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

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: 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

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: 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

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

BACKGROUND: Aldosterone induces renal injury independent of angiotensin II. This harmful effect might be mediated via inflammatory reaction. Aldosterone receptor blockade can retard renal damage in various renal diseases including diabetic nephropathy. However, it is not clear which mechanism is related to the beneficial effect of aldosterone receptor blockade in diabetic nephropathy. Therefore, we investigated whether aldosterone receptor blockade, spironolactone, inhibited inflammatory changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes. METHODS: To determine the inflammatory effects, urinary MCP-1 protein was measured by ELISA, and intrarenal MCP-1 mRNA and ED-1 expression were examined by RT-PCR and immunohistochemistry, respectively. RESULTS: Blood glucose concentration were higher in diabetic rats than in control rats. Urinary protein excretion was significantly higher in diabetic rats compared with controls since twenty weeks, and proteinuria of the diabetic rats was decreased by spironolactone treatment. Urinary excretion of monocyte chemoattractant peptide-1 (MCP-1) was rapidly increased at the early period in diabetic rats. Spironolactone suppressed urinary level of MCP-1 compared to untreated diabetic rats. Immunohistochemistry revealed a significant increase in ED-1 staining in the diabetic kidney, and spironolactone treatment significantly suppressed intrarenal ED-1 expression in diabetic rats. CONCLUSION: Aldosterone receptor blockade, spironolactone, suppressed proteinuria and inflammatory changes in diabetic rats. These results suggest that spironolactone may have an anti-inflammatory effect in diabetic nephropathy.
Aldosterone* ; Angiotensin II ; Animals ; Blood Glucose ; Diabetic Nephropathies* ; Enzyme-Linked Immunosorbent Assay ; Immunohistochemistry ; Inflammation ; Kidney ; Monocytes ; Proteinuria ; Rats ; Receptors, Mineralocorticoid* ; RNA, Messenger ; Spironolactone

Pseudohypoaldosteronism type 1 (PHA1) is a rare form of mineralocorticoid resistance characterized in newborns by salt wasting with dehydration, hyperkalemia and failure to thrive. This disease is heterogeneous in etiology and includes autosomal dominant PHA1 owing to mutations of the NR3C2 gene encoding the mineralocorticoid receptor, autosomal recessive PHA1 due to mutations of the epithelial sodium channel (ENaC) gene, and secondary PHA1 associated with urinary tract diseases. Amongst these diseases, autosomal dominant PHA1 shows has manifestations restricted to renal tubules including a mild salt loss during infancy and that shows a gradual improvement with advancing age. Here, we report a neonatal case of PHA1 with a NR3C2 gene mutation (a heterozygous c.2146_2147insG in exon 5), in which the patient showed failure to thrive, hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone levels. This is the first case of pseudohypoaldosteronism type 1 confirmed by genetic analysis in Korea.
Aldosterone ; Dehydration ; Epithelial Sodium Channels ; Exons ; Failure to Thrive ; Humans ; Hyperkalemia ; Hyponatremia ; Infant ; Infant, Newborn ; Korea ; Plasma ; Pseudohypoaldosteronism ; Receptors, Mineralocorticoid ; Renin ; Urologic Diseases