Aldosterone

Uninephrectomized rats drinking 1% sodium chloride were given aldosterone (Aldo, 0.75 gg/h, subcutaneous Is.c.I infusion), deoxycorticosterone (DOC, 20 mg/wk, s.c.), corticosterone (B, 2 mg/d, s.c.), or the antiglucocorticoid-antiprogestin RU486 (2 mg/d, s.c.) for 8 wk, and hemodynamic and tissue responses were compared with a non-steroid-treated control group. Aldo and DOC markedly increased systolic BP and caused considerable (40-50%) cardiac hypertrophy; B and RU486 caused neither hypertension nor cardiac hypertrophy. Measurements of ventricular cross-sectional areas showed hypertrophy due to an increase in mass of the left ventricle only. Cardiac hydroxyproline concentration was increased considerably by Aldo and DOC, to a lesser degree by RU486, and not by B. Aldo markedly elevated left ventricular interstitial collagen (2.5-fold vs control, P < 0.01 vs all groups); other steroid treatments also increased interstitial collagen over control (DOC X 1.8-, RU486 X 1.6-, B X 13-fold), with identical responses for right and left ventricles (r = 0.94). A different pattern of perivascular fibrosis was noted; DOC elevated perivascular collagen (2.1-fold vs control, P < 0.01 vs all other groups); RU486 raised levels 1.4-fold vs control, but neither Aldo nor B significantly affected perivascular collagen. These data are consistent with interstitial cardiac fibrosis reflecting type I (mineralocorticoid) receptor occupancy by administered Aldo or DOC, or by elevated endogenous B after type II (glucocorticoid) receptor blockade after RU486 administration; perivascular fibrosis may reflect a composite response after type I receptor agonist/type II glucocorticoid receptor antagonist occupancy. (J. Clin. Invest. 1994.93:2578-2583

Context: Excess production of aldosterone or cortisol has profound effects on cardiovascular function and impacts other major organ systems. The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in aldosterone-producing adenoma (APA) or cortisol-producing adenoma (CPA) are unknown.

The aim of the present study is to compare the diagnostic performance of CT and MR imaging in detecting aldosterone-producing adenoma and to compare the interobserver variability in the detection of an aldosterone-producing adenoma on CT and MR. A retrospective study of 34 patients with primary hyperaldosteronism was performed. A total of 17 cases of aldosterone-producing adenoma and 17 cases of bilateral adrenal hyperplasia were included. The final diagnosis of an adenoma was made by surgery with histological confirmation, whereas that of bilateral adrenal hyperplasia was made on adrenal venous sampling or a good biochemical and clinical response following medical treatment alone and in the absence of a unilateral radiological abnormality. The CT (n=30) and MR (n=24) scans were reviewed independently by two radiologists experienced in adrenal imaging, who were unaware of the cause of the primary hyperaldosteronism. The diagnostic performances of both observers in detecting an aldosterone-producing adenoma on CT and MR imaging were compared. The 16 adenomatous nodules that were detected on imaging ranged from 1 to 4.75 cm in diameter. The calculated sensitivity and specificity for detecting aldosterone-producing adenoma were 87 and 93% for one observer and 85 and 82% for the other observer on CT, and 83 and 83% for one observer and 92 and 92% for the other observer on MR, respectively. Receptor operating characteristics curve analysis showed similar performances of both observers in detecting an aldosterone-producing adenoma on CT and MR imaging. There was good interobserver agreement on CT (k=0.71) and on MR (k=0.67). We have demonstrated comparable diagnostic performance and good interobserver agreement on CT and MR imaging for the detection of aldosterone-producing adenoma.

To investigate the role of the renin-angiotensin-aidosterone system as a cause of hypertension, 20 hypertensive patients with coarctation of the aorta were studied during normal and low sodium tntake and after diuresis with furosemide. Etght patients wtth essential hypertension and 13 control subjects were similarly studied. Plasma renin activity values in patients with coarctation were similar to those in patients with essential hypertension and in control patients during normal and low sodium diets. However, after the administration of furosemide, plasma renin activity values were signtftcantiy higher in the patients with coarctation than in the other two groups (P CO.005 and <O.Ol, respectively). The values for urinary aidosterone, plasma volume and extraceil fluid volume (bromide space) were increased in patients with coarctation during both normal and low sodium intake. These renin and aidosterone responses and body fluid spaces in patients with coarctation suggest that their hypertension resembles a one-kidney Goidbiatt model. The data help to better define the role of the renin-angiotensin-aidosterone system in the hypertension of coarctation and thus may help guide the clinician in therapeutic interventions.

Objective-It is routine in intensive care medicine (ICM) to measure hypothalamic-pituitaryadrenal (HPA) function, commonly utilizing the ACTH stimulation test to diagnose absolute or relative adrenal insufficiency (RAI). It is therefore important to determine whether ICM therapies and testing themselves influence HPA test results. Design-Prospective, 96 h animal study. Setting-Research laboratory. Subjects-24 healthy canines. Interventions-Animals were randomized into two groups-awake and unrestrained or treated with intensive care medicine therapies including sedation, intubation and mechanical ventilation (SIM). Animals were further randomized to receive dexamethasone (or placebo) or undergo either a total of 4 or 7 ACTH stimulation tests over 96 h. Measurements and Main Results-SIM transiently increased both basal and post-ACTH total and free cortisol concentrations greater than twofold as compared to baseline for the first 24 h (p ≤ 0.05 for both). Performance of 7 stimulation tests increased both basal and post-ACTH total and free cortisol concentrations from baseline by greater than 1.5 fold for the duration of the 96 h study (p ≤ 0.05). Neither SIM nor the performance of more stimulation tests affected delta cortisol measurements (total or free cortisol, p=NS). In contrast, dexamethasone suppressed basal total cortisol concentrations by greater than twofold (p ≤ 0.005) at all time points and transiently increased delta total cortisol by approximately 35% during the first 24 h of the study (p ≤ 0.05). Conclusions-total and free cortisol measurements-whether pre-or post-ACTH or as a calculated delta-were altered by intensive care therapies or frequent ACTH stimulation testing with one exception. Delta free cortisol was the only HPA measurement unaffected by SIM, completion of more ACTH stimulation tests or dexamethasone therapy. These findings support the need to determine normal ranges for HPA testing in subjects receiving ICM before establishing laboratory criteria for the diagnosis of RAI.

Objective-Low salt (LS) diet activates the renin-angiotensin-aldosterone and sympathetic nervous systems, both of which can increase insulin resistance (IR). We investigated the hypothesis that LS diet is associated with an increase in IR in healthy subjects.

Sustained activation of the Renin-Angiotensin-Aldosterone System (RAAS) contributes to the pathogenesis of heart failure. Aldosterone (Aldo) is known to induce both myocardial hypertrophy and fibrosis through oxidative stress and proinflammatory pathways. Here we have investigated whether Aldo-mediated cardiomycocyte hypertrophy is dependent on TRAF3IP2, an upstream regulator of IKK and JNK. We also investigated whether the pro-mitogenic and pro-migratory effects of Aldo on cardiac fibroblasts are also mediated by TRAF3IP2. Aldo induced both superoxide and hydrogen peroxide in isolated adult mouse cardiomyocytes (CM), and upregulated TRAF3IP2 expression in part via the mineralocorticoid receptor and oxidative stress. Silencing TRAF3IP2 blunted Aldo-induced IKKβ, p65, JNK, and c-Jun activation, IL-18, IL-6 and CT-1 upregulation, and cardiomyocyte hypertrophy. In isolated adult mouse cardiac fibroblasts (CF), Aldo stimulated TRAF3IP2-dependent IL-18 and IL-6 production, CTGF, collagen I and III expression, MMP2 activation, and proliferation and migration. These in vitro results suggest that TRAF3IP2 may play a causal role in Aldo-induced adverse cardiac remodeling in vivo, and identify TRAF3IP2 as a potential therapeutic target in hypertensive heart disease.

A syndrome of renal tubular resistance to aldosterone has been identified in infants with obstructive uropathy and urinary tract (nfection. Six infants (ages 9 days to 7 months) were seen with fever, vomiting, polyuria, dehydration, or failure to thrive. Urine cultures were positive for Escherichia coli. Radiologic studies demonstrated bilateral ureterohydronephrosis (four patients), left ureteral duplication with upper pole hydronephrosis (one), and left vesicoureteral reflux (one). The infants had hyponatremia, hyperkalemia, and metabolic acidosis. Plasma aldosterone concentration was markedly elevated, and plasma renin activity was similar to or higher than that reported in normal infants of comparable age. Fractional excretion of potassium was not significantly different from control values, both in absolute terms or when related to glomerular filtration rate, but fractional sodium excretion was significantly increased. The UrJUN, ratio was significantly lower in the patients. After medical or surgical therapy (when appropriate), all blood and urine determinations returned to normal, except for UdUN~ values, which although higher, remained significantly diminished. Our data indicate that a hyperkalemic salt-losing state can arise in infants with obstructive uropathy and urinary tract infection as a consequence of tubular unresponsiveness to aldosterone, and that the clinician should rule out such cause before establishing the diagnosis of primary pseudohypoaldosteronism. (J PEDIATR 103:375, 1983) CHRONIC OBSTRUCTION OF THE URINARY TRACT is associated experimentally with marked reduction in renal blood flow and glomerular filtration rate ~ and with significant changes in the renal tubular handling of water and electrolytes5 The clinical counterpart of these findings has been less well studied, but impaired water reabsorption with secondary nephrogenic diabetes insipidus, 3 impaired sodium reabsorption leading to hyponatremic dehydration, 4-6 and decreased excretion of potassium and hydrogen ion with a resultant syndrome of hyperkalemic hyperchloremic metabolic acidosis v has been observed occasionally in patients with obstructive uropathy. We describe six infants with urinary tract infection and urologic abnormalities of varying severity, all of whom had apparent renal tubular

Studies have shown that patients with compensated heart failure (HF) receiving high diuretic doses associated with normal sodium diet and fluid intake restrictions demonstrated significant reductions in readmissions and mortality compared with those who received low-sodium diets, and over a 6-month observation period, a reduction in neurohormonal activation was also observed. The aim of this study was to evaluate the effects of different sodium diets associated with different diuretic doses and different levels of fluid intake on hospital readmissions and neurohormonal changes after 6-month follow-up in patients with compensated HF. Four hundred ten consecutive patients with compensated HF (New York Heart Association class II to IV) aged 53 to 86 years, with ejection fractions &lt;35% and serum creatinine &lt;2 mg/dl, were randomized into 8 groups: group A (n = 52): 1,000 ml/day of fluid intake, 120 mmol/day, and 250 mg furosemide twice daily; group B (n = 51): 1,000 ml/day of fluid...

In the present study, we observed expression and changes of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the gerbil hippocampal CA1 region, but not in the CA2/3 region, after 5 min of transient forebrain ischemia. In blood, corticosterone levels were increased biphasically at 30 min and 12 h after ischemia/reperfusion, and thereafter its levels were decreased. In the sham-operated group, MR and GR immunoreactivities were weakly detected in the CA1 region. By 3 days after ischemia, MR and GR were not significantly altered in the CA1 region: at 12 h after ischemia, GR was expressed in a few neurons in the CA1 region, whereas MR was not expressed in any neurons after ischemic insult. From 4 days after ischemia, MR and GR immunoreactivities were detected in astrocytes and microglia in the CA1 region, and at 7 days after ischemia, MR and GR immunoreactivities peaked in the hippocampal CA1 region. At this time, 55% of astrocytes and 30% of microglia showed MR immunoreactivity, and 20% of astrocytes and 40% of microglia showed GR immunoreactivity. Western blot analyses showed that the pattern of changes in MR and GR protein levels was similar to the immunohistochemical changes observed after transient forebrain ischemia. From 4 days after ischemia, MR and GR protein levels were increased time-dependently after ischemia. In conclusion, enhanced MR and GR expressions in astrocytes and microglia were detected in the hippocampal CA1 region 4-7 days after ischemia/reperfusion. At this time, GR immunoreactivity was abundant in microglia, whereas MR immunoreactivity was prominent in astrocytes. The specific distribution of corticosteroid receptors in the astrocytes and microglia may be associated with the differences of MR and GR functions against ischemic damage. #

Genetic polymorphisms in the Catechol O-Methyltransferase (COMT) gene have been linked to increased pain sensitivity in a number of studies. A literature search was performed to integrate the current knowledge of the gene, its regulation, influences of the polymorphisms upon enzyme function and its population distributions. Assessment also includes the current knowledge of the enzyme structure, isoforms, function and metabolic activities, substrates, and products. Other gene polymorphisms which may influence the components involved within the COMT enzymatic reaction, such as folate metabolism polymorphisms and cofactor availability, were also briefly assessed. A review of enzyme agonists and antagonist and how these may influence the enzymes functions, its substrates and products is undertaken in an attempt to understand the potential interactions between COMT and factors that may influence enzyme activity in the presence or absence of the COMT polymorphic forms.

Background: 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. Methods: 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 ten minutes daily for ten consecutive days. Two weeks after the last exposure, electrophysiological and biochemical assessments were performed. Results: 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. Conclusion: 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.

In vitro studies have demonstrated that cysteine groups present in most of the steroid receptors play an essential role in the steroid binding process as well as in the ability of this superfamily of signaling proteins to function as transcription factors. However, there is poor experimental evidence, if any, which demonstrates that under conditions of oxidative stress the steroid receptors in general, and the mineralocorticoid receptor in particular, are affected in vivo in a similar fashion as has been described for cell-free systems or cells in culture. In the present work we report that when mice are exposed to oxidative stress by treatment with L-buthionine-(S,R)-sulfoximine (L-(S,R)-BSO), a glutathione depleting agent, the aldosterone-dependent mineralocorticoid biological response (measured as sodium retention and potassium elimination) was diminished in a directly proportional manner with respect to the depletion of renal glutathione. Accordingly, the steroid binding capacity of the mineralocorticoid receptor was also abrogated, whereas the receptor protein level remained unchanged. The harmful effects observed in mice after glutathione depletion were efficiently prevented by co-treatment with glutathione monoethyl ester. Similar inhibition in the steroid binding capacity was also generated in vitro by receptor alkylation and receptor oxidation, an effect which was prevented in the presence of reducing agents. Since the glutathione deficit generated in vivo by treatment with L-(S,R)-BSO did not significantly affect other renal proteins which are known to be required for the mineralocorticoid mechanism of action, we suggest that in renal cells a low redox potential exerts drastic and uncompensated inhibition of the receptor-mediated mineralocorticoid biological response. This effect was ascribed to the loss of steroid binding capacity of oxidized receptor, most likely by modification of essential cysteines as supported by experiments where a decreased number of reactive thiols and reduced covalent binding of thiol-reactive ligand were evidenced on immunopurified receptor after in vivo treatment with L-(S,R)-BSO . ß

Splanchnic and systemic arteriolar vasodilationplays an important role in ascites formation incirrhosis. Octreotide produces splanchnicvasoconstriction, but the effects on systemichemodynamics and renal function are controversial. This studyevaluated the effect of subcutaneous octreotideadministration on systemic hemodynamics, endogenousvasoactive systems, and renal function in cirrhoticpatients with ascites. Twenty patients were included: 10received octreotide 250 μg/12 hr subcutaneously (forfive days), and 10 did not. No statistically significantchanges were found in mean arterial pressure and cardiac rate. Octreotide induced astatistically significant decrease in plasma reninactivity (P < 0.01), plasma aldosterone (P = 0.01)and plasma glucagon (P < 0.05). No significantvariations were observed in other systemic vasoactivesubstances (nitric oxide and prostacyclin). Renalfunction was not modified in either group. Inconclusion, in cirrhotic patients with ascites,subcutaneous octreotide administration decreases plasma glucagon, reninactivity, and aldosterone without changing in systemichemodynamics or renal function.

The humoral and hemodynamic effects of converting enzyme inhibition captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (+/- SEM) plasma renin activity (PRA) rose from 5.0 +/- 1.4 to 35.3 +/- 5.3 ng/ml/hr (P less than 0.01) and mean (+/- SEM) plasma aldosterone (PA) declined from 25.8 +/- 2.9 to 15.1 +/- 1.9 ng/ml (P less than 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone-producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induc...

Measurement of serum aldosterone is clinically important in the diagnosis of hypertension. While isotope dilution gas chromatography-mass spectrometry (ID-GC-MS) provides reliable results, it requires derivatization and is lengthy and time-consuming. Detection by liquid chromatography-mass spectrometry (LC-MS) is a potentially superior method. The analysis utilizes 0.5 mL of serum. The samples were extracted with dichloromethane-ether. The extract was evaporated to dryness and aldosterone was analyzed by LC-MS/MS operating in the negative mode ESI after separation on a reversed-phase column. Aldosterone was also measured by RIA. The calibration curves for analysis of serum aldosterone exhibited consistent linearity and reproducibility in the range of 60-3000 pmol/L. Interassay CVs were 4.3-7.5% at aldosterone concentrations of 97-993 pmol/L. The lower limit of quantitation (LOQ) was 30 pmol/L (signal to noise ratio = 10). The mean recovery of the analyte added to serum ranged from 95 to 102%. The regression equation by LC-MS/MS (x) and RIA (y) method was: y = 1.33x + 185 (r = 0.95; n = 124). Sensitivity and specificity of the LC-MS/MS method for serum aldosterone offer advantages over GC-MS by eliminating derivatization. The novel method is rapid, reliable and simple to perform with a routine LC-MS/MS spectrometer. The sensitivity is adequate for patient samples. Aldosterone concentrations reported by nonextraction RIA were consistently higher than those produced by LC-MS/MS.

We examined whether carbohydrate in beverages accelerated fluid retention during recovery from thermal and exercise-induced dehydration and whether it was caused in part by an enhanced renal Na+ reabsorption rate due to insulin secretion. After dehydrating by ∼2.3% body weight by exercise in a hot environment, seven young men underwent high-carbohydrate, low-carbohydrate, or control rehydration trials by drinking one of three beverages with 3.4 g glucose + 3.1 g fructose, 1.7 g glucose + 1.6 g fructose, or 0.0 g glucose + 0.0 g fructose per deciliter, respectively, in a common composition of electrolyte solution: 21 meq/l [Na+], 5 meq/l [K+], 16.5 meq/l [Cl−], 10 meq/l [citrate−3]. They drank the same amount of beverage as total body weight loss within 30 min. During the 60 min before the start of drinking and the following 180 min, we measured plasma volume (PV), plasma glucose ([Glc]p), serum insulin ([Ins]s), plasma Na+ concentrations, and the renal clearances of inulin, lithium,...

A 7-year-old girl had growth retardation, hypeflenslon, and hypOkalemic dlkalosls. Baseline serum aldosterone concentratlon and plasma renln actlvlty were low and unresponsive to sodium deprlvatlon and to orthostatlc changes, Baseline serum progesterone, 17-hydroxyprogesterone, 11-deoxycortlsol, and cortisol ievel$ were normal dnd adequately responsive to ACTH stimulation. No sterold was found abnormally elevated. A dlagnosls of 11t~-hydroXysterold dehydr~)genase deficlency was establlshed on the basls of elevated urinary tetrahydrocodlsol plus allotetrahydrocodlsol/tetrahydrocodlsonO ratio, determined by gas chromatography,mass spectrometry. Evaluation Of bone miner. al metabolism and parathyroid fun(~tlon, and skeletal radiographs, revealed the presence of rickets and secondary hyperparathyroldism. Treatment wlth spironolactone alone for 2 months Corrected hypertension, hypokalemlc alkaiosls, and all laboratory dnd radlologic evidence of rickets and hyper. parathyroldism, resultlng In acceleration Of growth rate. The response to spironolactorie suggests that a hypermineralocortlcoid state is responsible for the hypertensive syndrome and that rlckets and hyperparathyroldlsm could be a consequence of excess mlneralocodlcold activity.

Background and objective: The laboratory has a critical role to play in the screening and diagnosis of primary aldosteronism. This review highlights some of the important analytical considerations and the new developments in the determination of aldosterone and renin.

Resistant hypertension is common in clinical practice. The aim of our study was to evaluate inappropriate aldosterone activity in causing resistance to antihypertensive therapy. Among the patients consecutively evaluated for the first time between 1995 and 2001, we selected all those (n = 157) with an aldosterone-to-renin ratio (ARR) &gt;or=25 (ng/dL)/(ng/mL/h), and plasma aldosterone &gt;or=12 ng/dL. Eight patients with Conn adenoma were excluded from the study. Fifty-eight were diagnosed as idiopathic aldosteronism (IHA), the other 91 patients, who did not meet the criteria for primary aldosteronism, were operatively classified as aldosterone-associated hypertension (AAH). As a control group, we randomly chose 160 patients with essential hypertension and plasma aldosterone &lt;12 ng/dL (EH). Antihypertensive treatment was given in accordance to World Health Organization Guidelines (1999). The study end point was blood pressure (BP) &lt;140/90 mm Hg. During follow-up (22 +/- 2 mont...

Licorice has been considered a medicinal plant for thousands of years. The most common side effect is hypokalemic hypertension, which is secondary to a block of 11beta-hydroxysteroid dehydrogenase type 2 at the level of the kidney, leading to an enhanced mineralocorticoid effect of cortisol. We have investigated the effect of licorice on androgen metabolism in nine healthy women 22-26 years old, in the luteal phase of the cycle. They were given 3.5 g of a commercial preparation of licorice (containing 7.6% W.W. of glycyrrhizic acid) daily for two cycles. They were not on any other treatment. Plasma renin activity, serum adrenal and gonadal androgens, aldosterone, and cortisol were measured by radioimmunoassay. Total serum testosterone decreased from 27.8+/-8.2 to 19.0+/-9.4 in the first month and to 17.5+/-6.4 ng/dL in the second month of therapy (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). It returned to pre-treatment levels after discontinuation. Androstenedione, 17OH-progesterone, and LH levels did not change significantly during treatment. Plasma renin activity and aldosterone were depressed during therapy, while blood pressure and cortisol remained unchanged. Licorice can reduce serum testosterone probably due to the block of 17-hydroxysteroid dehydrogenase and 17-20 lyase. Licorice could be considered an adjuvant therapy of hirsutism and polycystic ovary syndrome.

The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-I converting enzyme (ACE) inhibitors and angiotensin II (Ang II) subtype-1 (AT 1 ) receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur whereby aldosterone levels return to, or exceed, baseline levels. The classical effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, the presence of mineralocorticoid receptors (MR) at nonepithelial sites in the brain, heart and vasculature, is consonant with the fact that aldosterone also has direct effects in these tissues. Substantial evidence now exists that supports the action of aldosterone at non-epithelial sites which in turn provokes a number of deleterious effects on the cardiovascular system including necrosis and fibrosis of the vasculature and the heart, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release and production of cardiac arrhythmias. Several studies have now shown that vascular and target-organ protective effects of MR antagonism occurs in the absence of significant blood pressure lowering or fluid loss, which is consistent with a major role for endogenous mineralocorticoids as direct mediators of cardiovascular injury. Adverse cardiovascular effects may occur in response to aldosterone alone, activation of the RAAS or aldosterone escape during chronic ACE inhibition or AT 1 receptor antagonism. The specific blockade of aldosterone action should prove to be of great therapeutic value in the prevention of cerebral and renal vascular disease and associated end-organ damage.

To monitor the hydration, core temperature, and speed (pace) of a triathlete performing an Ironman triathlon. A 35-year-old experienced male triathlete participated in the Western Australian Ironman triathlon on December 1, 2006. The participant was monitored for blood Na(+) concentration before the race (PRE), at the transitions (T1 and T2), halfway through the run (R21), and after the race (POST; 2hPOST). Core body temperature (T(c); pill telemetry) was recorded continuously, and running speed (s3 stride sensor) was measured during the run. The participant completed the race in 11 h 38 min, in hot conditions (26.6 +/- 5.8 degrees C; 42 +/- 19% rel. humidity). His T(c) increased from 37.0 to 38.6 degrees C during the 57-min swim, and averaged 38.4 degrees C during the 335-min bike (33.5 km x h(-1)). After running at 12.4 km x h(-1) for 50 min in the heat (33.1 degrees C), T(c) increased to 39.4 degrees C, before slowing to 10.0 km x h(-1) for 20 min. T(c) decreased to 38.9 degrees ...

Objective: To study the changes in blood volume and hormones controlling sodium and water homeostasis after infusions of 0.9% saline, Gelofusine (4% succinylated gelatin in 0.7% saline, weight-average molecular weight 30 kD), and Voluven (6% hydroxyethyl starch in 0.9% saline, weight-average molecular weight 130 kD) in healthy volunteers.

The renin-angiotensin-aldosterone-system appears to be involved in the development of cardiac fibrosis in rodents, characterized by nonepithelial cell proliferation and changes in the extracellular matrix. The aim of our study was to investigate the effect of high aldosterone concentrations on the proliferation of human cardiac interstitial cells in vitro. In addition, the effect of D-glucose as another risk factor for fibrosis, eg, in the diabetic heart, was investigated. Human cardiac myofibroblast cultures were established, and growth rates were measured by WST-1 assay in fetal calf serum-free Dulbecco's modified Eagle's medium (DMEM). Cells in culture showed a significant increase in number between 24 to 72 hours of cultivation under basal conditions (DMEM, 10% fetal calf serum). Aldosterone at high concentrations (10 Ϫ8 and 10 Ϫ7 mol/L) significantly (PϽ0.01) increased the proliferation of cultured cardiac myofibroblasts. Comparable effects were observed after incubation of the cells with high D-glucose concentrations (15 and 25 mmol/L, PϽ0.01). No additive growth stimulation was evident when the cells were incubated in medium containing both aldosterone and D -glucose. These results suggest a role for aldosterone and glucose in mediating the cardiac fibrosis through stimulation of myofibroblast growth in patients with dysregulated renin-angiotensin-aldosterone-system (especially hyperaldosteronism) and impaired glucose homeostasis. (Hypertension. 2002;39:756-760.)

People who visit high-altitude areas are exposed to a stressful environment and a good percentage of them suffer from high-altitude-induced diseases, including systemic hypertension. Identification of genetic markers for high-altitude-induced diseases would help to reduce the rate of morbidity/mortality from such diseases. The development of systemic hypertension on exposure to high altitude (3,500 m) for 30 days in otherwise normotensive natives of low-altitudes was investigated. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotypes and renin-angiotensinaldosterone system were simultaneously studied. In the hypertensives during their stay at high altitude, the ACE D allele frequency was significantly higher than in the normotensives (0.67 versus 0.32 c 2 1 = 10.6, P < 0.05). In the normotensives during their stay at high altitude, there was no significant increase in plasma aldosterone levels despite increased plasma renin activity. Results of the present study suggest that environmental changes and preexisting genetic factors, namely the ACE D allele, might be two of the factors predisposing natives of low altitudes to systemic hypertension, a polygenic disease, at high altitude.

Clinically inapparent adrenal masses are incidentally detected after imaging studies conducted for reasons other than the evaluation of the adrenal glands. They have frequently been referred to as adrenal incidentalomas. In preparation for a National Institutes of Health State-of-the-Science Conference on this topic, extensive literature research, including Medline, BIOSIS, and Embase between 1966 and July 2002, as well as references of published metaanalyses and selected review articles identified more than 5400 citations. Based on 699 articles that were retrieved for further examination, we provide a comprehensive update of the diagnostic and ther-apeutic approaches focusing on endocrine and radiological features as well as surgical options. In addition, we present recent developments in the discovery of tumor markers, endocrine testing for subclinical disease including autonomous glucocorticoid hypersecretion and silent pheochromocytoma, novel imaging techniques, and minimally invasive surgery. Based on the statements of the conference, the available literature, and ongoing studies, our aim is to provide practical recommendations for the management of this common entity and to highlight areas for future studies and research. (Endocrine Reviews 25: 309 -340, 2004) Luton JP, Le Bouc Y 2001 Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61:6762-6767 280. Heppner C, Reincke M, Agarwal SK, Mora P, Allolio B, Burns AL, Spiegel AM, Marx SJ 1999 MEN1 gene analysis in sporadic adrenocortical neoplasms. J Clin Endocrinol Metab 84:216 -219 281. Gicquel C, Bertagna X, Schneid H, Francillard-Leblond M, Luton JP, Girard F, Le Bouc Y 1994 Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 78:1444 -1453 282. Ilvesmaki V, Kahri AI, Miettinen PJ, Voutilainen R 1993 Insulinlike growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 77:852-858 283. Bourcigaux N, Gaston V, Logie A, Bertagna X, Le Bouc Y, Gicquel C 2000 High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. J Clin Endocrinol Metab 85:322-330 284.

Patients & Methods A total of 55 individuals were studied, 12 of them were patients with CRF and 43 healthy elderly subjects with normal renal function. Informed consent was obtained from all patients. Patients with diabetes mellitus, cardiac failure, cirrhosis, obstructive uropathy, hyperkalemia, hypokalemia, or taking any medication that could alter the potassium balance were excluded from the study. All subjects were on a diet containing 50 mmol of potassium intake daily (documented by a three-day dietary record). Plasma potassium, creatinine, urea, glucose and osmolality were measured in all as well. 24 h creatinine clearance (CrCl ) and TTKG were calculated. Statistical analysis was made using Student’s t-test. Results TTKG was significantly lower in the elderly group (4.2±1.9 vs 6.2±1.8 , P 0.005)Both groups had a significantly lower TTKG when compared to healthy young people (8±2). Plasma and urine potassium levels, as well as plasma osmolality were similar in the two groups. Only urine osmolality was lower in the CRF group (382±141 vs. 514±180, P=0.01) Conclusion Both old age and renal impairment lead to a reduced TTKG in comparison with young healthy people. Furthermore, TTKG is significantly lower in elderly healthy subjects compared to patients with CRF.