eplerenone and Metabolic-Syndrome

Topics: Aldosterone; Animals; Chronic Disease; Eplerenone; Humans; Kidney Diseases; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Podocytes; Proteinuria; Receptors, Mineralocorticoid; Risk Factors; Spironolactone

Key components of the metabolic syndrome (MetS), ie, obesity and insulin resistance, are associated with increased aldosterone production and mineralocorticoid receptor (MR) activation. Both MetS and hyperaldosteronism are proinflammatory and pro-oxidative states associated with cardiovascular disease. This review discusses emerging data that MR activation may contribute to abnormalities seen in MetS. In view of these data, MR antagonists may be beneficial in MetS, not only by controlling hypertension but also by reversing inflammation, oxidative stress, and defective insulin signaling at the cellular-molecular level. Clinical trials have demonstrated benefits of MR antagonists in heart failure, hypertension, and diabetic nephropathy, but additional trials are needed to demonstrate the clinical significance of MR blockade in MetS.

Topics: Aldosterone; Antihypertensive Agents; Eplerenone; Humans; Hypertension; Inflammation; Insulin Resistance; Lipid Metabolism; Lipids; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Obesity; Signal Transduction; Spironolactone

Topics: Adult; Aged, 80 and over; Biomarkers; Eplerenone; Female; Humans; Lipids; Male; Metabolic Syndrome; Middle Aged; Mineralocorticoid Receptor Antagonists; Spironolactone; Vasodilation

The prevalence of metabolic syndrome is especially high in older adults. Metabolic syndrome is associated with impaired vascular endothelial function, insulin resistance, and increased risk for cardiovascular disease but the underlying mechanisms are not fully elucidated. Plasma aldosterone is independently associated with metabolic syndrome and is linked to endothelial dysfunction and insulin resistance. Thus, we hypothesized that mineralocorticoid receptor (MR) blockade would improve flow-mediated dilation and insulin resistance in older adults with metabolic syndrome.. To test this hypothesis, we conducted a balanced, randomized, double-blind, placebo-controlled, crossover study using selective MR blockade (eplerenone; 100 mg/day) for 1 month with 1 month washout in older adults with metabolic syndrome (62.6 ± 3.2 yrs; mean ± standard error). We evaluated brachial artery flow-mediated dilation (ultrasonography), oxidative stress (oxidized low-density lipoproteins and F2-isoprostanes) and insulin resistance (homeostatic model assessment).. In response to MR blockade, flow-mediated dilation (5.37 ± 0.85 vs. 5.98 ± 1.29%; placebo vs. eplerenone; P = 0.4), oxidized low-density lipoproteins (51.6 ± 11.5 vs. 56.1 ± 10.9 U/L; P = 0.6), and F2-isoprostanes (0.07 ± 0.02 vs. 0.06 ± 0.01 pg/mL; P = 0.3) did not improve. Insulin resistance also did not change following MR blockade (1.04 ± 0.26 vs. 1.38 ± 0.50; P = 0.6). However, MR blockade resulted in a large reduction (10 mmHg) in systolic blood pressure (140 ± 6 vs. 130 ± 6 mmHg; P = 0.02), with no significant change in diastolic blood pressure (81 ± 3 vs. 75 ± 2 mmHg; P = 0.2).. Our data do not support a contributing role for MRs in endothelial dysfunction and insulin resistance in older adults with metabolic syndrome. However, our findings suggest MR activation is an important contributor to systolic hypertension in this patient group.

Topics: Aged; Brachial Artery; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Eplerenone; Humans; Insulin Resistance; Metabolic Syndrome; Middle Aged; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Placebos; Regional Blood Flow; Spironolactone; Ultrasonography; Vasodilation

Topics: Animals; Disease Models, Animal; Eplerenone; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Osteoarthritis; Rats

Hypertension is often associated with metabolic syndrome (MetS), and serves as a risk factor of MetS and its complications. Blood pressure circadian rhythm in hypertensive patients has been suggested to contribute to cardiovascular consequences and organ damage of hypertension. But circadian changes of BP and their response to drugs have not been clearly investigated in non-human primates (NHPs) of MetS with hypertension. Here, we identified 16 elderly, hypertensive MetS rhesus monkeys from our in-house cohort. With implanted telemetry, we investigate BP changes and its circadian rhythm, together with the effect of antihypertensive drugs on BP and its diurnal fluctuation. MetS hypertensive monkeys displayed higher BP, obesity, glucose intolerance, and dyslipidemia. We also confirmed impaired 24-h BP circadian rhythm in MetS hypertensive monkeys. Importantly, Eplerenone, a mineralocorticoid receptor blocker, exerts multiple beneficial effects in MetS hypertensive monkeys, including BP reduction, 24-h BP circadian rhythm restoration, and decreased plasma concentration of inflammation factors and advanced glycation end-products. In summary, we identified a naturally-developed hypertensive MetS NHP model, which is of great value in the studies on pathogenesis of MetS-associated hypertension and development of novel therapeutic strategies. We also provided multiple novel mechanistic insights of the beneficial effect of Eplerenone on MetS with hypertension.

Topics: Anesthesia, General; Animals; Antihypertensive Agents; Blood Pressure; Circadian Rhythm; Drug Evaluation, Preclinical; Eplerenone; Glycation End Products, Advanced; Hypertension; Macaca mulatta; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Models, Animal; Spironolactone; Telemetry; Wakefulness

Obesity, diabetes, fatty liver, and hypertension are major determinants of the metabolic syndrome. The effects of aldosterone and mineralocorticoid receptor blockers on fatty liver are largely unknown. The aim of the present study was to evaluate the relationships between aldosterone and the development of fatty liver.. In our experiments, we performed adrenalectomy (ADX) or administered 100 mg/kg/day eplerenone, a specific mineralocorticoid receptor blocker, to male C57BL/6 mice fed with a 60% fat diet for 20 weeks.. High-fat diet led to metabolic syndrome as indicated by increased body weight, elevated systolic blood pressure, impaired glucose tolerance, elevated insulin levels, and development of fatty liver. A marked reduction of aldosterone by ADX or blockade of aldosterone interaction with its receptor by eplerenone, which increased serum aldosterone considerably, resulted in reduced blood pressure, and reduced serum insulin and levels of triglycerides. However, differential effects were found on reduction of blood glucose to normal levels, which was observed only in ADX. Neither ADX nor eplerenone affected fatty liver formation or body weight. In cultured hepatocytes, triglyceride loading induced by high glucose, oleic acid or very low density lipoprotein was not affected by aldosterone, spironolactone or eplerenone.. Our results suggest that whereas aldosterone might be involved in some of the diet-induced insulin and glucose metabolic effects, it played no role in the development of fatty liver.

Topics: Adrenalectomy; Aldosterone; Animals; Blood Glucose; Blood Pressure; Cells, Cultured; Cholesterol; Diet, High-Fat; Disease Models, Animal; Eplerenone; Fatty Liver; Hepatocytes; Insulin; Insulin Resistance; Lipoproteins, VLDL; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Oleic Acid; Spironolactone; Triglycerides; Weight Gain

Because the renin-angiotensin-aldosterone system has been implicated in the development of insulin resistance and promotion of fibrosis in some tissues, such as the vasculature, we examined the effect of eplerenone, a selective mineralocorticoid receptor (MR) antagonist, on nonalcoholic steatohepatitis (NASH) and metabolic phenotypes in a mouse model reflecting metabolic syndrome in humans. We adopted liver-specific transgenic (Tg) mice overexpressing the active form of sterol response element binding protein-1c (SREBP-1c) fed a high-fat and fructose diet (HFFD) as the animal model in the present study. When wild-type (WT) C57BL/6 and liver-specific SREBP-1c Tg mice grew while being fed HFFD for 12 wk, body weight and epididymal fat weight increased in both groups with an elevation in blood pressure and dyslipidemia. Glucose intolerance and insulin resistance were also observed. Adipose tissue hypertrophy and macrophage infiltration with crown-like structure formation were also noted in mice fed HFFD. Interestingly, the changes noted in both genotypes fed HFFD were significantly ameliorated with eplerenone. HFFD-fed Tg mice exhibited the histological features of NASH in the liver, including macrovesicular steatosis and fibrosis, whereas HFFD-fed WT mice had hepatic steatosis without apparent fibrotic changes. Eplerenone effectively ameliorated these histological abnormalities. Moreover, the direct suppressive effects of eplerenone on lipopolysaccharide-induced TNFα production in the presence and absence of aldosterone were observed in primary-cultured Kupffer cells and bone marrow-derived macrophages. These results indicated that eplerenone prevented the development of NASH and metabolic abnormalities in mice by inhibiting inflammatory responses in both Kupffer cells and macrophages.

Topics: Animals; Cells, Cultured; Diet, High-Fat; Dietary Carbohydrates; Eplerenone; Fatty Liver; Fructose; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Non-alcoholic Fatty Liver Disease; Phenotype; Rats; Rats, Wistar; Spironolactone; Sterol Regulatory Element Binding Protein 1

Although some clinical studies have suggested that spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, appears to increase the blood glucose levels, experimental studies have not supported this notion. Here, we investigated the effect of SPL on blood glucose levels in SHR/NDmcr-cp(cp/cp) (ND) rats, an animal model of metabolic syndrome, in comparison with that of eplerenone (EPL), another MR antagonist. At the same dose of 100 mg/kg, SPL and EPL increased the urinary sodium-to-potassium ratio to a comparable extent, indicating that both agents have similar renal MR antagonistic efficacy in ND rats. Interestingly, SPL but not EPL significantly increased the level of blood glucose. The oral glucose tolerance test revealed that treatment with SPL led to glucose intolerance. The levels of serum insulin and adiponectin, regulators of the blood glucose level, were virtually unaffected by treatment with SPL. On the other hand, SPL induced a marked increase in the blood level of aldosterone, known to be a risk factor for insulin resistance. These results demonstrate that in comparison with EPL, SPL characteristically impairs glucose tolerance in an animal model of metabolic syndrome, in association with a higher blood level of aldosterone.

Topics: Animals; Area Under Curve; Blood Glucose; Eplerenone; Glucose; Glucose Intolerance; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Potassium; Rats; Sodium; Spironolactone

Recently, the role of aldosterone in metabolic syndrome (MS) has aroused interest and several reports have suggested that aldosterone blockade could be beneficial in reducing blood pressure (BP).. To examine the add-on effects of eplerenone (EP) on BP in patients with MS, 54 hypertensive patients with MS and 44 without MS were recruited. Systolic and diastolic BPs in mmHg before the initiation of EP was 144/84 ± 13/12 (MS group) and 147/85 ± 12/14 (non-MS group). Before the start of EP, all patients in both groups were treated with at least one antihypertensive drug. BPs were checked on every visit (at least every 2 months) and serum chemistries were measured every 4 months. The levels of microalbuminuria and aminoterminal pro-brain natriuretic peptide (NT pro-BNP) were determined before the start of and at the end of the study. Patients were followed for 1 year. If adverse effects were reported by patients or found in laboratory studies, EP was withdrawn.. One month after the start of EP, BPs were decreased to 140/80 ± 12/12 mmHg (MS group) versus 142/82 ± 11/12 mmHg (non-MS group) and there was no difference between the two groups. Towards the end of the study, BPs of both groups gradually decreased. At the end of the study, BPs of both groups were 129/76 ± 15/13 mmHg (MS group) versus 133/78 ± 13/11 mmHg (non-MS group). There was a significant difference in reduction of systolic BP between the two groups (p < 0.05). Add-on EP significantly decreased the levels of urinary excretion of albumin in MS patients but not in non-MS patients (p < 0.05). There was a significant correlation between reduction of systolic BP and NT pro-BNP but not microalbuminuria in the MS group (p < 0.05). There were no serious adverse effects in both groups.. EP may have some beneficial effects in lowering BP in patients with reduction of microalbuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Eplerenone; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Spironolactone

Eplerenone, a selective aldosterone blocker, has become clinically available in Japan since 2007. It has been reported that eplerenone has a potential antihypertensive effect, with a profile slightly different from that of spironolactone, and has fewer adverse reactions, suggesting that it may become a first-line treatment for hypertension. However, clinical data on hypertensive patients in Japan are lacking for eplerenone. In this study, we explored the clinical efficacy of eplerenone when it is added to an angiotensin-converting enzyme (ACE) inhibitor or a long-acting calcium channel blocker (CCB) in 68 (31 males, 37 females) Japanese patients with essential hypertension. After adding 50 mg of eplerenone to their basal treatment, blood pressure was significantly reduced at 4 weeks, and further reduced after 24 weeks of eplerenone treatment. Urinary albumin excretion decreased significantly after 24 weeks. There were no significant differences in general biochemical test values or electrolytes, but fasting serum triglycerides were significantly decreased after eplerenone treatment. The serum potassium level showed no significant change during treatment. There were no significant correlations between plasma renin activity or plasma aldosterone concentration (PAC) before eplerenone treatment and blood pressure after eplerenone treatment, showing that the antihypertensive effect of eplerenone is not affected by the patient's renin profile or pretreatment PAC values. Eplerenone was also effective in hypertensive patients with metabolic syndrome. In conclusion, eplerenone, when coadministered with an ACE inhibitor or a long-acting CCB, caused an extremely beneficial antihypertensive effect in Japanese patients with essential hypertension, without few clinically important adverse events.

Topics: Aged; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Asian People; Calcium Channel Blockers; Drug Therapy, Combination; Eplerenone; Female; Humans; Hypertension; Japan; Male; Metabolic Syndrome; Middle Aged; Mineralocorticoid Receptor Antagonists; Renin; Spironolactone; Treatment Outcome; Triglycerides

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na(+)/H(+) exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.

Topics: Aldosterone; Animals; Blood Pressure Determination; Disease Models, Animal; Echocardiography, Doppler; Eplerenone; Heart Failure, Diastolic; Heart Function Tests; Male; Metabolic Syndrome; Random Allocation; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Reference Values; Sensitivity and Specificity; Sodium Chloride; Spironolactone; Urinalysis; Ventricular Dysfunction, Left

Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.

Topics: Aldosterone; Animals; Antioxidants; Cyclic N-Oxides; Disease Models, Animal; Eplerenone; Hypertension; Kidney Diseases; Male; Metabolic Syndrome; Obesity; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Mutant Strains; Receptors, Cell Surface; Receptors, Leptin; Receptors, Mineralocorticoid; Renin; Sodium Chloride, Dietary; Spin Labels; Spironolactone

Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

Topics: Adipocytes; Adrenal Glands; Aldosterone; Animals; Cyclic N-Oxides; Disease Models, Animal; Eplerenone; Immediate-Early Proteins; Kidney Failure, Chronic; Male; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Obesity; Podocytes; Protein Serine-Threonine Kinases; Protein Synthesis Inhibitors; Proteinuria; Rats; Rats, Inbred SHR; Receptors, Mineralocorticoid; RNA, Messenger; Spin Labels; Spironolactone