Serum Aldosterone Concentration Research Articles

The salt sensitivity of Drd4-null mice is associated with the upregulations of sodium transporters in kidneys.

To explore the mechanism of the hypertension in dopamine receptor-4 (Drd4) null mice, we determined the salt sensitivity and renal sodium transport proteins in Drd4-/- and Drd4+/+ mice with varied salt diets. On normal NaCl diet (NS), mean arterial pressures (MAP, telemetry) were higher in Drd4-/- than Drd4+/+; Low NaCl diet (LS) tended to decrease MAP in both strains; high NaCl diet (HS) elevated MAP with sodium excretion decreased and pressure-natriuresis curve shifted to right in Drd4-/- relative to Drd4+/+ mice. Drd4-/- mice exhibited increased renal sodium-hydrogen exchanger 3 (NHE3), sodium-potassium-2-chloride cotransporter (NKCC2), sodium-chloride cotransporter (NCC), and outer medullary α-epithelial sodium channel (αENaC) on NS, decreased NKCC2, NCC, αENaC, and αNa+-K+-ATPase on LS, and increased αENaC on HS. NKCC2, NCC, αENaC, and αNa+-K+-ATPase in plasma membrane were greater in Drd4-/- than in Drd4+/+ mice with HS. D4R was expressed in proximal and distal convoluted tubules, thick ascending limbs, and outer medullary collecting ducts and colocalized with NKCC2 and NCC. The phosphorylation of NKCC2 was enhanced but ubiquitination was reduced in the KO mice. There were no differences between the mouse strains in serum aldosterone concentrations and urinary dopamine excretions despite their changes with diets. The mRNA expressions of renal NHE3, NKCC2, NCC, and αENaC on NS were not altered in Drd4-/- mice. Thus, increased protein expressions of NHE3, NKCC2, NCC and αENaC are associated with hypertension in Drd4-/- mice; increased plasma membrane protein expression of NKCC2, NCC, αENaC, and αNa+-K+-ATPase may mediate the salt sensitivity of Drd4-/- mice.

PREVALENCE AND OUTCOME OF PRIMARY ALDOSTERONISM IN PBMAH: A SINGLE CENTER STUDY AND A SYSTEMATIC REVIEW OF THE LITERATURE

Objective: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH), characterized by benign adrenocortical macronodules and variable levels of cortisol excess, can also lead to an excess of mineralocorticoids, although there is only anecdotal evidence. To assess the prevalence and characteristics of primary aldosteronism (PA) in patients with PBMAH. Design and method: We conducted a systematic review according to the PRISMA guidelines. We reviewed single case reports and case series of patients with PBMAH and PA in Pubmed, Embase and Cochrane from database inception to December 2023. PBMAH was defined radiologically as at least 1 bilateral adrenal nodule of at least 10 mm. Findings were compared to patients with PBMAH without PA derived from LMU Hospital and literature. Results: 1018 articles were screened, and 36 articles were assessed for eligibility. We identified 18 articles (8 single case reports and 10 case series), resulting in 68 cases with PBMAH with PA. Of those, 12 had cosecretion of cortisol. The prevalence of PA in PBMAH, in six studies (166 patients), ranged from 2-44%. The median age at diagnosis was 51.5 (47.5-56.2). The majority of patients with PBMAH and PA were male compared to patients with PBMAH without PA (59% vs 39%, p= 0.0295). At baseline, the mean arterial pressure was 112 mmHg (113-133) and the median duration of hypertension was 108 months (48-135). The serum aldosterone concentration and plasma renin activity were 253 ng/l (159-436) and 0.23 ng/ml/h (0.16-0.44), respectively. Adrenal nodules were smaller in patients with PBMAH with PA compared to patients with PBMAH without PA (22 vs 30 mm, p=0.0498). Treatment modality was reported in 30 cases: 28 patients underwent adrenalectomy (two bilateral, two subtotal, and 24 unilateral) and two received mineralocorticoid receptor antagonists (MRA). In comparison, fewer patients with PBMAH without PA underwent adrenalectomy (54/106, p=0.0005). Conclusions: PA in PBMAH appears to be more frequent than previously thought. Multicenter studies will help to clarify the association between these conditions and the most appropriate treatment modality.

Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. Ten healthy purpose-bred Beagle dogs. Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

Conn´s syndrome after kidney transplantation.

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least atriple combination of antihypertensives, including adiuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control.In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on across-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium.We present the case of apatient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from adeceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with adual combination of antihypertensives (amlodipine at adaily dose of 5 mg and carvedilol at adaily dose of 50 mg), without the need for adiuretics.We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome (Fig. 3, Ref. 19). Text in PDF www.elis.sk Keywords: kidney transplantation, primary hyperaldosteronism, hypokalaemia, metabolic alkalosis, secondary arterial hypertension.

Association of Elevated Serum Aldosterone Concentrations in Pregnancy with Hypertension.

Emerging evidence indicates a previously unrecognized, clinically relevant spectrum of abnormal aldosterone secretion associated with hypertension severity. It is not known whether excess aldosterone secretion contributes to hypertension during pregnancy. We quantified aldosterone concentrations and angiotensin peptides in serum (using liquid chromatography with tandem mass spectrometry) in a cohort of 128 pregnant women recruited from a high-risk obstetrics clinic and followed prospectively for the development of gestational hypertension, pre-eclampsia, superimposed pre-eclampsia, chronic hypertension, or remaining normotensive. The cohort was grouped by quartile of aldosterone concentration in serum measured in the first trimester, and blood pressure, angiotensin peptides, and hypertension outcomes compared across the four quartiles. Blood pressures and body mass index were greatest in the top and bottom quartiles, with the top quartile having the highest blood pressure throughout pregnancy. Further stratification of the top quartile based on increasing (13 patients) or decreasing (19 patients) renin activity over gestation revealed that the latter group was characterized by the highest prevalence of chronic hypertension, use of anti-hypertensive agents, pre-term birth, and intrauterine growth restriction. Serum aldosterone concentrations greater than 704 pmol/L, the 75th percentile defined within the cohort, were evident across all categories of hypertension in pregnancy, including normotensive. These findings suggest that aldosterone excess may underlie the development of hypertension in pregnancy in a significant subpopulation of individuals.

THU587 High Prevalence Of Primary Aldosteronism Diagnosis In Patients With Papillary Thyroid Cancer And Hypertension: A Cross-sectional Case-control Study

Abstract Disclosure: A.W. Maciel: None. T. Freitas: None. D.L. Danilovic: None. G.F. Fagundes: None. F. Freitas-Castro: None. L. Santana: None. A. Guimaraes: None. A. Pio-Abreu: None. J. V. Silveira: None. F. Consolim-Colombo: None. L. Bortolotto: None. M.C. Fragoso: None. A. Latronico: None. L. Drager: None. B.B. Mendonca: None. A.O. Hoff: None. M.Q. Almeida: None. Introduction: Aldosterone excess can cause oxidative stress leading to DNA damage in vitro and in vivo. Single case reports demonstrated a coincidence of primary aldosteronism (PA) with different malignancies. A higher prevalence of thyroid nodules and non-toxic multinodular goiter was described in patients with PA compared to those with essential hypertension (HT). A single study showed an association between PA and papillary thyroid cancer (PTC), but without a paired control group. Objective: To assess PA prevalence in a transversal cohort of patients with PTC and HT compared to a paired control group with HT. Methods: In this cross-sectional case-control study, PA was investigated in all patients with PTC and HT (n= 114), regardless of HT severity, under active surveillance at a cancer institute from 2019 to 2022. The control group included 228 (2:1) age-, sex- and body mass index (BMI)-matched individuals from a retrospective cohort of HT previously investigated for PA from 2011 to 2022. Serum aldosterone and plasma direct renin concentrations were measured by a chemiluminescent immunoassay. A positive PA screening was defined by aldosterone ≥10 ng/dL and aldosterone to renin ratio ≥2 ng/dL/μUI/mL. Results: Age, sex and BMI were not statistically different between PTC and control groups, respectively (age 59.8 ± 12 vs. 58.9 ± 12.3 yrs, p= 0.67; 79% vs. 81% women, p= 0.67; BMI 30.7 ± 5.8 vs. 30.8 ± 6.5 Kg/m2, p= 0.98). PA was diagnosed in 35 out of 114 PTC patients with HT. The prevalence of PA in the PTC group (30.5%, confidence interval (IC) 22.6%-40.1%) was significantly higher when compared to the paired control group with HT (11.84%, CI 8.08%-16.93%; p&amp;lt; 0.0001). Although PA prevalence was higher in the PTC group, only 20.2% had stage 3/resistant HT (vs. 38% in the control group, p= 0.003). The number of anti-hypertensive medications was lower in the PTC group compared to controls (2 drugs, 1 to 3 vs. 4 drugs, 3 to 5, respectively; p&amp;lt; 0.001). When analyzing only PA patients in both groups, frequency of stage 3/resistant HT and number of medications were lower in the PTC group (p&amp;lt; 0.001 and p&amp;lt; 0.001, respectively). Although HT was more severe in PA patients without PTC, aldosterone and renin levels were not different in PA patients from PTC and control groups, respectively (p= 0.15 and p= 0.34). Conclusion: PA prevalence was strikingly high among patients with PTC and HT, supporting the recommendation of PA screening in this patient group, regardless of HT severity. Presentation: Thursday, June 15, 2023

Prospective evaluation of a telmisartan suppression test as a diagnostic tool for primary hyperaldosteronism in cats.

In a previous study, telmisartan suppressed aldosterone secretion in healthy cats but not in cats with primary hyperaldosteronism (PHA). Telmisartan suppresses aldosterone secretion in middle-aged healthy cat and cats with diseases that may result in secondary hyperaldosteronism, but not in those with PHA. Thirty-eight cats: 5 with PHA; 16 with chronic kidney disease (CKD), subclassified as hypertensive (CKD-H) or non-hypertensive (CKD-NH); 9 with hyperthyroidism (HTH); 2 with idiopathic systemic arterial hypertension (ISH); and 6 healthy middle-aged cats. Prospective, cross-sectional study. Serum aldosterone concentration, potassium concentration, and systolic blood pressure were measured before and 1 and 1.5 hours after PO administration of 2 mg/kg of telmisartan. The aldosterone variation rate (AVR) was calculated for each cat. No significant difference in the minimum AVR was observed among groups (median [quartile 1 (Q1); quartile 3 (Q3)]: 25 [0; 30]; 5 [-27; -75]; 10 [-6; -95]; 53 [19; 86]; 29 [5; 78]) for PHA, CKD, HTH, ISH, and healthy cats, respectively (P = .05). Basal serum aldosterone concentration (pmol/L) was significantly higher in PHA cats (median [Q1; Q3]: 2914 [2789; 4600]) than in CKD-H cats (median [Q1; Q3]: 239 [189; 577], corrected P value = .003) and CKD-NH cats (median [Q1; Q3]: 353 [136; 1371], corrected P value = .004). The oral telmisartan suppression test using a single dose of 2 mg/kg telmisartan did not discriminate cats with PHA from healthy middle-aged cats or cats with diseases that may result in secondary hyperaldosteronism.

Comparison of Hemodynamic Response between Patients with Systolic Heart Failure Differing in Serum Aldosterone Concentrations during and after a 6-Minute Walk Test.

Aldosterone regulates hemodynamics, including blood pressure (BP), and is involved in the development and progression of cardiovascular diseases, including systolic heart failure (HF). While exercise intolerance is typical for HF, neither BP nor heart rate (HR) have specific characteristics in HF patients. This study compares BP and HR profiles during and after standardized exercise between patients with systolic HF with either lower or higher aldosterone concentrations. We measured BP and HR in 306 ambulatory adults with systolic HF (left ventricular ejection fraction (LVEF) <50%) during and after a 6 min walk test (6MWT). All patients underwent a resting transthoracic echocardiography, and venous blood samples were collected for biochemical analyses. The patients were also divided into tertiles of serum aldosterone concentration: T1 (<106 pg/mL), T2 (106 and 263 pg/mL) and T3 (>263 pg/mL), respectively. Individuals from T1 and T2 were combined into T1-T2 as the reference group for comparisons with patients from T3. The individuals from T3 had significantly lower systolic, mean and diastolic BPs at rest, at the end and at 1 and 3 min post-6MWT recovery, as well as a more dilated left atrium and right ventricle alongside a higher concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Higher serum aldosterone concentration in HF patients with an LVEF < 50% is associated with a lower 6MWT BP but not an HR profile.

PS-BPR01-3: DISSOCIATION OF SERUM ALDOSTERONE CONCENTRATIONS BETWEEN THE MEASUREMENT METHODS: A CASE REPORT

A 89-year-old woman was admitted to our hospital for syncope in 20XX-13. During the hospitalization, hypertension was pointed out. Despite 4 cm left adrenal mass suggestive of myelolipoma in contrast-enhanced magnetic resonance imaging (MRI), the serum and urine hormone levels in relation to secondary hypertension was within normal limits. Diagnosis of essential hypertension was made and treatment with olmesartan and azelnidipine was begun. In 20XX-5, her blood pressure was well controlled, and serum aldosterone level and active renin concentration (ARC) were 167 pg/ml and 6.8 pg/ml, respectively. Annual computed tomography (CT) scans showed virtually the same size of the adrenal tumor over 5 years. The trend toward increase in her blood pressure prompted us to repeat a blood test in 20XX, which turned out that serum aldosterone concentration was extremely high (1144 pg/ml), while ARC was suppressed to 1.7 pg/ml. In light of positive captopril challenge test, primary aldosteronism was suspected, and she was admitted to our hospital. However, systolic blood pressure was only mildly elevated (130 mmHg), though blood pressure medication had not been changed for 5 years. In addition, serum potassium value was 4.7 mEq/L and 24-hr urinary aldosterone was merely 3.4 μg/day under the salt-loaded state, which was inconsistent with exceedingly high serum aldosterone concentration and argued against the diagnosis of primary aldosteronism. Hence, validity of the method to quantitate serum aldosterone levels was questioned. To determine serum aldosterone concentration, radioimmunoassay (RIA) was applied in 20XX-5, yet chemiluminescent enzyme immunoassay (CLEIA) has been introduced since 20XX. Strikingly, reexamination of the same serum sample discovered that serum aldosterone value of 770 pg/ml in CLEIA was equivalent to 59 pg/ml by RIA method. As such, marked dissociation seems present between the two types of assays in this particular patient. Although tendency of correlation with regard to serum aldosterone levels between the two methods have been clarified, attention needs to be paid for the exception as in this case. Thus, it is fundamental to thoroughly evaluate patients with suspected primary aldosteronism as to whether the clinical course and serum aldosterone levels are compatible, and if not, it may be necessary to change the measurement method.

JS-NG-8: CASE REPORT: POSSIBLE NEW CHANNELOPATHY ASSOCIATED WITH ELEVATED ALDOSTERONE LEVELS

Background: Potassium channelopathies are associated with prolonged QT cardiac syndrome. New potassium channelopathies in somatic cells, including KCNJ5 mutations, also underlie some forms of primary hyperaldosteronism. We present a first-in-human report of an association between a KCNQ1 loss of function mutation manifesting with life threatening-ventricular tachycardia (VT), severe hypokalemia and presumed hyperaldosteronism. Case Presentation: The patient is a 51-year-old Asian woman known for obesity, Wolff-Parkinson-White post ablation, and recurrent syncopal episodes with polymorphic VT due to prolonged QTc, requiring an implantable cardioverter defibrillator. On initial presentation for syncope, spontaneous hypokalemia was discovered at 3.1 mmol/L. She had multiple hospitalizations for torsade storms and persistent hypokalemia resistant to aggressive potassium supplementation until addition of spironolactone. Investigations revealed a suppressed plasma renin activity &lt; 0.05 ng/L/s, serum aldosterone concentration at 302 pmol/L, and an aldosterone to renin ratio (ARR) &gt; 6040. Repeated ARR was &gt; 10980. Confirmatory saline suppression testing or adrenal vein sampling were not performed due to risk of recurrent VT associated with spironolactone cessation. A comprehensive evaluation for the etiology of this patient's clinical presentation revealed a mutation in the KCNQ1 gene type 1. Literature review: The voltage-dependent K(+) channel responsible for activating delayed K(+) current is composed of pore-forming KCNQ1 and regulatory KCNE1/3 subunits which loss of function predispose to sustained torsade de pointes. Animal models demonstrate that KCNQ1 and KCNE1 mRNAs are expressed in the zona glomerulosa of adrenal glands where potassium channels directly participate in the control of aldosterone production. Although KCNE3 is not expressed in mouse adrenals, its deletion is thought to cause activation of lymphocytes targeting adrenal glands, leading to hyperaldosteronism. Furthermore, administration of spironolactone to KCNE3 knockout mice ameliorates their QT prolongation and predisposition to VT. There have been no case reports of an association between KCNQ1/E1/E3 loss of function and hyperaldosteronism in humans. Conclusion: This raises the question if this mechanism can also be a component of human KCNQ1 and KCNE1/3-linked arrhythmogenesis and hyperaldosteronism. Alternatively, we can further speculate that patients with hyperaldosteronism who develop malignant arrhythmias during hypokalemia are subjects with impaired repolarization reserve as a consequence of variants in genes known to cause long QT syndrome. The variants, leading to subclinical ion channel dysfunction, are typically silent until unmasked by electrolytes abnormalities such as hypokalemia. To our knowledge, this case is a first report of a potentially novel channelopathy associated with hyperaldosteronism in humans. These findings are hypothesis generating and require further investigations.

Serum aldosterone effect on left ventricular structure and diastolic function in essential hypertension

Aldosterone has hypertrophic and profibrotic effects on the heart. This study aims to determine the relationship between serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with left ventricular (LV) geometry and diastolic function in essential hypertension (EH). We investigated 213 EH patients (50.3±12.6 years; 57.7% male). SAC, ARR measurements, and echocardiographic analysis were performed for participants. Overall, stepwise multiple regression analysis showed significant associations between SAC and interventricular septum, LV posterior wall thickness, LV amass, LV mass index, e' velocity, a' velocity, and E/e' ratio after adjustment of potentially confounding covariates. When patients were divided into three SAC tertiles, multivariate-adjusted analysis of covariance (ANCOVA) demonstrated a significant increase in LV mass (P ˂ 0.001), LV mass index (P ˂ 0.001), relative wall thickness (P=0.003), interventricular septum (P=0.001), LV posterior wall thickness (P=0.001) and E/e' ratio (P ˂ 0.001), but a decrease in e' velocity (P=0.002) from the first to third tertile of SAC. In logistic regression analysis, increased SAC was independently associated with concentric LV hypertrophy [OR: 1.21, 95% CI: 1.11-1.33, P ˂ 0.001]. No significant associations were found between ARR and echocardiographic parameters of LV structure or diastolic function. In conclusion, SAC, but not ARR, is independently associated with echocardiographic indices of LV structure and diastolic function and is also related to concentric LV hypertrophy. Our findings suggest that aldosterone's pro-hypertrophic and myocardial fibrosis effects contribute to alterations in LV structure and diastolic function in EH beyond blood pressure.

Neonatal Pseudohypoaldosteronism Type-1 in Japan.

(1) Background: Pseudohypoaldosteronism type 1 (PHA-1) is a disorder caused by renal tubular resistance to aldosterone and is characterized by problems with sodium regulation. PHA-1 is typically divided into primary PHA-1, which is caused by genetic mutation, and secondary PHA-1, which is associated with urinary tract abnormality. However, data on the clinical features of PHA-1 among newborn infants are limited. (2) Methods: We conducted a nationwide prospective surveillance study of neonatal PHA in Japan from 1 April 2019 to 31 March 2022 as part of a rare disease surveillance project of the Japan Society for Neonatal Health and Development. (3) Results: Fifteen cases (male:female = 7:8), including four primary, four secondary, and seven non-classified cases, were reported during the study period. The median gestational age and birthweight were 34 weeks (28–41) and 1852 g (516–4610), respectively. At the onset, the median serum Na and K levels were 132 mEq/L (117–137) and 6.3 mEq/L (4.7–8.3), respectively. The median plasma renin activity was 45 ng/mL/h (3.1–310, n = 9), active renin concentration was 1017 pg/mL (123–2909, n = 6), and serum aldosterone concentration was 5310 pg/mL (3250–43,700). (4) Conclusions: Neonatal PHA-1 was more common among preterm infants with no male predominance. It developed immediately after birth in cases without genetic or renal complications.

Dex modulates the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN.

Dexmedetomidine (Dex) is a highly selective α2 adrenergic agonist used in clinical anesthesia. Studies have shown that Dex can act on the collecting duct and reduce the body’s water reabsorption, thereby increasing water discharge. However, the specific mechanism of Dex on water homeostasis remains unclear. The hypothalamus is the regulatory center of water and salt balance and secretes related neurochemical hormones, such as arginine vasopressin (AVP), to regulate the discharge of water and salt. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus are also considered to be the key targets of the thirst loop. They are responsible for the secretion of AVP. The suprachiasmatic nucleus (SCN) is also one of the brain regions where AVP neurons are densely distributed in the hypothalamus. This study used C57BL/6J mice for behavior, immunofluorescence, and blood analysis experiments. Our results showed that Dex could not only depress the expression of AVP in the PVN but also reduce serum AVP concentration. The animal water intake was decreased without impairing the difference in food consumption and the urine excretion was enhanced after the intraperitoneal injection of Dex, while AVP supplementation restored the water intake and inhibited the urine excretion of mice in the Dex group. In addition, the renin-angiotensin-aldosterone system is vital to maintaining serum sodium concentration and extracellular volume. We found that serum sodium, serum chloride, serum aldosterone (ALD) concentration, and plasma osmolality were decreased in the Dex group, which inhibited water reabsorption, and the plasma osmolarity of mice in the Dex group supplemented with AVP was significantly higher than that in Dex group. We also found that Dex significantly increased the concentration of blood urea nitrogen and decreased the concentration of creatinine within the normal range of clinical indicators, indicating that there was no substantive lesion in the renal parenchyma. These results showed that Dex could modulate the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN without impairing renal function.

Evaluation of arterial stiffness and serum endocan levels in patients with primary aldosteronism with new-onset hypertension and long-term hypertension.

There is growing evidence that prolonged exposure to high serum aldosterone concentrations results in target organ damage to the heart, kidney, and arterial wall, and that primary aldosteronism (PA) is associated with increased cardiovascular risk. In this study, we aimed to evaluate cardiovascular disease (CVD) risk indicators such as arterial stiffness [with pulse wave velocity (PWV) measurement] in PA patients and endocan levels, which is a biomarker of endothelial dysfunction. 28 patients with PA were included in our study. As the control group, 14 patients with essential hypertension (EHT) and 28 normotensive healthy volunteers were included. Height, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum fasting glucose, insulin, hemoglobin A1c (HbA1c), C-reactive protein (CRP), lipids and endocan levels of all subjects in the PA, EHT and control groups were measured. PWV measurements were performed to assess arterial stiffness. In the PA group, PWV levels were similar to the EHT group, and endocan levels were lower than the EHT group. In the PA group, PWV levels were higher than the control group, and endocan levels were lower than the control group. When we compared the PA group with new-onset HT with the PA group with long-term HT, PWV levels were higher in the PA group with long-term HT. When we compared the long-term HT group with the EHT group, PWV levels were higher in the long-term HT PA group and endocan levels were higher in the EHT group. When we compared the PA group with long-term HT with the control group, PWV levels were higher in the PA group with long-term HT, and endocan levels were similar in both groups. In our study, it was determined that arterial stiffness increased in PA cases with long-term HT compared to PA cases with new-onset HT, EHT cases and normotensive healthy cases. We found that endocan levels in PA patients were also lower than both EHT patients and healthy controls.

Aldosterone in chronic kidney disease and renal outcomes.

Randomized controlled trials have demonstrated the efficacy of mineralocorticoid receptor (MR) antagonism in delaying chronic kidney disease (CKD) progression in diabetes; however, they have not investigated the role of aldosterone or whether these beneficial effects could be achieved in individuals without diabetes. The association between serum aldosterone concentrations and kidney disease progression was investigated among 3680 participants in the Chronic Renal Insufficiency Cohort. The primary outcome was CKD progression [defined as the composite of 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, whichever occurred first]. The associations between serum aldosterone and kidney disease outcomes were assessed using Cox proportional hazard models. At baseline, higher aldosterone concentrations were associated with a lower eGFR, lower serum potassium, greater urinary potassium, and protein excretion. Over a median follow-up of 9.6 years, 1412 participants developed CKD progression. In adjusted models, each doubling of serum aldosterone was associated with a 11% increased risk of CKD progression [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.04-1.18]. Individuals with the highest quartile of serum aldosterone had a 45% increased risk of CKD progression (HR 1.45, 95% CI 1.22-1.73) compared with the lowest quartile. The risk for CKD progression was similar regardless of whether patients had concomitant diabetes (P-interaction = 0.10). Higher serum aldosterone levels among individuals with CKD are independently associated with an increased risk for kidney disease progression, irrespective of concomitant diabetes. These findings provide mechanistic support for MR antagonists in delaying CKD progression and suggest that they may also have a role in those without diabetes.

Exposure to chronic stressor upsurges the excitability of serotoninergic neurons and diminishes concentrations of circulating corticosteroids in rats two weeks thereafter.

Exposure to predator scent (PS) has been used as a model of stress associated with danger to life and body integrity. Under stress conditions, the brain serotoninergic (5-HT) system plays an important role. We tested the hypothesis that repeated PS exposure alters the excitability of 5-HT neurons of the dorsal raphe nucleus. To study the mechanisms involved, we approached serum and adrenal corticosterone and aldosterone concentrations, as well as brain-derived neurotrophic factor (BDNF) expression. Adult male Sprague-Dawley rats were exposed to PS for 10min daily for 10 consecutive days. Two weeks after the last exposure, electrophysiological and biochemical assessments were performed. Measurements by in vivo electrophysiology showed increased firing activity of 5-HT neurons in rats exposed to PS. Exposure to PS resulted in reduced serum corticosterone and aldosterone concentrations. Concentrations of both corticosteroids in the adrenal glands and the relative weight of the adrenals were unaffected. The gene expression of hippocampal BDNF of rats exposed to PS remained unaltered. PS exposure failed to induce changes in the gene expression of selected adrenal steroidogenic factors. Reduced corticosteroid concentrations in the blood appear to be the result of increased metabolism and/or tissue uptake rather than altered steroidogenesis. The decrease in circulating corticosterone in rats who experienced repeated PS may represent part of the mechanisms leading to increased excitability of 5-HT neurons. The increase in 5-HT neuronal activity might be an important compensatory mechanism designated to diminish the harmful effects of the repeated PS exposure on the brain.

Аналіз клінічних, генетичних і гендерних детермінант неефективного лікування в пацієнтів з артеріальною гіпертензією

Актуальність. Поліморфізм промоторної ділянки гену альдостеронової синтази CYP11B2 -344C/T (rs1799998) вiдiграє одну з ключових ролей в модуляції об’єм- і натрій-залежних механізмів артерiальноï гiпертензiï (АГ). Пошук маркерів ефективності антигіпертензивної терапії (АГТ) обумовлений частим недосягненням цільових рівнів АТ незалежно від характеру, дози антигіпертензивних препаратів (АГП), прихильності пацієнта до лікування.Мета. Метою роботи було визначити роль поліморфізму -344С/Т гену CYP11B2 в поєднанні з традиційними факторами ризику (ФР) в контролі артеріального тиску у пацієнтів з АГ ІІ-ІІІ ст.Матеріали та методи. Обстежено 93 пацієнта з АГ ІІ-ІІІ ст. Пацієнти були розділені на 2 групи: 1 гр . (n=38) – пацієнти з цільовим рівнем АТ на тлі АГТ, 2 гр. (n = 55) – пацієнти з АТ≥135/85 мм рт. ст. Всім пацієнтам виконували стандартні клініко-лабораторні дослідження, оцінювали ФР, виконували генотипування методом полімеразної ланцюгової реакції з визначенням довжини рестрикційних фрагментів та визначенням гаплотипу -344С/Т CYP11B2.Результати. Групи пацієнтів з різними рівнями АТ були порiвнюванi за частотою модифікованих ФР, кількісним та якісним складом АГТ. У групі осіб з неконтрольованою АГ частка курців, а також пацієнтів з супутнім цукровим діабетом 2 типу була достовірно вище в порівнянні з пацієнтами 1 гр. Аналіз частот алель них варіантів гену -344С/Т CYP11B2 показав, що частка пацієнтів, що мають Т- монозиготний генотип, була достовірно вище серед пацієнтів 2 гр.Висновок. Наявність Т-алеліі TТ-генотипу -344С/Т CYP11B2 в поєднанні з множинними ФР асоціювалася з недостатнім контролем АТ , незалежно від АГТ.

The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin—low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Heightened Cardiovascular Risk in Hypertension Associated With Renin-Independent Aldosteronism Versus Renin-Dependent Aldosteronism: A Collaborative Study.

BackgroundWhile both renin‐dependent and renin‐independent aldosterone secretion contribute to aldosteronism, their relative associations with cardiovascular disease (CVD) risk has not been investigated.Methods and ResultsA total of 2909 participants from the FOS (Framingham Offspring Study) with baseline, serum aldosterone concentration, and plasma renin concentration who attended the sixth examination cycle and were followed up until 2014 and who were free of CVD were included. We further recruited 2612 hypertensive participants from the CONPASS (Chongqing Primary Aldosteronism Study). Captopril challenge test was performed to confirm renin‐dependent or ‐independent aldosteronism in CONPASS. Among 1433 hypertensive subjects of FOS, when compared with those with serum aldosterone concentration <10 ng dL−1 (normal aldosterone), participants who had serum aldosterone concentration ≥10 ng dL−1 and plasma renin concentration ≤15 mIU L−1 (identified as renin‐independent aldosteronism) showed a higher risk of CVD (hazard ratio, 1.40 [95% CI, 1.08–1.82]), while those who had serum aldosterone concentration ≥10 ng dL−1 and plasma renin concentration >15 mIU L−1 (identified as renin‐dependent aldosteronism) showed an unchanged CVD risk. In CONPASS, renin‐independent aldosteronism carried a significantly higher risk of CVD than normal aldosterone (odds ratio, 2.57 [95% CI, 1.13–5.86]), while the CVD risk remained unchanged in renin‐dependent aldosteronism. Elevation of the urinary potassium‐to‐sodium excretion ratio, reflective of mineralocorticoid receptor activity, was only observed in participants with renin‐independent aldosteronism.ConclusionsAmong patients with hypertension, renin‐independent aldosteronism is more closely associated with CVD risk than renin‐dependent aldosteronism.

Th17/Treg imbalance in patients with primary hyperaldosteronism and resistant hypertension.

Inflammation plays a pivotal role in blood pressure regulation. Data on experimental models of hypertension and hypertensive patients reflect the imbalance between T regulatory (Treg) and Th17 effector cells (Th17). The aim of this study was to quantify peripheral blood Treg lymphocytes and Th17 subsets in individuals with primary hyperaldosteronism (PHA) and resistant hypertension (RHT) presenting with elevated blood pressure levels and augmented cardiovascular risk when compared with normotensive controls (CTRL). Twenty CTRL participants, 21 patients with PHA, and 20 patients with RHT were enrolled. Plasma renin and angiotensin II, serum aldosterone concentration, ambulatory blood pressure monitoring (ABPM), echocardiography, clinical data, and phenotype of peripheral blood cells were assessed. There were no statistically significant differences in terms of age and sex between the groups. Similar systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in ABPM were observed in individuals with PHA and RHT. PHA patients had lower angiotensin II and 4‑fold higher aldosterone concentrations than CTRL patients. Both, PHA and RHT were associated with cardiac hypertrophy and coronary artery disease. RHT patients presented a significantly higher CD4+IL‑17A+ T cell number when compared with PHA and CTRL ones. The number of CD4+CD25+FOXP3+ T cells did not differ between patients with secondary hypertension and normotensive controls. Finally, positive correlations between the data on 24 h SBP and the content of CD4+IL‑17A+ and CD4+CD25+FOXP3+ in the PHA were found. Elevated 24 h SBP in PHA was associated with the increased numbers of CD4+IL‑17 and CD4+CD25+FOXP3+ T cells.