldosteronism (PA) is an endocrine related condition leading to arterial hypertension due to inappropriately high and unregulated aldosterone concentration. Recently, a broad spectrum of PA has been recognized, which brings new challenges associated with early identification of this condition that affect renal epithelial and extrarenal tissues. Reports have shown the potential role of extracellular vesicles (EVs) and EV cargo as novel and complementary biomarkers in diagnosis and prognosis of PA. In vivo and in vitro studies have identified specific EV surface antigens, EV-proteins, and EV microRNAs that can be useful to develop novel diagnostic algorithms to detect, confirm, or follow up the PA. Moreover, the study of EVs in the field of PA provides further insight in the pathophysiological mechanism of the PA disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hyperaldosteronism is a relatively more common disorder than previously recognized. Patients with hyperaldosteronism are at high risk for cardiovascular events. Patients suspected of having hyperaldosteronism should undergo initial screening and subsequent confirmatory testing to establish a biochemical diagnosis. Although adrenal computed tomography/magnetic resonance imaging scans often define a disease's subtype, adrenal vein sampling, in order to determine lateralization, may be necessary in some patients who are surgical candidates. Medical therapy using optimal doses of mineralocorticoid receptor antagonists can control symptoms and normalize plasma renin activity. The long-term outcome of patients treated with either surgical or optimal medical therapy appears similar., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Accurate quantification of plasma aldosterone (ALD) and renin activity (PRA)is critical for the diagnosis of primary aldosteronism (PA). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is considered the "gold standard" method for the determination of ALDand PRA. The aim of this study is to develop a new LC-MRM/MS assay for quantifying plasma ALD, PRA, and angiotensin II (Ang II) simultaneously and validate its effectiveness. To be more specific, plasmasamples were prepared by solid-phase extraction and separated in an ultra-performance reversed-phase column. MS detection was performed via a triple quadrupole mass spectrometer containing both positive and negative ion monitoring modes. The developed assay was then validated according to the standard guidelines and the influence of sample incubation on ALD and Ang II concentration was evaluated. In addition, the variation of endogenous Ang I was explored. The proposed LC-MRM/MS method was compared another LC-MS/MS method, which detects ALD, Ang I, and Ang II separately. Analyteswere separated and quantified within 5 min. The assay wasvalidated to be linear up to 5000 pg/ml for ALD and Ang II and 33.3 ng/ml/h for PRA.The lower limit of quantification (LLOQ) was 15 pg/ml, 15 pg/ml, and 0.1 ng/ml/hfor ALD, Ang II, and PRArespectively. Specificity, precision, accuracy, and stability were tested to meet the requirements of the guidelines. Significant changes were not found in ALD and Ang II concentrations over the 3 h-incubation. In addition, it was demonstratedthat the resultof PRA was not stronglyinfluenced by the endogenous Ang I. Comparison with another LC-MS/MS method was performed using the same apparatusand the proposed method was proved to be in good coincidence with the correlation coefficients rangingfrom 0.955to0.996. A sensitive and reliable method for simultaneousquantification of ALD, PRA, and Ang II has been developed and this study will significantly promote laboratory workflow efficiency and throughput., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The procedure for the captopril challenge test (CCT) in diagnosing primary aldosteronism (PA) is not standardized. We performed a meta-analysis to evaluate the controversial diagnostic value and influential factors of the post-captopril aldosterone/renin ratio (ARR)., Methods: We searched literature in databases for eligible studies (until October 1, 2020). We extracted information regarding study and patient characteristics, CCT methods, outcome data. We pooled studies using the random-effect model. We performed meta-regression and six pre-specified subgroup analyses to explore heterogeneity., Results: Nineteen studies involving 4568 subjects were included. The pooled sensitivity and specificity were 0.825 (95% CI 0.804-0.844) and 0.919 (95% CI 0.908-0.928). The area under the summary receiver operating characteristic curve was 0.9487 (95% CI 0.9207-0.9767). Meta-regression revealed that heterogeneity might derive from time interval ( p  = 0.0117) and study population ( p  = 0.0033). Subgroup analyses showed significant differences between the subgroups stratified by the dose, posture, study region, time interval, cut-off value and study population for sensitivity and/or specificity ( p  < 0.05)., Conclusion: Post-captopril ARR is comparably valuable for diagnosing PA at cut-offs from 12.0 to 50.0. Conducting the CCT in the supine position with 25 mg of captopril may attain greater sensitivity. Conducting the CCT in the seated position with 50 mg of captopril may attain greater specificity. A 90-min time interval may perform best in both the sensitivity and specificity.

Context: Previous studies have proposed cutoff value of baseline plasma aldosterone concentration (bPAC) under renin suppression that could diagnose primary aldosteronism (PA) without confirmatory testing. However, those studies are limited by selection bias due to a small number of patients and a single-center study design., Objective: This study aimed to determine cutoff value of bPAC and baseline plasma renin activity (bPRA) for predicting positive results in confirmatory tests for PA., Design: The multi-institutional, retrospective, cohort study was conducted using the PA registry in Japan (JPAS/JRAS). We compared bPAC in patients with PA who showed positive and negative captopril challenge test (CCT) or saline infusion test (SIT) results., Patients: Patients with PA who underwent CCT (n = 2256) and/or SIT (n = 1184) were studied., Main Outcome Measures: The main outcomes were cutoff value of bPAC (ng/dL) and bPRA (ng/mL/h) for predicting positive CCT and/or SIT results., Results: In patients with renin suppression (bPRA ≤ 0.3), the cutoff value of bPAC that would give 100% specificity for predicting a positive SIT result was lower than that for predicting a positive CCT result (30.85 vs 56.35, respectively). Specificities of bPAC cutoff values ≥ 30.85 for predicting positive SIT and CCT results remained high (100.0% and 97.0%, respectively) in patients with bPRA ≤ 0.6. However, the specificities of bPAC cutoff values ≥ 30.85 for predicting positive SIT and CCT results decreased when patients with bPRA > 0.6 were included., Conclusion: Confirmatory testing could be omitted in patients with bPAC ≥ 30.85 in the presence of bPRA ≤ 0.6., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Low-renin hypertension affects 30% of hypertensive patients. Primary hyperaldosteronism presents with low renin and aldosterone excess. Low-renin, low-aldosterone hypertension represents a wide spectrum of disorders that includes essential low-renin hypertension, hereditary forms of hypertension, and hypertension secondary to endogenous or exogenous factors. This review addresses the different conditions that present with low-renin hypertension, discussing an appropriate diagnostic approach and highlighting the genetic subtypes within familial forms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Resistant hypertension is a common clinical entity, defined as suboptimal blood pressure response to multiple therapies after excluding medication nonadherence and secondary forms of hypertension. Patients with resistant hypertension generally share several comorbidities. Resistant hypertension is more common in individuals of African descent. Blood pressure should be optimized using multiple strategies, including lifestyle changes and single-pill combination therapies, with the aim of reducing cardiovascular events while reducing side effects from using antihypertensive therapy. A renin/aldosterone-based diagnostic and treatment approach will help tailor therapy. The use of mineralocorticoid receptor antagonists or amiloride as appropriate is favored., (Published by Elsevier Inc.)

Background: Aldosterone has been linked with obesity, metabolic syndrome (MetS), pro-inflammatory, and prothrombotic states; however, most studies relate these indicators with primary aldosteronism (PA), excluding non-PA patients., Objective: To determine whether aldosterone, renin, or the plasma aldosterone/renin ratio (ARR) are associated with metabolic disorders and inflammatory/vascular biomarkers in a non-PA population., Methods: We studied 275 patients including adolescents and adults of both genders and measured plasma and urinary aldosterone and determined the plasma renin activity. In all subjects, the presence of MetS was determined according to Adult Treatment Panel III. Renal, vascular, inflammatory, and mineralocorticoid activity biomarkers were evaluated., Results: The ARR correlated with the number of variables of MetS (r = 0.191, P = 0.002), body mass index (BMI; r = 0.136, P = 0.026), systolic blood pressure (r = 0.183, P = 0.002), diastolic blood pressure (r = 0.1917, P = 0.0014), potassium excreted fraction (r = 0.174, P = 0.004), low-density lipoprotein (r = 0.156, P = 0.01), plasminogen activator inhibitor type 1 (r = 0.158, P = 0.009), microalbuminuria (r = 0.136, P = 0.029), and leptin (r = 0.142, P = 0.019). In a linear regression model adjusted by age, BMI, and gender, only the ARR was still significant (r = 0.108, P = 0.05). In a logistic regression analysis, the ARR predicted MetS index (odds ratio (OR) = 1.07 [95% confidence interval (CI) = 1.011-1.131], P= 0.02) even after adjusting for age, BMI, and gender. On the other hand, aldosterone showed no association with MetS or inflammatory markers., Conclusion: These results suggest a continuum of cardiometabolic risk beyond the classic PA threshold screening. The ARR could be a more sensitive marker of obesity, MetS, and endothelial damage in non-PA patients than aldosterone or renin alone. Prospective studies are needed to develop future screening cutoff values., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: The aldosterone/renin ratio is the initial screening test for primary hyperaldosteronism (PHA), but little data exists regarding ethnic variations in this., Methods: Following clinical observation of a high prevalence of abnormal aldosterone/renin ratio (ARR) in patients of African-origin, we retrospectively reviewed all ARR measurements in a single centre over 10 years. Rates of hypokalaemia, intraventricular septal thickness (IVS, by echocardiography) and adrenal imaging were recorded when available., Results: Aldosterone/renin ratio was available in 1473 patients, and abnormal in 374 (25.4%). Abnormal ARR was observed in 305/1349 (22.6%) of European-origin and 69/124 (55.6%) of African-origin patients (P < 0.001). Among those with abnormal ARR, hypokalaemia (<3.5 mmol/L) was documented on at least one occasion in 171/305 (56.1%) European-origin and 43/69 (62.3%) African-origin patients (P = 0.35). Median (range) IVS was 1.57 (0.78-2.80) cm in African-origin and 1.20 (0.69-2.18) cm in European-origin patients (P < 0.002); IVS did not correlate with aldosterone or ARR however. Adrenal adenoma was identified in 41/170 (24.1%) of European-origin and 4/29 (13.7%) African-origin patients (P = 0.15), while hyperplasia was identified in 35/170 (20.5%) of European and 8/29 (27.5%) African patients (P = 0.39)., Conclusion: In summary, ARR was abnormal in 55.6% of African-origin patients screened at an Irish hospital. Rates of hypokalaemia were similar between European-origin and African-origin patients. These findings have implications for the use of current screening guidelines for ARR in African-origin patients and also for the mechanistic role of aldosterone in hypertensive complications in African-origin patients., (© 2018 John Wiley & Sons Ltd.)

Background Mechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross-sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance ( IR ), β-cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study. Methods and Results Homeostatic model assessment of IR ( HOMA 2- IR ) and HOMA 2-β were used to estimate IR and β-cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti-diabetic medication use at follow-up. Linear regression was used to examine cross-sectional associations of aldosterone with fasting plasma glucose, HOMA 2- IR and HOMA 2-β; Cox regression was used to estimate hazard ratios ( HR ) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non-Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log-aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA 2- IR and 6% higher HOMA 2-β ( P<0.01). A 1- SD increase in log-aldosterone was associated with a 44% higher risk of incident diabetes mellitus ( P<0.01) with the greatest increase of 142% ( P<0.01) observed in Chinese Americans ( P for interaction=0.09 versus other ethnicities). Similar cross-sectional findings for log-plasma renin activity existed, but log-plasma renin activity was not associated with incident diabetes mellitus after full adjustment. Conclusions Aldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.

Pregnant women with chronic hypertension are at risk for increased blood pressure and superimposed preeclampsia (SPE) in late pregnancy. Alterations in the renin-aldosterone system are a feature of normal pregnancy; however, their role in chronic hypertension with and without SPE is less clear. We performed a prospective, longitudinal trial of 108 women with chronic hypertension and measured plasma renin activity (PRA), 24-hour urine sodium, urine potassium, and urine aldosterone (Ualdo) at 12, 20, 28, and 36 weeks and postpartum. SPE developed in 34% of pregnancies. PRA was lower in women who developed SPE at weeks 28 (5.99 versus 6.22 ng/mL per hour; P <0.001) and 36 (5.71 versus 7.74 ng/mL per hour; P =0.002). Ualdo was lower in women with SPE compared with those without SPE at 28 weeks (59.6 versus 81.3 μg/d; P =0.039). Mean arterial pressure was inversely related to both PRA ( r =-0.23; P <0.0001) and Ualdo ( r =-0.11; P =0.029). PRA and Ualdo were positively associated with each other ( r =0.5327; P <0.0001) after adjusting for urine potassium, urine sodium, serum potassium, and mean arterial pressure. PRA and Ualdo were lower in women of black race compared with other racial groups ( P <0.001). Our results demonstrate that in women with chronic hypertension PRA and Ualdo increase in early pregnancy and subsequently decrease in women who develop SPE. These findings are consistent with the hypothesis that sodium retention may contribute to the elevation in blood pressure in SPE., (© 2018 American Heart Association, Inc.)

Background: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Reported prevalences of PA vary considerably because of a large heterogeneity in study methodology., Aim: To examine the proportion of patients with PA among patients with newly diagnosed, never treated hypertension., Design and Setting: A cross-sectional study set in primary care., Method: GPs measured aldosterone and renin in adult patients with newly diagnosed, never treated hypertension. Patients with elevated aldosterone-to-renin ratio and increased plasma aldosterone concentration underwent a saline infusion test to confirm or exclude PA. The source population was meticulously assessed to detect possible selection bias., Results: Of 3748 patients with newly diagnosed hypertension, 343 patients were screened for PA. In nine out of 74 patients with an elevated aldosterone-to-renin ratio and increased plasma aldosterone concentration the diagnosis of PA was confirmed by a saline infusion test, resulting in a prevalence of 2.6% (95% confidence interval = 1.4 to 4.9). All patients with PA were normokalaemic and 8 out of 9 patients had sustained blood pressure >150/100 mmHg. Screened patients were younger ( P <0.001) or showed higher blood pressure ( P <0.001) than non-screened patients., Conclusion: In this study a prevalence of PA of 2.6% in a primary care setting was established, which is lower than estimates reported from other primary care studies so far. This study supports the screening strategy as recommended by the Endocrine Society Clinical Practice Guideline. The low proportion of screened patients (9.2%), of the large cohort of eligible patients, reflects the difficulty of conducting prevalence studies in primary care clinical practice., (© British Journal of General Practice 2018.)

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell-deficient C57BL/6 Kit W-sh/W-sh mice in comparison with wild-type C57BL/6 mice. Kit W-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 Kit W-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction., (© 2017 American Heart Association, Inc.)

A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase the primary angiotensin II forming enzyme in the human heart, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: This study examined the association of aldosterone and plasma renin activity (PRA) with incident cardiovascular disease (CVD), using a composite endpoint of coronary heart disease, stroke, and/or heart failure and mortality among African Americans in the Jackson Heart Study., Background: There is a paucity of data for the association of aldosterone and PRA with incident CVD or all-cause mortality among community-dwelling African Americans., Methods: A total of 4,985 African American adults, 21 to 94 years of age, were followed for 12 years. Aldosterone, PRA, and cardiovascular risk factors were collected at baseline (from 2000 to 2004). Incident events included coronary heart disease and stroke (assessed from 2000 to 2011) and heart failure (assessed from 2005 to 2011). Cox models were used to estimate hazard ratios (HRs) for incident CVD and mortality, adjusting for age, sex, education, occupation, current smoking, physical activity, dietary intake, and body mass index., Results: Among 4,160 participants without prevalent CVD over a median follow-up of 7 years, there were 322 incident CVD cases. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HR of 1.26 (95% confidence intervals [CI]: 1.14 to 1.40) and 1.16 (95% CI: 1.02 to 1.33) for incident CVD, respectively. Over a median of 8 years, 513 deaths occurred among 4,985 participants. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HRs of 1.13 (95% CI: 1.04 to 1.23) and 1.12 (95% CI: 1.01 to 1.24) for mortality, respectively., Conclusions: Elevated aldosterone and PRA may play a significant role in the development of CVD and all-cause mortality among African Americans., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA)., Objective: To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation., Participants: Six hundred sixty-three normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications., Design: Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile = "Inappropriate/Excess MR Activity;" middle PRA tertile = "Intermediate MR Activity;"; and highest PRA tertile = "Physiologic MR Activity." All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake, and associations with stimulated PRA phenotypes were performed., Results: Participants with lower stimulated PRA had greater autonomous aldosterone secretion [higher aldosterone-to-renin ratio (P = 0.002), higher urine aldosterone excretion rate (P = 0.003), higher systolic blood pressure (P = 0.004), and lower renal plasma flow (P = 0.04)] and a nonsignificant trend toward lower serum potassium and higher urine potassium excretion, which became significant after stratification by hypertension status., Conclusions: In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized MR activation., (Copyright © 2017 Endocrine Society)

Background: The most popular screening test for primary aldosteronism is the plasma aldosterone/renin ratio (ARR). Medications, dietary sodium, posture, and time of day all affect renin and aldosterone levels and can result in false-negative or false-positive ARRs if not controlled. Most antihypertensive medications affect the ARR and can interfere with interpretation of results. To our knowledge, no study has been undertaken to evaluate the effects of moxonidine on the ARR., Methods: Normotensive, nonmedicated male volunteers (n = 20) underwent measurement (seated, midmorning) of plasma aldosterone (by high-performance liquid chromatography-tandem mass spectrometry), direct renin concentration (DRC), plasma renin activity (PRA), cortisol, electrolytes and creatinine; and urinary aldosterone, cortisol, electrolytes and creatinine at baseline and after 1 week of moxonidine at 0.2 mg/d and a further 5 weeks at 0.4 mg/d., Results: Compared with baseline, despite the expected significant falls in both systolic and diastolic blood pressure, levels of plasma aldosterone [median, 134 (range, 90 to 535) pmol/L], DRC [20 (10 to 37) mU/L], PRA [2.2 (1.0-3.8) ng/mL/h], and ARR using either DRC [8.0 (4.4 to 14.4)] or PRA [73 (36 to 218)] were not significantly changed after either 1 [135 (98-550) pmol/L, 20 (11-35) mU/L, 2.0 (1.2-4.1) ng/mL/h, 8.8 (4.2 to 15.9), and 73 (32-194), respectively] or 6 weeks [130 (90-500) pmol/L, 22 (8 to 40) mU/L, 2.1 (1.0 to 3.2) ng/mL/h, 7.7 (4.3 to 22.4), and 84 (32 to 192), respectively] of moxonidine. There were no changes in any urinary measurements., Conclusion: Moxonidine was associated with no significant change in the ARR and may therefore be a good option for maintaining control of hypertension when screening for primary aldosteronism., (Copyright © 2017 Endocrine Society)

Background: Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the cause of chronic fatigue syndrome (CFS). A small heart or reduced left ventricular volume with reduced cardiac output has been reported to be common in patients with ME. The main circulatory blood volume regulators may be down-regulated., Methods: Plasma levels of the neurohumoral factors that regulate circulatory blood volume were determined in 18 patients with ME and 15 healthy subjects (Controls)., Results: The echocardiographic examination revealed that the mean values for the left ventricular end-diastolic diameters, stroke volume index, and cardiac index as well as the mean blood pressure were all significantly smaller in the ME group than in the Controls. The mean plasma renin activity (1.6±1.0ng/ml/h vs. 2.5±1.5ng/ml/h, p=0.06) was considerably lower in the ME group than in the Controls. Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls. Desmopressin (120μg), a synthetic version of arginine vasopressin, was orally administered for five successive days to 10 patients with ME. In five patients (50%), the symptoms of orthostatic intolerance during a 10min active standing test were ameliorated in association with a significant increase in urinary osmotic pressure and decrease in heart rate. Furthermore, in five patients (50%), the performance status scores for the activities of daily living were improved., Conclusions: Both the renin-aldosterone and ADH systems were down-regulated despite the existence of reduction in cardiac preload and output in patients with ME. Desmopressin improved symptoms in half of the patients., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS +/- mice. On high salt diet (HS), BPs of hAS +/- mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS +/- mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.

Nowadays, GLP-1 receptor agonists are widely used as effective and safe antidiabetic medications. In addition to glucose-dependent insulin secretion, their effects reach beyond glucose control. Previously, it has been shown that acute administration of GLP-1 receptor agonists increases circulating glucocorticoid and mineralocorticoid levels in both humans and rodents. So far, no studies have reported the effects of chronic administration of GLP-1 receptor agonists on the hypothalamic-pituitary-adrenal axis in humans. The aim of the current study was to examine the effects of acute and chronic treatment with the GLP-1 receptor agonist liraglutide on adrenal function in humans. Ten healthy volunteers were recruited into a single group open-label clinical trial. Each participant was tested for baseline levels, and after acute and chronic treatment with 0.6 mg liraglutide daily. A graded glucose infusion test was performed 3 times. We found that aldosterone tended to be suppressed (albeit not statistically different) after acute administration of liraglutide, and increased after chronic dosing; the difference was statistically significant when compared between acute and chronic dosing. Changes in aldosterone levels followed the changes in renin concentrations and the aldosterone-to-renin ratio remained stable. No statistically significant differences were observed in ACTH or cortisol levels. In conclusion, we have shown that a low dose of GLP-1 receptor agonist may interfere with renin and aldosterone release. Further studies in a larger patient sample and with higher doses of GLP-1 receptor agonists are warranted to corroborate this finding. The study protocol was registered at clinical.trials.gov (NCT02089256) and EU Clinical Trial Register (2014-000238-43)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The decrease in kidney perfusion as often observed in hypertensive individuals does not necessarily occur in a symmetrical fashion, thereby potentially introducing left-right differences in response to vasoactive agents. Increased aldosterone levels have been associated with reduced renal perfusion in normotensive and hypertensive individuals, but it is unknown whether both kidneys are equally affected in this respect and how angiotensin II is involved in this relationship. Therefore, our aim was to investigate the association of both aldosterone and the aldosterone-renin ratio with side-selective renal blood flow in essential hypertension., Methods: We studied 146 essential hypertensive patients with patent renal arteries who had undergone renal angiography for exclusion of renal artery stenosis. Prior to contrast administration, blood samples were drawn for the determination of renin and aldosterone levels, and side-selective renal blood flow was measured using the 133Xenon washout technique., Results: Left mean renal blood flow (MRBF) was significantly lower than right MRBF (227±74 vs. 250±76mL * min-1 * 100g kidney-1, P = 0.01). We could not demonstrate a correlation of ln aldosterone or ln renin with left or right kidney perfusion. Ln aldosterone-renin ratio (ARR), however, was inversely and independently associated with left MRBF (β = -13.993, P = 0.02; fully adjusted model) but not with right MRBF., Conclusions: A higher ARR corresponds to reduced perfusion of the left kidney, yet is not associated with right kidney perfusion. Especially under circumstances of diminished right renal blood flow, this may affect blood pressure and kidney function.

(Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release.

Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Among patients with resistant hypertension, primary aldosteronism (PA) is worth detecting as it appears to be particularly common in this cohort. It is associated with excessive cardiovascular morbidity in relation to the degree of hypertension and reduced quality of life, both of which can be abrogated with specific surgical or medical treatment. Knowledge concerning factors (including medications) which can influence the results of screening by aldosterone/renin ratio (ARR) testing is expanding, and is important to appreciate, particularly in patients with resistant hypertension, in whom the need for multiple medications can render interpretation challenging. Advances in approaches to confirmatory testing, subtype differentiation and assay methodology are helping to improve feasibility and reliability of the diagnostic workup for PA and new treatment approaches are emerging. Major developments in understanding the genetic bases for PA hold promise towards further improvements and options in diagnosis and therapy.

A successful pregnancy requires an accommodating environment. Salt and water availability are critical for plasma volume expansion. Any changes in sodium intake would alter aldosterone, a hormone previously described beneficial in pregnancy. To date, it remains ambiguous whether high aldosterone or high salt intake is preferable. We hypothesized that increased aldosterone is a rescue mechanism and appropriate salt availability is equally effective in maintaining a normotensive blood pressure (BP) phenotype in pregnancy. We compared normotensive pregnant women (n=31) throughout pregnancy with young healthy female individuals (n=31-62) and performed salt sensitivity testing within the first trimester. Suppression of urinary tetrahydro-aldosterone levels by salt intake as measured by gas chromatography-mass spectrometry and urinary sodium excretion corrected for creatinine, respectively, was shifted toward a higher salt intake in pregnancy (P<0.0001). In pregnancy, neither high urinary tetrahydro-aldosterone nor sodium excretion was correlated with higher BP. In contrast, in nonpregnant women, systolic BP rose with aldosterone (P<0.05). Testing the impact of salt on BP, we performed salt sensitivity testing in a final cohort of 19 pregnant and 24 nonpregnant women. On salt loading, 24-hour mean arterial pressure rose by 3.6±1.5 and dropped by -2.8±1.5 mm Hg favoring pregnant women (P<0.01; χ(2)=6.04; P<0.02). Our data suggest first that salt responsiveness of aldosterone is alleviated in conditions of pregnancy without causing aldosterone-induced hypertension. Second, salt seems to aid in BP lowering in pregnancy for reasons incompletely elucidated, yet involving renin suppression and potentially placental sensing mechanisms. Further research should identify susceptible individuals and clarify effector mechanisms.

This review describes the changes that occur in circulating renin-angiotensin-aldosterone system (RAAS) components in human pregnancy. These changes depend on endocrine secretions from the ovary and possibly the placenta and decidua. Not only do these hormonal secretions directly contribute to the increase in RAAS levels, they also cause physiological changes within the cardiovascular system and the kidney, which, in turn, induce reflex release of renal renin. High levels of ANG II play a critical role in maintaining circulating blood volume, blood pressure, and uteroplacental blood flow through interactions with the ANG II type I receptor and through increased production of downstream peptides acting on a changing ANG receptor phenotype. The increase in ANG II early in gestation is driven by estrogen-induced increments in angiotensinogen (AGT) levels, so there cannot be negative feedback leading to reduced ANG II production. AGT can exist in various forms in terms of redox state or complexed with other proteins as polymers; these affect the ability of renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I production varies not only because levels of renin change in response to homeostatic demand but also because AGT changes not only in concentration but in form. Activation of the circulating and intrarenal RAASs is essential for normal pregnancy outcome subserving the increased demand for salt and, hence, water during pregnancy. Thus, the complex integration of the secretions and actions of the circulating maternal renin-angiotensin system in pregnancy plays a key role in pregnancy outcome.

We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

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.

Aldosterone, the key hormone in the mineralocorticoid pathway, plays a fundamental role in salt and water homeostasis, blood pressure regulation, and cardiovascular remodeling. Both genomic and nongenomic mechanisms influence aldosterone-induced renal sodium reabsorption. Furthermore, the mineralocorticoid receptors in nonepithelial tissues, including the heart and vascular smooth muscle cells, have recently been discovered. Thus, aldosterone likely has pleiotropic effects that contribute to the modulation of blood pressure. Among patients with hypertension in general, and among those with more severe or resistant hypertension in particular, a higher-than-expected prevalence of primary hyperaldosteronism is noted. Among individuals with resistant hypertension, aldosterone antagonists have also been shown to be effective in lowering blood pressure. Most significantly, recent community-based studies among non-hypertensive individuals in the general population have demonstrated that both higher serum aldosterone concentrations and a higher aldosterone to renin ratio portend a greater risk of developing hypertension. The combination of the aforementioned observations underscores the importance of the mineralocorticoid pathway in the pathogenesis of hypertension.

Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT(1)R) blockade. This is important as, even with contemporary use of AT(1)R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT(1)R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT(1)R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (i.e. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels., (Published by Elsevier B.V.)

The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-β1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4).

Aims: Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results., Methods and Results: We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass (P= 0.001), LV mass index (P= 0.001), relative wall thickness (P= 0.011), and LV posterior wall thickness (P< 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31-2.68; P= 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling., Conclusion: Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.

Background: Plasma aldosterone to renin ratio (ARR) is the most popular screening test for primary aldosteronism (PAL). Certain medications are known to cause false-negative or -positive ARRs by affecting renin and aldosterone levels. There are no previously published data on the effects of antidepressants on ARR., Methods: Normotensive, depressed male patients (n = 26) underwent measurement (seated, midmorning) of plasma aldosterone, direct renin concentration (DRC), renin activity (PRA), electrolytes and creatinine and urinary aldosterone, cortisol, electrolytes, and creatinine at baseline and after 2 and 6 wk treatment with sertraline (n = 14) or escitalopram (n = 12)., Results: For both antidepressants, treatment was associated with rises in aldosterone [sertraline: baseline, mean ± sd, 243 ± 34; 2 wk, 256 ± 33; 6 wk, 267 ± 34 pmol/liter (P < 0.01 by ANOVA); escitalopram, 261 ± 36, 269 ± 38, 282 ± 40 pmol/liter (P < 0.05)], DRC [19.5 ± 2.2, 33.5 ± 2.0, 39.0 ± 2.4 mU/liter (P < 0.001); 24.5 ± 2.4, 34.0 ± 2.7, 42.8 ± 2.4 mU/liter (P < 0.001)], and PRA [2.24 ± 0.21, 2.58 ± 0.26, 4.68 ± 0.42 ng/ml · h (P < 0.001); 4.31 ± 0.22, 5.57 ± 0.36, 6.42 ± 0.53 ng/ml · h (P < 0.001)]. ARR fell significantly whether calculated using DRC [sertraline, 13.7 ± 2.2, 7.5 ± 0.7, 6.8 ± 0.7 (P < 0.001); escitalopram, 11.5 ± 1.9, 8.0 ± 1.1, 6.6 ± 1.0 (P < 0.001)], or PRA [116.6 ± 15.8, 108.4 ± 15.6, 60.4 ± 6.2 (P < 0.001); 61.2 ± 8.1, 50.0 ± 7.7, 45.6 ± 6.0 (P < 0.01)]., Conclusion: Selective serotonin reuptake inhibitor antidepressants can significantly reduce ARR and therefore potentially increase the risk of false-negative results when screening for PAL. Further studies in hypertensive patients, including patients with confirmed PAL, are required.

Primary aldosteronism (PA) is defined as inappropriately high and (relatively or absolutely) autonomous aldosterone secretion, which is not adequately suppressible by sodium loading. Recent evidence shows that the PA prevalence ranges from 3 to 32%. This high prevalence of PA is suggested to be the result of both more intense screening for PA and improvement of laboratory procedures. Inappropriate high aldosterone secretion is paralleled by severe target organ damage, underlining the importance for the identification of PA at an early stage. The aldosterone to renin ratio (ARR), which reflects aldosterone hypersecretion in regard to its principal trophin renin, is currently considered the most reliable tool for PA screening. Accumulating evidence, however, points to a considerable intra-individual variation of this ratio, emphasizing the importance of standardized screening procedures. In particular, laboratory methods, posture, antihypertensive medication, and dietary salt intake are significant effectors of ARR variation. Furthermore, differentiation between low-renin essential hypertension and PA is difficult and probably arbitrary. It is the purpose of the present review to issue the reliability of the ARR as a screening tool for PA. This review also provides an overview about the physiology of the renin-angiotensin-aldosterone system, highlights current laboratory methods for aldosterone and renin determination, and addresses potential influence factors on the ARR., (Georg Thieme Verlag KG Stuttgart-New York.)

In patients with dilated cardiomyopathy (DCM) abnormal myocardial blood flow (MBF) has been associated with coronary microvascular dysfunction. The aim of this study was to test the hypothesis that osteopontin (OPN) plasma levels could be associated with the activation of the renin-aldosterone system (RAS) in these patients and be involved in mediating myocardial and coronary damage. In 66 patients with idiopathic left ventricular dysfunction of variable severity the plasma levels of OPN were correlated with biomarkers of systemic metabolism, RAS activation, myocardial dysfunction and with clinical indexes of left ventricle (LV) function and perfusion obtained by 2D-echocardiography and PET. As compared to controls, patients showed a significant increase of inflammatory markers (OPN: 508+/-30.8ng/ml vs. 426.9+/-16.4, p<0.05 and interleukin (IL)-6: 1.71+/-0.29pg/ml vs. 0.38+/-0.03pg/ml, p<0.001) and of indexes of cardiac damage. OPN levels were significantly correlated with the extent of microvascular dysfunction (MBF at rest: p=0.01; during dipyridamole: p=0.0003) and with plasma renin activity (PRA) (r=0.26, p=0.04). Both in patients with milder or more severe LV dysfunction lower MBF values were associated with higher OPN levels and PRA. These results suggest a interdependent role of RAS and vascular inflammation in cardiomyopathy., (2009 Elsevier Ltd. All rights reserved.)

Background: Increased aldosterone concentrations and volume expansion of normal pregnancies are hallmarks of normal pregnancies and blunted in pre-eclampsia. Accordingly, we hypothesized an active mineralocorticoid system to protect from pre-eclampsia., Methods: In pregnant women (normotensive n = 44; pre-eclamptic n = 48), blood pressure, urinary tetrahydro-aldosterone excretion and activating polymorphisms (SF-1 site and intron 2) of the aldosterone synthase gene (CYP11B2) were determined; 185 non-pregnant normotensive individuals served as control. Amino acid-changing polymorphisms of the DNA- and agonist-binding regions of the mineralocorticoid receptor were evaluated by RT-PCR, SSCP and sequencing., Results: Urinary tetrahydro-aldosterone excretion was reduced in pre-eclampsia as compared to normal pregnancy (P < 0.05). It inversely correlated with blood pressure (r = 0.99, P < 0.04). Homozygosity for activating CYP11B2 polymorphisms was preferably present in normotensive as compared to pre-eclamptic pregnancies, identified (intron 2, P = 0.005; SF-1 site, P = 0.016). Two mutant haplotypes decreased the risk of developing pre-eclampsia (RR 0.16; CI 0.05-0.54; P < 0.001). In contrast, intron 2 wild type predisposed to pre-eclampsia (P < 0.0015). No functional mineralocorticoid receptor mutant has been observed., Conclusions: High aldosterone availability is associated with lower maternal blood pressure. In line with this observation, gain-of-function variants of the CYP11B2 reduce the risk of developing pre-eclampsia. Mutants of the mineralocorticoid receptor cannot explain the frequent syndrome of pre-eclampsia.

African Americans, particularly men, have the highest morbidity and mortality rates from hypertension in the United States. The authors studied 527 African Americans in a general clinical research center to determine whether there are sex differences in the relationships between hypertension with insulin resistance (IR) and aldosterone, which are risk factors for cardiovascular disease. Measurements included ambulatory blood pressure (BP), anthropometric measures, plasma renin activity, plasma aldosterone (PA) concentration, and fasting serum lipids, glucose, and insulin. IR was estimated using the Homeostasis Model Assessment (HOMA) model. BP correlated with aldosterone in both sexes. However, both BP and PA correlated with IR in men, but not in women. Compared with men in the lower tertile of HOMA-IR, men in the upper tertile had higher mean systolic BP, a higher odds ratio of having hypertension, and higher levels of PA. The association of IR with both hypertension and PA in men, but not in women, may contribute to the high prevalence of cardiovascular disease in African American men.

Background: Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid., Methods: In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites., Results: Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical., Conclusion: In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.

Important mechanism of pathogenesis of hypertension in obesity is renin-aldosterone system in adipose tissue. Adrenal cells can be also stimulated to aldosterone secretion by local adrenal fat cells and also by other factors from fat tissue (lipids, endocrine disruptors). Local system renin-aldosteron is active also in other tissues and organs in obesity related hypertension. Feed back is closed by recently investigated fact that aldosteron hypersecretion can cause metabolic syndrome. Between systemic approach to obesity a new phenomenon of organ obesity is coming - adipokines from local fat cells can influence organ and tissue function e.g. in essential hypertension.

Purpose of Review: Aldosterone and its mineralocorticoid receptor represent an ancient signaling system. Indeed, the mineralocorticoid receptor is older than its agonist. Both have probably served various functions through the eons and salt preservation may be relatively recent. A large body of evidence suggests that aldosterone conducts signaling in vascular cells and contributes substantially to vascular remodeling and target organ damage. A blood pressure and salt balance-independent effect was first observed in two large heart failure trials., Recent Findings: Mineralocorticoid receptor blockade has now been shown to reduce proteinuria even in the face of angiotensin converting enzyme inhibition and AT1 receptor blockade. Mineralocorticoid receptor blockade effectively reduces target organ damage in every hypertensive model tested, irrespective of circulating renin and aldosterone levels. Protection is also observed in nonhypertensive diabetic and hyperlipidemic models. Signaling in vascular cells involves primarily the mitogen activated protein kinase pathway with participation of the epidermal growth factor receptor. Novel signaling molecules have been shown to participate in aldosterone-mediated actions including the murine double-minute type 2 protein that participates in antiapoptotic and proliferative effects. Clinically, mutations in the mineralocorticoid receptor have shed additional light on its importance., Summary: A resurgence of interest in aldosterone reflects its importance and clinical relevance for vascular remodeling and target organ damage.

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.