Increase In Plasma Aldosterone Concentration Research Articles

FRI128 Hiding In Plain Sight: Late Diagnosis Of Primary Hyperaldosteronism In Patient With Atypical Presentation

Abstract Disclosure: R.A. Zielinski: None. A. Syeda: None. B. Esayag-Tendler: None. Background: Primary hyperaldosteronism (PHA) can go undiagnosed in patients with primary hypertension without hypokalemia and increased plasma aldosterone concentration (PAC). Case: The patient is a 72-year-old male with a history of hypertension (HTN) diagnosed at age 55 who presented to the endocrinology clinic for further evaluation. He was asymptomatic. His antihypertensive regimen included atenolol 25 mg daily and amlodipine-benazepril 10-40 mg daily. Blood pressure (BP) was well-controlled with a goal BP under 130/80 mm Hg. Physical exam was without AV nicking in a limited retina exam, no abdominal tenderness, and no peripheral edema. Family history is notable for HTN in his father and HTN complicated by stroke in a sister and a brother, all diagnosed at an older age. Labs done 5 years prior showed potassium (K) of 4.3 mmol/L [3.6 - 5.1 mmol/L], PAC of 3.2 ng/dl [upright 4.0 - 31.0 ng/dl], and plasma renin activity (PRA) of 0.1 ng/ml/hr [upright 0.5-4.0 ng/ml/hr]. More recent labs showed K of 3.8 mmol/L, PAC of 21.5 ng/dl and PRA of 0.3 ng/ml/hr. Repeat labs 6 months later showed K of 3.4 mmol/L, PAC of 15 ng/dL and PRA of 0.2 ng/mL/hr. A 3-day dexamethasone suppression test was performed to exclude familial hyperaldosteronism or glucocorticoid remediable aldosteronism. Following the test, K was 3.6 mmol/L, PAC was 11.3 ng/dl, and cortisol was undetectable. CT abdomen showed bilateral nodular thickening of the adrenal glands without a distinct adenoma. Adrenal venous sampling was done before and after ACTH stimulation. Prior to ACTH stimulation, the mean ratio of the dominant adrenal aldosterone concentration corrected with cortisol from left to right was 1.32. Following ACTH stimulation, the ratio was 2.79. A ratio greater than 4 is consistent with a good outcome after adrenalectomy. Hence, it was decided to pursue medical management. The cause of our patient’s primary hyperaldosteronism is likely due to bilateral idiopathic hyperplasia. He was started on eplerenone 25 mg twice daily and salt restriction with a goal of increasing the PRA above 1 ng/ml/hr. Discussion and Conclusion: It was initially thought that PHA represents 1% of all patients with primary HTN. However, more recent studies indicate that the prevalence is significantly higher. Additionally, the PAC in patients with PHA can fluctuate and patients can present with normokalemia, making the diagnosis more difficult to establish. It is an important diagnosis to establish and treat appropriately because there is a higher risk of cardiovascular morbidity and mortality in patients with PHA compared to patients with primary HTN. Presentation: Friday, June 16, 2023

Abstract 137: Impact of Leptin Deficiency Compared to Neuronal Specific Leptin Receptor Deletion on Cardiometabolic Regulation

The main goal of this study was to compare the impact of whole-body leptin deficiency with neuronal specific leptin receptor (LR) deletion on metabolic and cardiovascular regulation. Liver fat, diacylglycerol acyltransferase-2 (DGTA2) and CD36 protein content were measured in male and female wild-type (WT, n=5/sex), nervous system LR deficient (LR/Nestin-Cre, n=6/sex), and leptin deficient (ob/ob, n=5) mice. Blood pressure (BP) and heart rate (HR) were recorded by telemetry, and motor activity (MA) and oxygen consumption (VO 2 ) were monitored at 24 weeks of age. Female and male LR/Nestin-Cre and ob/ob mice were heavier than WT mice (62±5 and 61±3 vs 31±1 g), hyperphagic (6.2±0.5 and 6.1±0.7 vs 3.5±1.0 g/day), with reduced VO 2 (27±1 and 33±1 vs 49±3 ml/kg/min) and decreased MA (3±1 and 7±2 vs 676±105 cm/hr). LR/Nestin-Cre and ob/ob mice were also hyperinsulinemic and hyperglycemic compared to WT mice. LR/Nestin-Cre mice had high plasma leptin levels while ob/ob mice had undetectable leptin levels. Despite comparable obesity, LR/Nestin-Cre mice had lower liver fat content (83% reduced) and DGTA2 and CD36 protein levels than ob/ob mice. Male WT, LR/Nestin-Cre, and ob/ob mice exhibited similar BP (111±3, 110±1 and109±2 mmHg), whereas female LR/Nestin-Cre mice had higher BP compared to WT females despite similar metabolic phenotypes compared to male LR/Nestin-Cre mice. No significant increases in plasma aldosterone concentration was observed in male LR/Nestin-Cre compared to WT mice (495±48 vs. 440±62 pg/ml); however, female LR/Nestin-Cre mice had ~14 fold higher plasma aldosterone concentration compared to female WT mice (707±97 vs. 50±3 pg/ml). These results indicate that although nervous system LRs play a crucial role in regulating body weight and glucose homeostasis, peripheral LRs also regulate liver fat deposition and modulate BP in a sex dependent manner. (NHLBI-PO1HL51971, NIGMS P20GM104357 and U54GM115428)

Prevalence of primary aldosteronism in primary care: a cross-sectional study.

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. To examine the proportion of patients with PA among patients with newly diagnosed, never treated hypertension. A cross-sectional study set in primary care. 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. 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. 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.

Aldosterone Hypothesis for Cognitive Impairment in Diabetes Mellitus

Increased plasma aldosterone concentration is significantly associated with dementia, which is accentuated by diabetes mellitus (DM). Angiotensin II (AngII) deteriorates cognitive function through neuronal degradation. Lipoproteins, a major source of cholesterol for aldosterone biosynthesis, undergo glycoxidative modifications in the presence of hyperglycemia. We hypothesize that there would be a pathophysiological link between diabetically-modified lipoproteins, angiotensin II, and increased plasma aldosterone concentration for induction of cognitive impairment. Glycoxidized lipoproteins produce significantly more aldosterone from AngII-sensitized adrenocortical cells compared to their native counterparts. The elucidation of signaling mechanisms revealed that modified lipoproteins follow the similar signaling mechanism like AngII for adrenocortical aldosterone release via ERK1/2 and Janus kinase-2 (Jak-2)-mediated pathways. The enhanced aldosterone release from AngII-sensitized adrenocortical cells induced by glycoxidatively modified lipoproteins may play a crucial role in cognitive dysfunction in diabetic individuals along with AngII via a prevailing mode of signaling cascade involving ERK1/2- and Jak-2-dependent pathways.

Prenatal corticosterone exposure programs sex-specific adrenal adaptations in mouse offspring.

Maternal stress can impair foetal development and program sex-specific disease outcomes in offspring through the actions of maternally produced glucocorticoids, predominantly corticosterone (Cort) in rodents. We have demonstrated in mice that male but not female offspring prenatally exposed to Cort (33 µg/kg/h for 60 h beginning at E12.5) develop cardiovascular/renal dysfunction at 12 months. At 6 months of age, renal function was normal but male offspring had increased plasma aldosterone concentrations, suggesting that altered adrenal function may precede disease. This study investigated the long-term impact of prenatal exposure to Cort on adrenal growth, morphology and steroidogenic capacity as well as plasma Cort concentrations in offspring at postnatal day 30 (PN30), 6 months and 12 months of age. Prenatal Cort exposure decreased adrenal volume, particularly of the zona fasciculata, in male offspring at PN30 but increased both relative and absolute adrenal weight at 6 months of age. By 12 months of age, male Cort-exposed offspring had reduced absolute adrenal weight in association with increased adrenal plaque deposition (lipogenic pigmentation). Plasma Cort concentrations were elevated in male 6-month offspring but not at other ages. mRNA expression of Mc2r (ACTH receptor) was increased in males at PN30, and Cyp11a1 expression was decreased at 6 and 12 months of age. There were no changes in the adrenals of female Cort-exposed offspring. This study demonstrates that prenatal Cort exposure induces offspring adrenal gland dysfunction in an age- and sex-specific manner, which may contribute to long-term programmed disease in male offspring after maternal stress.

Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism

The major physiological regulators of aldosterone production from the adrenal zona glomerulosa are potassium and angiotensin II; other acute regulators include adrenocorticotropic hormone (ACTH) and serotonin. Their interactions with G-protein coupled hormone receptors activate cAMP/PKA pathway thereby regulating intracellular calcium flux and CYP11B2 transcription, which is the specific steroidogenic enzyme of aldosterone synthesis. In primary aldosteronism (PA), the increased production of aldosterone and resultant relative hypervolemia inhibits the renin and angiotensin system; aldosterone secretion is mostly independent from the suppressed renin–angiotensin system, but is not autonomous, as it is regulated by a diversity of other ligands of various eutopic or ectopic receptors, in addition to activation of calcium flux resulting from mutations of various ion channels. Among the abnormalities in various hormone receptors, an overexpression of the melanocortin type 2 receptor (MC2R) could be responsible for aldosterone hypersecretion in aldosteronomas. An exaggerated increase in plasma aldosterone concentration (PAC) is found in patients with PA secondary either to unilateral aldosteronomas or bilateral adrenal hyperplasia (BAH) following acute ACTH administration compared to normal individuals. A diurnal increase in PAC in early morning and its suppression by dexamethasone confirms the increased role of endogenous ACTH as an important aldosterone secretagogue in PA. Screening using a combination of dexamethasone and fludrocortisone test reveals a higher prevalence of PA in hypertensive populations compared to the aldosterone to renin ratio. The variable level of MC2R overexpression in each aldosteronomas or in the adjacent zona glomerulosa hyperplasia may explain the inconsistent results of adrenal vein sampling between basal levels and post ACTH administration in the determination of source of aldosterone excess. In the rare cases of glucocorticoid remediable aldosteronism, a chimeric CYP11B2 becomes regulated by ACTH activating its chimeric CYP11B1 promoter of aldosterone synthase in bilateral adrenal fasciculate-like hyperplasia. This review will focus on the role of ACTH on excess aldosterone secretion in PA with particular focus on the aberrant expression of MC2R in comparison with other aberrant ligands and their GPCRs in this frequent pathology.

Hormonal changes following a low-salt diet in patients with Ménière's disease.

A low-salt diet has been the main treatment modality for Ménière's disease (MD) since the 1930s, although the mechanisms behind this therapy have not yet been elucidated. Salt reduction is associated with a physiological increase in plasma aldosterone concentration. Several experimental reports have suggested that aldosterone may increase endolymph absorption in the inner ear, particularly in the endolymphatic sac. Therefore, aldosterone elevations due to a low-salt diet may increase endolymph absorption in the endolymphatic sac. In this study, urinary sodium excretion, plasma aldosterone, and other hormones were measured during low-salt diet therapy in patients with MD. We included 13 patients with unilateral definite MD diagnosed at the Kagawa University Hospital. A national registered dietitian provided nutritional guidance initially for 14 enrolled patients with MD and prescribed them a low-salt diet (2g Na/day). Twenty-four hour urine was sampled at baseline, at 2, 4, 6, and 8 weeks, and at 6, 12, 18, and 24 months after initiating the low-salt diet. Urine osmotic pressure, and Na, K, and Cl levels were measured, and 24-h urinary Na, K, and Cl excretion was estimated. Aldosterone, cortisol, hormones (including anti-diuretic hormone), Na, K, and Cl in the blood were measured, alongside plasma osmotic pressure. A total of 13 patients followed the low salt diet therapy for more than 2 years, while one patient dropped out. Group 1 (n=7) included patients with a mean urinary sodium excretion amount lower than 3g/day and Group 2 (n=6) included those with more than 3g/day. Vertiginous states of all Group 1 patients comprised complete control (Class A, 100%), while Group 2 patients included Class A (four patients, 66%), Class C (one patient, 17%), and Class D (one patients, 17%). Plasma aldosterone concentrations significantly increased during the 2-year low-salt diet; concentrations in Group 1 tended to be higher than that in Group 2. Hearing improvements after 2 years in Group 1 were significantly better than that in Group 2. The plasma concentration of the hormones except aldosterone was not significantly changed during 2-year low-salt diet. A low-salt diet was an effective treatment for patients with Ménière's disease. This treatment will have a greater effect, when sodium intake is reduced to less than 3g/day. A low-salt diet may induce an increase in the plasma aldosterone concentration that can activate ion transport and absorbing endolymph in the endolymphatic sac.

Effects of renal Na+/Ca2+ exchanger 1 inhibitor (SEA0400) treatment on electrolytes, renal function and hemodynamics in rats.

Na(+)/Ca(2+) exchanger 1 (NCX1) controls intracellular Ca(2+) concentration in various cell types. In the kidney, NCX1 is expressed mainly in the distal tubular basolateral membrane as well as in vascular smooth muscle. Tubular NCX1 is involved in Ca(2+) reabsorption, and NCX1 in renal arterioles may control intraglomerular pressure. However, the functions of renal NCX1 have not been studied in vivo. Therefore, this study examined the effects of renal NCX1 blockade on water and solute metabolism, renal function and blood pressure in rats. Wistar-Kyoto rats were uninephrectomized, and an osmotic mini pump was implanted to infuse the remnant kidney cortex with a specific NCX1 inhibitor, SEA0400 (SEA), or vehicle for 7 days. Serum Ca(2+) concentration and urinary Ca(2+) excretion were similar between the vehicle- and SEA-treated groups. However, serum phosphate was significantly decreased by 8 % in the SEA group, with similar urinary phosphate excretion between the two groups. Systolic blood pressure was higher in the SEA group (117 ± 3 vs. 126 ± 1 mmHg, n = 9-11), with a 1.6-fold increase in plasma aldosterone concentration. However, SEA significantly reduced urinary protein excretion and the glomerular sectional area by 16 and 8 %, respectively. Similar experiment in spontaneously hypertensive rats produced different results. Renal SEA treatment reduced serum phosphate concentration, urinary protein and glomerular size with higher systemic blood pressure compared to control Wistar-Kyoto rats. Further study on renal NCX1 may be beneficial in delineating the pathophysiology of glomerular pressure control and calcium/phosphate regulations.

Treatment of Aldosterone‐Secreting Adrenocortical Tumors in Cats by Unilateral Adrenalectomy: 10 Cases (2002–2012)

BackgroundPrimary hyperaldosteronism (PHA) in cats occurs as a consequence of excessive hormone production by an adrenocortical tumor. Median survival time, association between tumor type and prognosis, and the likelihood that cats require continued medical therapy after surgery have not been systematically evaluated.ObjectivesTo determine the median survival time of cats with PHA treated by unilateral adrenalectomy. To examine if tumor type, anesthesia time, or tumor location (left or right side) affect survival and if affected cats require continued postoperative treatment for persistent hypertension or hypokalemia.AnimalsTen client‐owned cats.MethodsRetrospective study. Cats were diagnosed with PHA based on clinical signs, increased plasma aldosterone concentration, and advanced imaging. Cats underwent unilateral adrenalectomy. Survival time (days alive after surgery) was determined for each cat. Factors affecting median survival time were investigated, including histopathology, anesthesia time, and location (side) of the tumor.ResultsEight of 10 cats survived to discharge from the hospital post adrenalectomy. Overall median survival was 1,297 days (range 2–1,582 days). The only significant factor affecting median survival time was anesthesia time >4 hours. Tumor type and location (side) did not significantly affect median survival time. No cats required continued medical treatment for PHA.Conclusions and Clinical ImportanceAlthough PHA in cats is still considered an uncommon condition, it should be considered in middle to older aged cats with hypokalemic polymyopathy and systemic hypertension. Surgical correction by unilateral adrenalectomy is a viable approach to definitive treatment of PHA with no need for continued medical management.

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

Expression of aldosterone synthase and adrenocorticotropic hormone receptor in adrenal incidentalomas from normotensive and hypertensive patients: Distinguishing subclinical or atypical primary aldosteronism from adrenal incidentaloma

The present study aimed to investigate the expression of aldosterone synthase (CYP11B2), adrenocorticotropic hormone receptor (ACTH-R) and their regulating transcription factors in adrenal incidentalomas (AIs) from normotensive and hypertensive patients to distinguish subclinical or atypical primary aldosteronism (PA) from AIs. Total RNA was extracted from 8 normal adrenal cortices (NAs), 46 AIs, 15 aldosterone-producing adenomas (APAs) and 6 idiopathic hyperaldosteronisms (IHAs). Real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry were performed to determine the mRNA and protein expression of CYP11B2, ACTH-R, steroidogenic factor-1 (SF1) and dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1 (DAX-1) in the different tissues. The AI hypertensive subgroup displayed increased plasma aldosterone concentration (PAC) and PAC/PRA ratio (ARR) and decreased plasma renin activity (PRA) compared to the normotensive group. CYP11B2, ACTH-R and SF1 mRNAs were significantly higher in the APA group compared to the other groups, and gradually increased in AI hypertensive samples. DAX-1 mRNA was expressed faintly in PA compared with NA. In normotensive-AI samples, DAX-1 mRNA was higher compared to PA and AI hypertensive samples. Significant differences in gene expression levels in AIs were observed between probable and improbable PA patients. Immunohistochemical results were consistent with those of real-time PCR. Plasma aldosterone levels were positively correlated with CYP11B2, ACTH-R and SF1 mRNA and inversely correlated with DAX-1 mRNA. In conclusion, a significant number of hypertensive-AI patients may have subclinical forms of PA. CYP11B2, ACTH-R and their regulating transcription factors may be noteworthy in distinguishing subclinical PA from AIs.

Angiotensin III Stimulates Aldosterone Secretion from Adrenal Gland Partially via Angiotensin II Type 2 Receptor But Not Angiotensin II Type 1 Receptor

Angiotensin II (Ang II) and Ang III stimulate aldosterone secretion by adrenal glomerulosa, but the angiotensin receptor subtypes involved and the effects of Ang IV and Ang (1-7) are not clear. In vitro, different angiotensins were added to rat adrenal glomerulosa, and aldosterone concentration in the medium was measured. Ang II-induced aldosterone release was blocked (30.3 ± 7.1%) by an Ang II type 2 receptor (AT2R) antagonist, PD123319. Candesartan, an Ang II type 1 receptor (AT1R) antagonist, also blocked Ang II-induced aldosterone release (42.9 ± 4.8%). Coadministration of candesartan and PD123319 almost abolished the Ang II-induced aldosterone release. A selective AT2R agonist, CGP42112, was used to confirm the effects of AT2R. CGP42112 increased aldosterone secretion, which was almost completely inhibited by PD123319. In addition to Ang II, Ang III also induced aldosterone release, which was not blocked by candesartan. However, PD123319 blocked 22.4 ± 10.5% of the Ang III-induced aldosterone secretion. Ang IV and Ang (1-7) did not induce adrenal aldosterone secretion. In vivo, both Ang II and Ang III infusion increased plasma aldosterone concentration, but only Ang II elevated blood pressure. Ang IV and Ang (1-7) infusion did not affect blood pressure or aldosterone concentration. In conclusion, this report showed for the first time that AT2R partially mediates Ang III-induced aldosterone release, but not AT1R. Also, over 60% of Ang III-induced aldosterone release may be independent of both AT1R and AT2R. Ang III and AT2R signaling may have a role in the pathophysiology of aldosterone breakthrough.

Plasma aldosterone concentration and cardiovascular response to low sodium intake in horses in training

Horses in training lose large amounts of sodium but little is known about the cardiovascular response to low sodium intake. To investigate the effect of low sodium intake on plasma aldosterone (pAldo) concentrations and the cardiovascular system of athletic horses, and to identify markers of low sodium intake. Seven Standardbred geldings in training (trained twice a week) were randomly offered a standardised diet supplemented (NaS, 58 mg Na/kg bwt) and not supplemented (NaN, 3 mg Na/kg bwt) with NaCl for 5 weeks in a changeover design. Blood samples were taken once a week and in Week 5, before and following an exercise test until 22.30 h and analysed for blood sodium (bNa), total plasma protein (TPP), pAldo, troponin I and packed cell volume (PCV). Blood pressure (BP) was measured and pulse wave recorded at rest with high definition oscillometric-technique (HDO). ECG and echocardiography were recorded. Water intake was measured before and on the day of exercise and voluntary saline intake was measured for 2 days after each period. Faecal samples were taken weekly and analysed for sodium and potassium content. The pAldo and the PCV was higher in NaN compared to NaS. There were no differences between diets in BP, ECG, plasma troponin I and echocardiogram but HDO pulse amplitude tended to be smaller on diet NaN. Water intake was lower on diet NaN and saline intake higher. The response to exercise in bNa, pAldo, PCV and TPP was different on the 2 diets. Faecal potassium/sodium ratio was higher on NaN than on NaS. This study shows that 5 weeks of low sodium intake increased plasma aldosterone concentration and PCV but no alterations in heart function was observed. Faecal potassium/sodium ratio could be used to assess sodium status in horses.

Hypokalemia induced myopathy as first manifestation of primary hyperaldosteronism - an elderly patient with unilateral adrenal hyperplasia: a case report

IntroductionPrimary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia.Case presentationA 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland.ConclusionThis report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia.

Salt and acid-base metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients

Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca(2+) and Mg(2+) absorption. Because of the reduced tight junction permeability ratio for Na(+) over Cl(-), we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na(+) loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na(+) was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO(3)(-) excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.

Matching salt intake to physiological need in rats using foraging protocols

Several studies of the quantitative relationship between sodium need and sodium intake in rats are reviewed. Using acute diuretic treatment 24 h beforehand, intake matches need fairly accurately when intake is spread out in time by using a hypotonic solution of NaCl. In contrast, using a hypertonic solution, intake is typically double the need. Using the same diuretic treatment, although the natriuresis occurs within approximately 1 h, the appetite appears only slowly over 24 h. Increased plasma levels of aldosterone parallel the increased intake; however, treatment with metyrapone blocks the rise in aldosterone but has no effect on appetite. Satiation of sodium appetite was studied in rats using sodium loss induced by chronic diuretic treatment and daily salt consumption sessions. When a simulated foraging cost was imposed on NaCl access in the form of a progressive ratio lever press task, rats showed satiation for NaCl (break point) after consuming an amount close to their estimated deficit. The chronic diuretic regimen produced hypovolemia and large increases in plasma aldosterone concentration and renin activity. These parameters were reversed to or toward non-depleted control values at the time of behavioral satiation in the progressive ratio protocol. Satiation mechanisms for sodium appetite thus do appear to exist. However, they do not operate quantitatively when concentrated salt is available at no effort, but instead allow overconsumption. There are reasons to believe that such a bias toward overconsumption may have been beneficial over evolutionary time, but such biasing for salt and other commodities is maladaptive in a resource-rich environment.

Matching salt intake to physiological need in rats using foraging protocols

Several studies of the quantitative relationship between sodium need and sodium intake in rats are reviewed. Using acute diuretic treatment 24 h beforehand, intake matches need fairly accurately when intake is spread out in time by using a hypotonic solution of NaCl. In contrast, using a hypertonic solution, intake is typically double the need. Using the same diuretic treatment, although the natriuresis occurs within ~1 h, the appetite appears only slowly over 24 h. Increased plasma levels of aldosterone parallel the increased intake; however, treatment with metyrapone blocks the rise in aldosterone but has no effect on appetite. Satiation of sodium appetite was studied in rats using sodium loss induced by chronic diuretic treatment and daily salt consumption sessions. When a simulated foraging cost was imposed on NaCl access in the form of a progressive ratio lever press task, rats showed satiation for NaCl (break point) after consuming an amount close to their estimated deficit. The chronic diuretic regimen produced hypovolemia and large increases in plasma aldosterone concentration and renin activity. These parameters were reversed to or toward non-depleted control values at the time of behavioral satiation in the progressive ratio protocol. Satiation mechanisms for sodium appetite thus do appear to exist. However, they do not operate quantitatively when concentrated salt is available at no effort, but instead allow overconsumption. There are reasons to believe that such a bias toward overconsumption may have been beneficial over evolutionary time, but such biasing for salt and other commodities is maladaptive in a resource-rich environment.

Characteristics of salt appetite in chronically sodium-depleted rats using a progressive ratio schedule of procurement

Satiation of sodium appetite of rats was studied using a protocol of sodium loss induced by chronic diuretic treatment and daily salt consumption sessions. In the first experiment in which NaCl was freely available from a drinking spout, rats consumed substantially more hypertonic NaCl than their estimated physiological deficit. In the second and third experiments, a simulated foraging cost was imposed on obtaining NaCl. In these experiments, rats were required to perform a progressive ratio lever press task to procure aliquots of hypertonic NaCl, and under these conditions they showed a break point or satiation for NaCl when they had consumed an amount close to their estimated deficit. In the fourth experiment, we found that the chronic diuretic regimen produced hypovolemia along with large increases in plasma aldosterone concentration and renin activity, and that all of these parameters were reversed toward non-depleted control values at the time of behavioral satiation in the progressive ratio protocol. Examination of natriuresis revealed that excessive intake of NaCl had no lasting benefit in this protocol: NaCl consumed in excess of need on 1 day was completely lost at the subsequent diuretic treatment. In the final two experiments, we showed that oral preloads of NaCl had no significant effect on progressive ratio procurement of NaCl, but that oral preloads reduced subsequent oral drinking. The data are discussed in terms of definitions of satiation of appetite in regard to the tightly regulated domain of body fluid homeostasis, and by extension, their relevance to systems such as energy homeostasis where set points appear to be less tightly regulated.

Aldosterone Antagonism in Chronic Kidney Disease

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Non‐selective nonsteroidal anti‐inflammatory drugs and cardiovascular events: is aldosterone the silent partner in crime?

Non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) have long been known to cause gastrointestinal and renal toxicity. More recently, adverse cardiovascular effects have been associated with the selective COX-2 inhibitors. However, current studies that show an increased cardiovascular risk with non-selective NSAIDs raise the question of the exclusive contribution of COX-2 to this type of toxicity. Aldosterone, a key cardiovascular hormone, can induce deleterious effects, such as myocardial fibrosis and vascular stiffening. Non-selective NSAIDs inhibit the metabolism of aldosterone in vitro by human renal tissue, predicating an increased plasma aldosterone concentration in vivo. The question remains whether inhibition of aldosterone metabolism by non-selective NSAIDs is a casual or causal factor in NSAID-induced cardiovascular toxicity.