Eplerenone Administration Research Articles

Eplerenone improves hyperglycemia and sympathetic excitation in chronic renocardiac syndrome in rats.

We aimed to assess the efficacy of eplerenone, a steroidal mineralocorticoid receptor antagonist known to reduce blood pressure and mitigate cardiovascular disease (CVD) progression, in retarding the progression of chronic kidney disease (CKD) and CVD in a rat model of type 4 cardiorenal syndrome (CRS). We grouped rats into four experimental categories: sham surgery, sham treatment with eplerenone, nephrectomy without eplerenone (Nx), and nephrectomy with eplerenone (Nx + EP). For the Nx + EP group, rats received five-sixths nephrectomy, inducing CKD and CVD conditions such as renal hypertension and hyperglycemia, and were then treated with eplerenone (100mg/kg/day, orally) over 4weeks after an initial 4-week observation period. Heart rate, blood pressure, blood sugar levels, and sympathetic nerve excitation were monitored biweekly. In addition, assessments of renal and cardiac tissues, including evaluation of renal tubulointerstitial injury, glomerular injury, and cardiomyocyte hypertrophy, were conducted at week 8. Eplerenone administration mitigated CKD and CVD progression in the Nx + EP group, evident by improved blood pressure (217.3 ± 5.4 versus 175.3 ± 5.6), blood sugar (121.8 ± 1.3 versus 145.6 ± 6.0) level, reduced sympathetic nerve excitation, and cardiomyocyte hypertrophy compared to the Nx group. However, renal tubulointerstitial injury, glomerular injury, and cardiovascular dysfunction, which were increased in rats with type 4 CRS, did not show significant changes with eplerenone treatment. Our study demonstrated that eplerenone treatment did not exacerbate type 4 CRS but improved blood pressure, blood sugar levels, sympathetic nerve excitation, and cardiomyocyte hypertrophy in this model.

Long-term effect of eplerenone treatment in children with chronic allograft nephropathy.

Literature supports the protective role of mineralocorticoid antagonist (MRA) against the renal injury induced by aldosterone in kidney transplant recipients. However, there is limited data available regarding the safety and efficacy of MRAs in pediatric renal transplant patients. Therefore, we aimed to investigate the effect of long-term eplerenone administration in children with chronic allograft nephropathy (CAN). Twenty-six renal transplant children with biopsy-proven CAN, an estimated glomerular filtration rate (eGFR ) > 40 mL/min per 1.73 m2 and with a significant proteinuria were included. Selected patients were randomly divided into two groups as follows; Group 1 (n = 10) patients received 25 mg/day eplerenone and Group 2 (n = 16) patients did not receive eplerenone for 36 months. Patients were examined in the renal transplant outpatient clinic biweekly for the first month and once a month thereafter. The primary outcome of the patients was compared. Mean eGFR stayed stable in group 1 patients, but significantly decreased in group 2 at 36 months (57.53 ± 7.53 vs. 44.94 ± 8.04 mL/min per 1.73 m2 , p = .001). Similarly, spot protein-creatinine ratio was significantly lower in group 1 compared to group 2 patients at 36 months (1.02 ± 7.53 vs. 3.61 ± 0.53, p < .001). Eplerenone associated hyperkalemia was not observed in group 1 patients (4.6 ± 0.2 vs. 4.56 ± 0.3, p = .713). The long-term eplerenone administration blunted the chronic allograft nephropathy by maintaining a stable eGFR levels and decreasing urine protein-creatinine ratio. Eplerenone associated hyperkalemia was not observed in our study.

Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-β1 pathway in mice induced with aldosterone.

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.

Gitelman syndrome, a rare cause of refractory hypokalemia. A case repor

Introduction: Gitelman syndrome is a rare hereditary primary renal tubular disorder, with a prevalence of approximately 1 to 10 cases per 40 000 people. It does not have specific symptoms, so its diagnosis depends on high clinical suspicion by the treating physical and a sequential approach to hypokalemia, especially in young patients. Thus, a diagnostic algorithm is proposed at the end of this report. Case presentation: A 23-year-old woman with a history of hospitalization due to hypokalemia presented to the emergency service with intermittent cramping in her lower limbs, which was exacerbated by gastrointestinal symptoms. Laboratory tests reported the following findings: metabolic alkalosis, elevated levels of potassium, magnesium, chloride and sodium in urine, and reduced levels of calcium in urine. Thus, potassium supplementation and eplerenone administration were started, obtaining the complete resolution of symptoms. At her last follow-up appointment, the patient was asymptomatic, and her serum electrolyte levels were normal. In addition, during her hospital stay and due to the high suspicion of Gitelman syndrome, a genetic study was performed, which reported a mutation of the SCL12A3 gene, confirming the diagnosis. Conclusion: The sequential approach to a patient with recurrent hypokalemia is very important to reach an accurate diagnosis among a wide range of differential diagnoses.

Effects of Eplerenone on Blood Pressure and Echocardiographic and Serum Biochemical Variables in Five Healthy Dogs: A Pilot Study.

Eplerenone (EP), an aldosterone antagonist, is reported to produce renal and cardiac protective effects in noncanine species. However, there are no detailed reports available on cardiovascular effects of EP in dogs. This study aimed to determine effect of EP on echocardiographic parameters, blood pressures, and biochemical variables in healthy dogs. Five healthy Beagle dogs were randomly divided and repeatedly used in each of 3 dose groups, receiving 2.5, 5, or 10 mg/kg BW EP orally q24 h for 4 wks. Serum biochemical test, blood pressure, and Doppler echocardiography measurements were performed before EP administration and at 1, 2, and 4 weeks after EP administration. Treatment with EP reduced mean blood pressure in a dose-dependent manner and significantly (but in a dose-independent manner) decreased left atrium/aorta ratio, early diastolic transmitral flow, early diastolic transmitral flow/late diastolic transmitral flow, peak velocity of early diastolic transmitral flow/peak velocity of early diastolic mitral annular motion, left ventricle and right ventricle Tei indices, stroke volume, cardiac output, and mid systole myocardial velocity gradient 1 to 4 weeks after administration. Deceleration time of early diastolic transmitral flow significantly increased after EP administration. No significant changes were observed in serum biochemical variables. The results indicated that EP might reduce preload, thereby decreasing left atrial size. In addition, reduction of left ventricular stiffness may have theoretically taken place but this could not be tested using the present study design. It is suggested that EP administration within the dose range used in this study is safe for administration to healthy dogs. Further studies are needed to explore both safety and efficacy, as well as to seek a recommended dose range of EP treatment in client-owned dogs with heart disease.

High-salt diet promotes crystal deposition through hypertension in Dahl salt-sensitive rat model.

To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone—Pilot Study

Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.

Eplerenone attenuates pathological pulmonary vascular rather than right ventricular remodeling in pulmonary arterial hypertension

BackgroundAldosterone is a mineralocorticoid hormone critically involved in arterial blood pressure regulation. Although pharmacological aldosterone antagonism reduces mortality and morbidity among patients with severe left-sided heart failure, the contribution of aldosterone to the pathobiology of pulmonary arterial hypertension (PAH) and right ventricular (RV) heart failure is not fully understood.MethodsThe effects of Eplerenone (0.1% Inspra® mixed in chow) on pulmonary vascular and RV remodeling were evaluated in mice with pulmonary hypertension (PH) caused by Sugen5416 injection with concomitant chronic hypoxia (SuHx) and in a second animal model with established RV dysfunction independent from lung remodeling through surgical pulmonary artery banding.ResultsPreventive Eplerenone administration attenuated the development of PH and pathological remodeling of pulmonary arterioles. Therapeutic aldosterone antagonism – starting when RV dysfunction was established - normalized mineralocorticoid receptor gene expression in the right ventricle without direct effects on either RV structure (Cardiomyocyte hypertrophy, Fibrosis) or function (assessed by non-invasive echocardiography along with intra-cardiac pressure volume measurements), but significantly lowered systemic blood pressure.ConclusionsOur data indicate that aldosterone antagonism with Eplerenone attenuates pulmonary vascular rather than RV remodeling in PAH.

Randomized Controlled Trial of Mineralocorticoid Receptor Blockade in Children with Chronic Kidney Allograft Nephropathy.

We showed that mineralocorticoid receptor blockade (MRB) prevented acute and chronic cyclosporine nephropathy (CsA-Nx) in the rat. The aim of this translational study was to investigate the effect of long-term eplerenone administration on renal allograft function in children with biopsy-proven chronic allograft nephropathy (CAN). Renal transplant children <18 years, biopsy-proven CAN, and a GFR>40 ml/min per 1.73 m2 were included. Patients with BK virus active nephritis, recurrence of renal disease, GFR decline in previous 3 months, or treated with calcium antagonists or antifungal drugs were excluded. They were randomized to receive placebo (n=10) or eplerenone 25 mg/d for 24 months (n=13). Visits were scheduled at baseline, 6, 12, and 24 months. At each period, a complete clinical examination was performed and blood and urine samples were taken. Urine creatinine, 8-hydroxylated-guanosine, heat shock protein 72 (HSP72), and kidney injury molecule (KIM-1) levels were also assessed. In kidney biopsy samples, the tubulo-interstitial area affected by fibrosis (TIF) and glomerulosclerosis were measured at baseline and after 24 months. The baseline eGFR was 80±6 in the placebo and 86±6 ml/min per 1.73 m2 in the eplerenone group; at 24 months it was 66±8 and 81±7 ml/min per 1.73 m2, respectively (P=0.33; 95% confidence intervals, -18 to 33 at baseline, and -11 to 40 after 24 months). The albumin-to-creatinine ratio was 110±74 in the placebo, and 265±140 mg/g in the eplerenone group; and after 24 months it was 276±140 and 228±88 mg/g, respectively (P=0.15; 95% confidence intervals, -283 to 593, and -485 to 391, respectively). In addition, the placebo exhibited a greater TIF, glomerulosclerosis, and urinary HSP72 compared with the eplerenone group. Although this study was underpowered to provide definitive evidence that long-term eplerenone administration attenuates the progression of CAN in pediatric transplant patients, it encourages testing the potential benefit of MRB in this pediatric population.

Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.

Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. C57bl6 mice were fed a choline-deficient and amino acid-defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity.

The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression. Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (Ccr), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined. On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced Ccr, induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function. Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.

Effect of eplerenone in percutaneous coronary intervention‐treated post‐myocardial infarction patients with left ventricular systolic dysfunction: a subanalysis of theEPHESUStrial

EPHESUS was a multicentre, double-blind clinical trial in which 6632 patients with acute myocardial infarction (AMI) complicated by LV systolic dysfunction (LVSD) were randomized to receive eplerenone (n = 3319) or placebo (n = 3313). A total of 1580 EPHESUS patients were treated with PCI, which is now the standard treatment for AMI. This EPHESUS substudy examined the effects of eplerenone upon cardiovascular outcomes in PCI-treated patients. EPHESUS patients were divided into PCI-treated and non-PCI-treated cohorts, and the effect of eplerenone upon mortality and other major adverse cardiovascular outcomes was assessed in each cohort. The PCI-treated patients (n = 1580) were younger, and had better renal function and fewer co-morbidities than non-PCI-treated patients (n = 5052). Cardiovascular mortality was significantly lower in PCI-treated patients as compared with non-PCI-treated patients (7% vs. 16%, P < 0.0001). However, the incidence of non-fatal events was similar in PCI-treated and non-PCI-treated cohorts. There was no statistical difference between the PCI-treated and non-PCI-treated cohorts in the primary or secondary outcomes of the trial. Eplerenone administration, compared with placebo, in the PCI-treated cohort did not affect PCI-related clinical outcomes, including recurrence of angina, the occurrence of acute coronary syndromes, or the need for further revascularization. The beneficial effects of eplerenone in the EPHESUS trial exist for both PCI- and non-PCI-treated AMI patients with LVSD. Eplerenone has minimal, if any, effect upon reducing PCI-related adverse events in the PCI-treated cohort.

Positive effect of eplerenone treatment on endothelial progenitor cells in patients with chronic heart failure

Endothelial progenitor cells (EPCs) are known to play a significant role in reendothelialization and vascular repair. Recently, a mineralocorticoid receptor was demonstrated to be expressed by EPCs. The study aimed to evaluate a potential influence of eplerenone treatment on the total number of EPCs in patients with chronic heart failure. Eighty-seven male patients with chronic heart failure were included (age: 23-83 years; body mass index 29.1 ± 5.1 kg/m²; New York Heart failure classification (NYHA) I: 29 patients, NYHA II: 32 patients, NYHA III: 26 patients). Numbers of circulating EPCs were quantified immediately using flow cytometry. Twenty-eight patients received therapy with eplerenone. Patients were further characterized by echocardiography, spirometry and laboratory markers. Patients with ongoing eplerenone administration showed higher levels of circulating cells expressing CD34+ (p<0.05) and CD34+KDR+ (p<0.05) and CD34+CD133+KDR+ cells (p<0.05). The effects of eplerenone treatment could be shown to be independent of NYHA status, genesis of the underlying cardiovascular morbidity, left ventricular function and co-medication. Patients with chronic heart failure treated with eplerenone show higher numbers of EPCs. The clinical benefit for treatment with eplerenone has been demonstrated even for patients with mild heart failure and might be partially mediated by EPCs.

Hepatoprotective effect of the selective mineralocorticoid receptor antagonist, eplerenone against carbon tetrachloride-induced liver injury in rats

Background. Eplerenone is a selective mineralocorticoid receptor (MR) antagonist, and its potential protective role in cardiovascular injury has been reported by several studies. However, whether and how this drug can ameliorate hepatic injury in rats is unknown.Material and methods. The present study was conducted to investigate effect of eplerenone against liver injury induced by carbon tetrachloride (CCl4) in rats. The biochemical liver function tests and oxidative stress parameters including malondialdehyde (MDA), reactive oxygen species (ROS), in addition to the reduced glutathione (GSH) levels were evaluated. Moreover, serum tumor necrotic factors (TNF-α) level and histopathological changes were examined.Results. Our results show that pre-treatment with eplerenone (4 mg/kg per day for 4 weeks) revealed attenuation in serum activities of alanine aminotransferase (ALT), aspartate aminotransferase, (AST), alkaline phosphatase (ALP) and bilirubin levels that were enhanced by CCl4. Further, pre-treatment with eplerenone inhibited the elevated hepatic MDA content and restored hepatic GSH to its normal level. The enhanced hepatic ROS production in CCl4-treated group was markedly decreased by eplerenone administration. Eple-renone pre-treatment significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased serum TNF-α level. Histopathological studies showed that eplerenone alleviated the liver damage and reduced the lesions caused by CCl4.Conclusion. Collectively, the present study provides a proof to hepatoprotective actions of eplerenone via reducing oxidative stress and inflammatory responses in CCl4-induced liver damage in rat model.

Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial†

To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes. The 6632 patients of the EPHESUS study were randomized from day 3 to 14 after the index AMI (median = 7 days), of these 3319 were assigned to eplerenone. We analysed the differential effects of time-to-eplerenone initiation vs. placebo, based on the median time to initiation of treatment (<7 days-'earlier', > or =7days-'later'). Effects on outcomes were evaluated over a mean 16-month follow-up, using Cox proportional hazards regression analysis. The earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (P = 0.001) when compared with the 'earlier' placebo' and also reduced the risks of cardiovascular (CV) hospitalization/CV mortality by 24% (P < 0.0001) and sudden cardiac death (SCD) by 34% (P < 0.0001). In contrast, later eplerenone initiation (> or =7 days) had no significant effect on outcomes. Interactions between time-to-randomization and treatment were significant. These associations remained substantially unchanged after risk adjustment in multivariable models. An earlier eplerenone administration (3-7days) post-AMI improved outcomes in patients with LVSD and HF. This benefit was not observed when eplerenone was initiated later (> or =7days).

Aldosterone and Metabolic Syndrome

The classic role of aldosterone is to regulate water and electrolyte balance and, therefore, blood pressure homeostasis.1 Apart from that, experimental studies have demonstrated that aldosterone induces structural and functional alterations in the heart, kidneys, and vessels with effects such as myocardial fibrosis, nephrosclerosis, vascular inflammation and remodeling, and disturbed fibrinolysis.2,3 This damage seems to be aldosterone mediated, and aldosterone blockade with mineralocorticoid receptor (MR) antagonists, such as spironolactone, may prevent the onset of these effects.4,5 On the other hand, it cannot completely be ruled out that potassium and high blood pressure also play additional key roles in this damage.6,7 This evidence has impressively been supported by clinical studies, such as the Randomized Aldactone Evaluation Study and the Eplerenone Post-Acute Myocardial Infarction Survival and Efficacy Study.8,9 For example, increased mortality in patients with chronic heart failure has been associated with elevated aldosterone plasma levels,10 and high circulating plasma aldosterone levels predict the clinical outcome in patients after myocardial infarction.11 Furthermore, primary aldosteronism (PA) has been demonstrated to enhance the risk of cardiovascular events12 and kidney disease.13 In summary, aldosterone is considered a cardiovascular risk factor, promoting disease processes such as cardiac fibrosis, nephrosclerosis, and arteriosclerosis,2,3,14 all of which are increased in patients with obesity and the metabolic syndrome.15,16 The term “metabolic syndrome” (MSyn) has evolved various definitions in recent times; most of the studies introduced here use slight modifications. Nevertheless, all of the definitions used have a common denominator, which is reflected in a definition by the American Heart Association/National Heart, Lung, and Blood Institute.17 According to this definition, the MSyn is considered as a constellation of interrelated risk factors of metabolic origin, including arterial hypertension, dyslipidemias, alterations in glucose homeostasis with type 2 diabetes mellitus, and abdominal …

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor kappaB (NF-kappaB) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-kappaB, protein kinase CbetaII, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca(2+)-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.

Eplerenone Antagonizes Atherosclerosis, But What Is the Agonist?

A recent analysis of the Framingham Heart Study implicated elevated serum aldosterone as an independent risk factor for the development of cardiovascular disease.1 Although adrenal-derived aldosterone may prove to be important in this regard, less evident is the source of aldosterone and the mechanism for mineralocorticoid receptor (MR) activation in studies such as the Randomized ALdactone Evaluation Study (RALES)2 and the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study (EPHESUS),3 where MR blockade exerts obvious cardiovascular benefit but adrenal aldosterone levels are normal. In this issue of Hypertension , the article by Takai et al4 documents such a study and thereby adds to the discussion not only of the applicability of MR blockade in cardiovascular disease but also of the mechanisms for MR activation. The authors report that monkeys with diet-induced hypercholesterolemia treated with the selective MR antagonist eplerenone had reduced extent of atherosclerotic lesions in aorta and carotid arteries compared with placebo-treated monkeys. The results extend the beneficial influence of MR blockade to a model with similarities highly relevant to the atherogenic process in humans. Rajagopalan et al5 were the first to demonstrate that local vascular expression of MR might play a role in atherosclerosis. In this study, dietary hypercholesterolemia in rabbits was associated with increased aorta superoxide generation. Eplerenone administration to hypercholesterolemic rabbits normalized superoxide generation, decreased NADH and NADPH oxidase activity to basal levels, and nearly normalized endothelium-dependent vasorelaxation. A study by Keidar et al6 showed similar inhibition of atherosclerosis when eplerenone was administered to apolipoprotein E (apoE)-deficient mice. …

Eplerenone Shows Renoprotective Effect by Reducing LOX-1–Mediated Adhesion Molecule, PKCε-MAPK-p90RSK, and Rho-Kinase Pathway

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.

Eplerenone stimulates eNOS through VEGF and inhibiting iNOS via NF-kappaB induced by the oxidative stress-LOX-1 pathway

Stimulating endothelial cells with vascular endothelial growth factor (VEGF) activates endothelial nitric oxide synthase (eNOS) and regulation of inducible NOS (iNOS) expression is mediated via nuclear factor-kappaB (NF-kappaB). We investigated the impact of eplerenone, a novel selective aldosterone blocker, on cardiac dysfunction and cardiovascular remodeling in Dahl salt-sensitive (DS) rats with heart failure. Specifically, we hypothesized that eplerenone stimulates eNOS through VEGF and inhibits iNOS via NF-kappaB following the development of oxidative stress and activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway. Eplerenone (10, 30, and 100 mg/kg/day) or vehicle was given from left ventricular hypertrophy stage (11 weeks) to failing stage (18 weeks) for 7 weeks. Decreased fractional shortening in failing rats was significantly ameliorated by eplerenone treatment. Downregulated eNOS and VEGF expression in the DS rats was increased by eplerenone. Upregulated expression of iNOS, LOX-1, NAD(P)H oxidase p22 phox, p47 phox, gp91 phox and activated p65 NF-kappaB phosphorylation in DS rats was inhibited by eplerenone. Eplerenone administration resulted in significantly improvement of cardiac function and remodeling and suppression of atrial natriuretic peptide expression. These results suggest that the cardioprotective effects of eplerenone may be mediated in part by reducing oxidative stress by stimulating eNOS through VEGF and inhibiting iNOS via NF-kappaB following activation of the LOX-1 pathway.