No abstract available.
Receptors, Mineralocorticoid*

BACKGROUND: There have been few studies to evaluate the prognostic implications of guideline-directed therapy according to the temporal course of heart failure. This study assessed the relationship between adherence to guideline-directed therapy at discharge and 60-day clinical outcomes in de novo acute heart failure (AHF) and acute decompensated chronic heart failure (ADCHF) separately. METHODS: Among 5,625 AHF patients who were recruited from a multicenter cohort registry of Korean Acute Heart Failure, 2,769 patients with reduced ejection fraction were analyzed. Guideline-directed therapies were defined as the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), β-blocker, and mineralocorticoid receptor antagonist. RESULTS: In de novo AHF, ACEI or ARB reduced re-hospitalization (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.34–0.95), mortality (HR, 0.41; 95% CI, 0.24–0.69) and composite endpoint (HR, 0.52; 95% CI, 0.36–0.77) rates. Beta-blockers reduced re-hospitalization (HR, 0.62; 95% CI, 0.41–0.95) and composite endpoint (HR, 0.65; 95% CI, 0.47–0.90) rates. In ADCHF, adherence to ACEI or ARB was associated with only mortality and β-blockers with composite endpoint. CONCLUSION: The prognostic implications of adherence to guideline-directed therapy at discharge were more pronounced in de novo heart failure. We recommend that guideline-directed therapy be started as early as possible in the course of heart failure with reduced ejection fraction.
Angiotensins ; Cohort Studies ; Heart Failure ; Heart ; Humans ; Mortality ; Receptors, Mineralocorticoid

OBJECTIVETo investigate the mRNA and protein expression of mineralocorticoid receptor (MR) in patients with atrial fibrillation.

METHODSTwenty-five patients with rheumatic heart valve disease, 12 in sinus rhythm and 13 in chronic atrial fibrillation (>or= 6 months), underwent transthoracic echocardiography and right and left atrial lateral wall tissue samples were obtained from these patients during mitral/aortic valve replacement operation. Realtime quantitative PCR and Western blot were used to determine the mRNA and protein expression of MR in atria specimens. The distribution of MR in human atria was analyzed by specific immunohistochemical staining.

RESULTSThe left atrial diameters increased markedly in atrial fibrillation group compared with that in sinus rhythm group (P<0.01). And the results showed that the level of mRNA and protein of MR were increased significantly in atrial fibrillation group compared with those in sinus rhythm group (P<0.01 or 0.05), whereas the expression of mRNA and protein of MR were found to be no difference between left atria and right atria both in fibrillation and sinus groups (all P>0.05). The special immunohistochemical staining demonstrated that MR was abundant in the human atrial myocardium and MRs were located mainly in the cytoplasm of atrial cells, which were more evident in atrial fibrillation group than those in sinus rhythm group.

CONCLUSIONThese findings suggested that MRs were upregulated in atrial fibrillation and aldosterone antagonists may be effective in treating atrial fibrillation.

Adult ; Atrial Fibrillation ; metabolism ; Humans ; Male ; Middle Aged ; Myocardium ; metabolism ; RNA, Messenger ; genetics ; Receptors, Mineralocorticoid ; metabolism

BACKGROUND: Eplerenone is a selective mineralocorticoid receptor antagonist which effectively blocks mineralocorticoid receptors in various tissues throughout the body. The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients post acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The aim of this study was to evaluate pharmacokinetic characteristics and tolerability after multiple oral administration of eplerenone 100 mg for 7 days in healthy Korean volunteers. METHODS: A double-blind, randomized, placebo-controlled, parallel study was conducted in 22 healthy Korean subjects. Healthy males and females between age of 20 and 55 years were enrolled. Each subject received 100 mg eplerenone (N=16) or placebo (N=6) for 7 days. Blood samples for pharmacokinetic parameter determination on day 7 were collected pre-dose and up to 36 hours after last drug administration. Adverse events were reported throughout the treatment period. RESULTS: The steady-state concentration of eplerenone reached after multiple administration of eplerenone 100 mg for 7 days. The mean eplerenone Cmax of 1620.1 ng/mL was obtained at 1.0 hour (range 0.5 to 2 hours). The mean AUC0-24h,ss at day 7 was 8763.6 ng/mL*h. The mean oral clearance and mean terminal half-life of eplerenone were 13.0 L/h and 3.4 hours. There were some drug-related mild adverse events after eplerenone administration, but all adverse events recovered without any treatment. CONCLUSION: In this study, the pharmacokinetic parameters after multiple oral doses of eplerenone 100 mg for 7 days were evaluated and eplerenone at these doses were well tolerated in healthy Korean subjects.
Administration, Oral ; Female ; Half-Life ; Heart Failure ; Humans ; Male ; Myocardial Infarction ; Receptors, Mineralocorticoid ; Spironolactone ; Ventricular Dysfunction, Left

Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.
Acidosis ; Dehydration ; Epithelial Sodium Channels ; Failure to Thrive ; Humans ; Hyperkalemia ; Hyponatremia ; Infant, Newborn* ; Kidney ; Korea ; Male* ; Pseudohypoaldosteronism* ; Receptors, Mineralocorticoid*

BACKGROUND: Striatin and caveolin-1 (cav-1) are scaffolding/regulating proteins that are associated with salt-sensitive high blood pressure and promote renal sodium and water reabsorption, respectively. The mineralocorticoid receptor (MR) interacts with striatin and cav-1, while aldosterone increases striatin and cav-1 levels. However, no in vivo data have been reported for the levels of these proteins in the kidney. METHODS: Male Wistar rats were intraperitoneally injected with normal saline solution, aldosterone alone (Aldo: 150 µg/kg body weight), or aldosterone after pretreatment with eplerenone, an MR blocker, 30 minutes before the aldosterone injection (eplerenone [Ep.]+Aldo). Thirty minutes after the aldosterone injection, the amount and localization of striatin and cav-1 were determined by Western blot analysis and immunohistochemistry, respectively. RESULTS: Aldosterone increased striatin levels by 150% (P<0.05), and cav-1 levels by 200% (P<0.001). Eplerenone had no significant effect on striatin levels, but partially blocked the aldosterone-induced increase in cav-1 levels. Aldosterone stimulated striatin and cav-1 immunoreactivity in both the cortex and medulla. Eplerenone reduced cav-1 immunostaining in both areas; however, striatin intensity was reduced in the cortex, but increased in the medulla. CONCLUSION: This is the first in vivo study demonstrating that aldosterone rapidly enhances renal levels of striatin and cav-1. Aldosterone increases striatin levels via an MR-independent pathway, whereas cav-1 is partially regulated through MR.
Aldosterone ; Animals ; Blotting, Western ; Caveolin 1 ; Humans ; Hypertension ; Immunohistochemistry ; Kidney ; Male ; Rats ; Rats, Wistar ; Receptors, Mineralocorticoid ; Sodium ; Sodium Chloride ; Water

mineralocorticoid receptor determined by reverse transcription-polymerase chain reaction was decreased in the experimental group. These results suggest that the changes in sodium transporters are causally related with an increased intraluminal pressure in the salivary duct in the ligated gland.]]>
Animals ; Atrophy ; Blotting, Western ; Humans ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Mineralocorticoid ; RNA, Messenger ; Salivary Ducts ; Sodium ; Submandibular Gland

BACKGROUND: Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS: Animals were divided into six groups as follows: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS: Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor-1, transforming growth factor-beta1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION: Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug.
Aldosterone ; Animals ; Collagen Type IV ; Connective Tissue Growth Factor ; Diabetic Nephropathies ; Fibronectins ; Lisinopril ; Mineralocorticoid Receptor Antagonists ; Peptidyl-Dipeptidase A ; Plasminogen Activators ; Rats ; Rats, Inbred OLETF ; Receptors, Mineralocorticoid ; Renin-Angiotensin System ; RNA, Messenger ; Spironolactone

Hypokalemia is a common clinical problem. The kidney is responsible for long term potassium homoeostasis, as well as the serum potassium concentration. The main nephron site where K secretion is regulated is the cortical collecting duct, mainly via the effects of aldosterone. Aldosterone interacts with the mineralocorticoid receptor to increase sodium reabsorption and potassium secretion; the removal of cationic sodium makes the lumen relatively electronegative, thereby promoting passive potassium secretion from the tubular cell into the lumen through apical potassium channels. As a result, any condition that decreases the activity of renal potassium channels results in hyperkalemia (for example, amiloride intake or aldosterone deficiency) whereas their increased activity results in hypokalemia (for example, primary aldosteronism or Liddle's syndrome). The cause of hypokalemia can usually be determined from the history. If there is no apparent cause, the initial step is to see if hypokalemia is in associated with systemic hypertension or not. In the former group hypokalaemia is associated with a high mineralocorticoid effect or hyperactive sodium channel as in Liddle's syndrome. In hypertensive hypokalemic patients, measurement of the renin, aldosterone, and cortisol concentrations would be of help in differential diagnosis.
Aldosterone ; Amiloride ; Diagnosis, Differential ; Humans ; Hydrocortisone ; Hyperaldosteronism ; Hyperkalemia ; Hypertension ; Hypokalemia ; Kidney ; Mineralocorticoids ; Nephrons ; Potassium ; Potassium Channels ; Receptors, Mineralocorticoid ; Renin ; Sodium ; Sodium Channels

Pseudohypoaldosteronism (PHA), a rare syndrome of systemic or renal mineralocorticoid resistance, is clinically characterized by hyperkalemia, metabolic acidosis, and elevated plasma aldosterone levels with either renal salt wasting or hypertension. PHA is a heterogeneous disorder both clinically and genetically and can be divided into three subgroups; PHA type 1 (PHA1), type 2 (PHA2) and type 3 (PHA3). PHA1 and PHA2 are genetic disorders, and PHA3 is a secondary disease of transient mineralocorticoid resistance mostly associated with urinary tract infections and obstructive uropathies. PHA1 includes two different forms with different severity of the disease and phenotype: a systemic type of disease with autosomal recessive inheritance (caused by mutations of the amiloride-sensitive epithelial sodium channel, ENaC) and a renal form with autosomal dominant inheritance (caused by mutations of the mineralocorticoid receptor, MR). In the kidneys, the distal nephron takes charge of the fine regulation of water absorption and ion handling under the control of aldosterone. Two major intracellular actors necessary for the action of aldosterone are the MR and the ENaC. Impairment of the intracellular aldosterone signal transduction pathway results in resistance to the action of mineralocorticoids, which leads to PHA. Herein, ion handling the distal nephron and the clinico-genetic findings of PHA are reviewed with special emphasis on PHA type 1.
Absorption ; Acidosis ; Aldosterone ; Epithelial Sodium Channels ; Hyperkalemia ; Hypertension ; Kidney ; Mineralocorticoids ; Nephrons ; Phenotype ; Plasma ; Pseudohypoaldosteronism* ; Receptors, Mineralocorticoid ; Signal Transduction ; Urinary Tract Infections ; Water ; Wills