Eplerenone Treatment Research Articles

Central serous chorioretinopathy induced by drugs metabolized by cytochrome P450 3A4.

The purpose of this study was investigate whether replacing or discontinuing drugs that are inhibitors or substrates of cytochrome P450 3A4 (CYP3A4) may improve the clinical course of central serous chorioretinopathy (CSC). A retrospective observational study included 43 patients with active CSC. Twenty seven patients (32 eyes, group 1) were using drugs that act as substrates or inhibitors of CYP3A4. In 25 of these 27 patients, treatments including steroids, calcium channel blockers, anticoagulants, statins, beta-adrenolytics, angiotensin receptor antagonists, antidepressants, muscarinic receptor antagonists, phosphodiesterase type 5 inhibitors, and others were discontinued or replaced with medications not affecting CYP3A4. Sixteen patients (19 eyes, group 2) not using any medication that affects CYP3A4, were given eplerenone, rifampicin, or laser treatment. Main outcomes measures were assessed by functional and anatomical images obtained using multimodal imaging techniques. The average follow-up time was 12 months. In group I after discontinuing or replacing substrates or inhibitors of CYP3A4, improvements were observed in 18 patients (22 eyes). None of the patients that were using drugs affecting CYP3A4 improved with eplerenone therapy, however, all 18 patients improved after discontinuing the drugs. All these drugs had a blocking effect on eplerenone therapy. Best corrected visual acuity (BCVA) improved in 14 eyes, remained unchanged in 5 eyes, and worsened in 3 eyes. In 21 of the 22 eyes, subretinal fluid absorption was observed with optical coherence tomography (OCT). Mean central retinal thickness decreased from 361 μm to 219 μm. One patient (2 eyes) was unable to change treatment (due to neoplasm), one patient (1 eye) did not agree to change or stop treatment, and seven patients (7 eyes) were lost to follow-up. Of the 16 patients (19 eyes) who were treated with eplerenone, rifampicin, or laser, improvements were observed in 14 patients (16 eyes), two patients (2 eyes) were lost to follow-up, and CSC worsened in 1 eye. We concluded that patients with CSC should not take substrates or inhibitors of CYP3A4. These drugs should be replaced with alternatives that act through other metabolic pathways.

A combined CaMKII inhibition and mineralocorticoid receptor antagonism via eplerenone inhibits functional deterioration in chronic pressure overloaded mice.

In the diseased and remodelled heart, increased activity and expression of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide‐3‐related‐peptide (AC3I)) together with eplerenone treatment (AC3I‐Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I‐Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT‐Epler) and mice with only CaMKII inhibition (AC3I‐No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro‐fibrotic TGF‐β/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro‐fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis.

Reduced Diuretic Dose in Patients Treated With Eplerenone: Data From the EPHESUS Trial.

Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status. Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; P for interaction, 0.54). Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

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.

1411The effect of eplerenone on fibrosis in hypertrophic cardiomyopathy. A randomised controlled trial assessed using cardiopulmonary exercise testing and cardiovascular magnetic resonance

Abstract Background Recent studies have implicated aldosterone, a hormone of the renin-angiotensin-aldosterone system to cardiac hypertrophy, and cardiac and vascular fibrosis in cardiomyopathy. High levels of circulating aldosterone have been shown to cause myocardial and aortic fibrosis in animal models. In humans, high aldosterone concentrations have been associated with endothelial dysfunction, myocardial infarction, left ventricular hypertrophy and death. Aldosterone antagonism with spironolactone or eplerenone reverses the process of fibrosis in animal models. Purpose Left ventricular dysfunction due to hypertrophic cardiomyopathy (HCM) is a disorder associated with an increased risk of morbidity and premature mortality. An important pathological feature seen in cardiomyopathy is the development of fibrosis and its association with functional impairment and arrhythmia, including predisposition to sudden cardiac death. This trial observes the effect of eplerenone on myocardial fibrosis and exercise tolerance in patients with HCM. Methods 42 patients were recruited into a double-blinded, placebo-controlled randomised study. Each patient had an established diagnosis of HCM without exclusion criteria (figure 1). 2 patients withdrew before enrolment. Enrolled patients were established on maximally tolerated doses of standard drugs used in the treatment of HCM and the doses of these drugs remained unchanged in the 2 months preceding enrolment to the trial. Patients were randomised to receive a maximal dose of 50mg eplerenone (n=21) or placebo (n=19). The patients underwent cardiopulmonary exercise testing and cardiovascular magnetic resonance (CMR) scan at baseline and 52 week follow up. Results At 52 weeks follow up there was no difference between placebo and treatment groups in peak oxygen consumption (−1.05 vs 0.63, p=0.32), anaerobic threshold (0.4 vs 1.45, p=0.31) or ventilatory efficiency slope (−0.77 vs 1.76, p=0.065). In addition, there was no significant difference observed in LV mass or fibrosis as assessed by CMR. Inclusion and Exclusion Criteria Conclusion In the first randomised controlled trial using eplerenone in humans with HCM, we report no effect of treatment after 52 weeks on exercise capacity compared with placebo. In addition, we report no effect of treatment on the presence of fibrosis detected by CMR. Interpretation of these results are limited by small sample size and further studies will require a multi-centre recruitment process. The data presented here support the feasibility of eplerenone treatment in patients with HCM and provide statistical power calculation for future trials.

Involvement of Vanin-1 in Ameliorating Effect of Oxidative Renal Tubular Injury in Dahl-Salt Sensitive Rats.

In salt-sensitive hypertension, reactive oxygen species (ROS) play a major role in the progression of renal disease partly through the activation of the mineralocorticoid receptor (MR). We have previously demonstrated that urinary vanin-1 is an early biomarker of oxidative renal tubular injury. However, it remains unknown whether urinary vanin-1 might reflect the treatment effect. The objective of this study was to clarify the treatment effect for renal tubular damage in Dahl salt-sensitive (DS) rats. DS rats (six weeks old) were given one of the following for four weeks: high-salt diet (8% NaCl), high-salt diet plus a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water), high-salt diet plus eplerenone (100 mg/kg/day), and normal-salt diet (0.3% NaCl). After four-week treatment, blood pressure was measured and kidney tissues were evaluated. ROS were assessed by measurements of malondialdehyde and by immunostaining for 4-hydroxy-2-nonenal. A high-salt intake for four weeks caused ROS and histological renal tubular damages in DS rats, both of which were suppressed by tempol and eplerenone. Proteinuria and urinary N-acetyl-β-D-glucosaminidase exhibited a significant decrease in DS rats receiving a high-salt diet plus eplerenone, but not tempol. In contrast, urinary vanin-1 significantly decreased in DS rats receiving a high-salt diet plus eplerenone as well as tempol. Consistent with these findings, immunohistochemical analysis revealed that vanin-1 was localized in the renal proximal tubules but not the glomeruli in DS rats receiving a high-salt diet, with the strength attenuated by tempol or eplerenone treatment. In conclusion, these results suggest that urinary vanin-1 is a potentially sensitive biomarker for ameliorating renal tubular damage in salt-sensitive hypertension.

Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials.

After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone. Clinical factors and biomarkers were evaluated as predictors of a PIIINP decrease from randomization to month 9 in 323 patients from the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Additionally, the association between PIIINP decrease and the composite of cardiovascular (CV) death or CV hospitalization were also explored. External validation was performed in the REMINDER trial. Female sex, eplerenone, reperfusion therapy, potassium < 4mmol/L, circulating levels of PIIINP ≥ 3.6ng/mL and PINP ≥ 27ng/mL predicted a PIIINP decrease (AUC = 0.75). Randomization PIIINP showed a significant interaction with the treatment allocation: patients with PIIINP ≥ 3.6ng/mL had a better response (decrease in PIIINP) to eplerenone (OR for PIIINP ≥ 3.6 = 2.9, 95% CI 1.46-5.89, p = 0.003) and OR for PIIINP < 3.6 = 1.09, 95% CI 0.55-2.2, p = 0.8; interactionp = 0.026). These findings were internally robust using another statistical approach (LOESS). External validation showed good discrimination (AUC = 0.70). There was a tendency toward a lower rate of CV death/CV hospitalizations in patients with decreased PIIINP (adjusted HR = 0.52, 95% CI 0.26-1.02, p = 0.058). In patients who had a myocardial infarction, clinical factors used in combination and treatment with eplerenone were associated with a PIIINP decrease. Interestingly, higher randomization PIIINP levels might help in identifying patients more prone to have an "anti-fibrotic response" when treated with MRAs. Predictors of an antifibrotic response after MI complicated by HF. Several clinical factors and biomarkers predicted a PIIINP decrease after an MI complicated by HF. There was a significant interaction between baseline PIIINP levels and eplerenone treatment: patients with baseline PIIINP ≥ 3.6 mmol/L treated with eplerenone had the best response (PIIINP decrease).

Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets.

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic β-cells and improving glucose homeostasis.

Eplerenone for the treatment of chronic central serous chorioretinopathy: 3-year clinical experience

Background/aimsThe efficacy of mineralocorticoid receptor antagonist eplerenone to treat chronic central serous chorioretinopathy (CSCR) has been established. However, previous studies have been limited by small cohort size and short follow-up...

Eplerenone improves endothelial function and arterial stiffness and inhibits Rho-associated kinase activity in patients with idiopathic hyperaldosteronism: a pilot study.

Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA). Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA. After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 ± 0.25 to 0.69 ± 0.25 (P < 0.01) and NID from 12.8 ± 5.8 to 14.9 ± 6.9% (P = 0.02) and it decreased baPWV from 1540 ± 263 to 1505 ± 281 (P = 0.04) and ROCK activity from 1.20 ± 0.54 to 0.89 ± 0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 ± 3.4 to 4.6 ± 3.6%, P = 0.99) or brachial IMT (decrease from 0.28 ± 0.07 to 0.28 ± 0.04 mm, P = 0.14). Eplerenone improves microvascular endothelial function, vascular smooth muscle function, arterial stiffness and ROCK activity in patients with IHA. URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

OR04-3 Lysine-Specific Demethylase-1 (LSD1) Deficiency Increases Aldosterone Signaling via Mineralocorticoid Receptor Activation

Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation of gene transcription. We have shown that human risk allele carriers of a LSD1 variant as well as a LSD1 heterozygous knockout mice (LSD1+/-) have salt sensitive hypertension (HTN), but low aldosterone (ALDO) and plasma renin activity (PRA) levels. However, in young mice ALDO levels are inappropriately increased for the level of salt intake. Thus, we hypothesize that despite the low ALDO levels, the salt sensitive HTN is mineralocorticoid mediated secondary to an overactive mineralocorticoid receptor(MR). To test our hypothesis, wild-type (LSD1+/+) and LSD1+/- mice were fed a liberal sodium (1.6% Na+) diet for 7 days and were then randomized to placebo or eplerenone (Epl) treatment for 2 weeks. Systolic blood pressures (SBP) were measured before and after the intervention; albumin/creatinine ratios (A/C), plasma ALDO, as well as urine ALDO, sodium and potassium were measured at the end of the study. Results: Compared with LSD1+/+, LSD1+/- mice displayed higher SBP at the beginning of the study (132 ± 2.6 mmHg vs 113.8 ± 2.0 mmHg; P<0.001). As compared to placebo, treatment with eplerenone significantly reduced SBP in LSD1+/- but not LSD1+/+ mice (LSD1+/-+ epl: 120.8 ± 1.6 mmHg vs LSD1+/- + placebo 134.1± 4.3 , P = 0.02). LSD1+/- mice also displayed significantly higher A/C ratios than the LSD1+/+ (68.0 ± 23.6 µg/mg vs 22.1 ± 1.6 µg/mg, P = 0.04), and treatment with eplerenone reduced A/C in LSD1+/- mice to levels indistinguishable from those in the LSD1+/+ (LSD1+/- + epl. 27.3 ± 2.9 µg/mg vs LSD1+/+ + epl 26.0 ± 1.7 µg/mg). Urine ALDO/creatinine ratios were significantly lower in LSD1+/- vs. LSD1+/+ (26.1 ± 4.0 pg/mg vs 39.4 ± 4.1 pg/mg ,P = 0.03). Plasma ALDO showed a similar trend for lower levels in LSD1+/- vs. LSD1+/+ (21.8 ± 5.1 ng/dl vs 33.5 ± 6.1 ng/dl). In contrast, LSD1+/- had significantly higher 24-hr urine potassium than the LSD1+/+ mice (0.29 ± 0.1 mmol vs 0.15 ± 0.02 mmol, P= 0.05), yet similar ALDO responses to eplerenone, suggesting increased MR activity. Conclusion: Our data support our hypothesis that inappropriately activated MR signaling mediates the cardio-renal defects in the LSD1 deficient mouse. These findings support the concept that treatment with an MR antagonist may result in improved cardio- and reno-vascular outcomes in human LSD1+/- risk allele carriers.

Anatomical and Functional Changes of the Retina and the Choroid after Resolved Chronic CSCR.

Background: To investigate anatomical/functional changes after oral eplerenone therapy for chronic central serous chorioretinopathy (CCSC) in successfully treated eyes and fellow eyes and assess timing of foveal subretinal fluid (SRF) resolution. Methods: Twenty-one eyes of 21 patients suffering from CCSC with monolateral foveal SRF successfully treated with oral eplerenone were enrolled in this retrospective study (group 1). The fellow eyes (21 eyes; group 2), healthy or affected by CCSC, without foveal SRF were considered in the analysis. A control healthy group was enrolled as well (healthy controls; n = 21). Main outcome measures during follow-up included changes of best corrected visual acuity (BCVA, logMAR), central macular thickness (CMT; µm), SRF (µm), subfoveal choroidal thickness (SFCT; µm), superficial capillary plexus density (SCPD, %), deep capillary plexus density (DCPD, %), and choriocapillaris density (CCD, %) and percentage of eyes showing foveal SRF resolution at different time points. Results: Functional and anatomical parameters significantly improved during the study in group 1. BCVA increased significantly (p < 0.001), while CMT, SFCT, and SRF decreased significantly (p < 0.001; p < 0.001, and p = 0.037, respectively). SCPD, DCPD, and CCD did not show any statistically significant difference during follow-up. In 71.4% of eyes, resolution of SRF was observed within 60 days and in the remaining 28.6%, at 120 days. In fellow eyes, SFCT decreased significantly (p < 0.001), whilst all other parameters did not modify. Conclusions: Eplerenone treatment in chronic CSCR potentially improves recovery of retinal and choroidal morphology as well as visual acuity gain. A complete resolution of foveal SRF was observed in all eyes during a 4-month follow-up, with most eyes healing at 2 months.

Activation of the Mineralocorticoid Receptor Leads to Increases in Protein Disulfide Isomerase Activity

Activation of the mineralocorticoid receptor (MR), a critical component of the Renin‐Angiotensin‐Aldosterone (ALDO) System (RAAS), plays an important role in inflammatory and vascular endothelial responses in addition to its well‐described effects on sodium and water homeostasis. Activation of endothelial cells and leukocytes leads to, among other factors, increased protein disulfide isomerase (PDI) release. PDI is a multifunctional oxidoreductase that catalyzes thiol/disulfide interchange reactions within the endoplasmic reticulum, is also present in circulation and at the cell surface of platelets, lymphocytes, erythrocytes and endothelial cells and plays a critical role in initiating thrombus formation. However, the interaction of ALDO, MR activation and PDI remain unclear. We hypothesized that MR activation would lead to increased PDI levels thus contributing to inflammation and oxidative stress. We first studied EA.hy926 (EA) cells, a human endothelial cell line that expresses MR. We incubated EA cells with ALDO (10 −8 M), an MR agonist, for 24 hr and observed a rise in PDI mRNA levels by qRT‐PCR (p&lt;0.01, n=5), an event that was blocked by pre‐incubation of EA cells with 1 μM canrenoic acid (CA), an MR antagonist (p&lt;0.05, n=5). Consistent with these results, measurements of PDI levels by ELISA confirmed a rise in PDI that was likewise blocked by CA (p&lt;0.01, n=4). Also, we measured PDI activity in the supernatant of ALDO‐stimulated EA cells using a Di‐E‐GSSH fluorescent marker and observed a rise in PDI activity following ALDO (10^−8 M) incubation when compared to vehicle treatment (p&lt;0.05, n=5). We then studied the effects of ALDO on HL‐60 cells, a human promyelocytic cell line that was induced to differentiate into neutrophil‐like leukocytes by incubation for 5 days with 1.3% DMSO. In these cells, we detected the presence of MR by western blot analyses and observed that ALDO (10^−8 M) stimulated a rise in PDI activity that was blocked by CA (p&lt;0.05, n=6). To test the in vivo effects of MR activation on PDI activity, we characterized a well‐described rodent model of RAAS‐mediated increased BP, inflammation and target organ damage using exogenous angiotensin II (AngII) infusion in Sprague–Dawley rats. Rats were randomized to three conditions: (1) control; (2) AngII infused (80 ng/min × 28 days); (3) AngII + eplerenone (100 mg eplerenone/kg/day × 21 days), an MR antagonist. Consistent with our in vitro data, AngII infusion led to significant increases in plasma PDI activity that was significantly reduced by approximately 65% following eplerenone treatment (p&lt;0.05, n=5/group). Thus, MR activation represents a novel mechanism for PDI regulation that may contribute to the deleterious effects of disordered RAAS activity in cardiovascular disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension.

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16-18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg-1·min-1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg-1·day-1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5-14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10-9-10-5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10-5 mol/l) and indomethacin (10-4 mol/l). We used GSK2193874 (10-7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10-9-10-5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na+ delivery.

Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels via both fast (24h) and slow (5-7days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo. The slow effect does not require increased processing or surface expression, is refractory to acute eplerenone treatment, and is preserved ex vivo. Both slow and fast effects contribute to Na retention in vivo. Increased Na+ reabsorption in the proximal tubule also promotes Na conservation under conditions of chronic dietary Na restriction, reducing Na+ delivery to the distal nephron. Changes in the activity of the epithelial Na channel (ENaC) help to conserve extracellular fluid volume. In rats fed a low-salt diet, proteolytic processing of ENaC increased within 1day, and was almost maximal after 3days. The rapid increase in the abundance of cleaved αENaC and γENaC correlated with decreased urinary Na+ excretion and with increased ENaC surface expression. By contrast, ENaC activity, measured ex vivo in isolated cortical collecting ducts, increased modestly after 3days and required 5days to reach maximal levels. The mineralocorticoid receptor antagonist eplerenone reversed the increase in cleaved γENaC and induced natriuresis after 1 or 3days but failed to alter either ENaC currents or Na+ excretion after 7days of Na restriction. We conclude that Na depletion, through aldosterone, stimulates ENaC via independent fast and slow mechanisms. In vivo, amiloride-induced natriuresis increased after 1day of Na depletion. By contrast, hydrochlorothiazide (HCTZ)-induced natriuresis decreased gradually over 7days, consistent with increased ability of ENaC activity to compensate for decreased Na+ reabsorption in the distal convoluted tubule. Administration of amiloride and HCTZ together increased Na+ excretion less in Na-depleted compared to control animals, indicating decreased delivery of Na+ to the distal nephron when dietary Na is restricted. Measurements of creatinine and Li+ clearances indicated that increased Na reabsorption by the proximal tubules is responsible for the decreased delivery. Thus, Na conservation during chronic dietary salt restriction entails enhanced transport by both proximal and distal nephron segments.

The selective mineralocorticoid receptor antagonist eplerenone prevents decompensation of the liver in cirrhosis.

The mineralocorticoid receptor (MR) contributes to fibrosis in various tissues, and MR antagonists, like eplerenone, are used to prevent fibrosis. The role of MR antagonists in hepatic fibrosis and cirrhosis is unknown. Here, we investigated the role of MRs and eplerenone in cirrhosis development. Liver fibrosis (5weeks) and cirrhosis, without (8weeks) and with ascites (12weeks), were induced by CCl4 in rats and comprehensively analysed. The effect of eplerenone on the development of cirrhosis with ascites was assessed. MR expression, cellular and subcellular distribution and impact of hypoxia were investigated in vivo and ex vivo. Primary rat hepatocytes and cell lines were used to investigate MR trafficking and transcriptional activity mechanistically. In cirrhosis with ascites, MR mRNA and protein expressions were reduced in hepatocytes of hypoxic areas. While in normoxic areas MRs were mainly cytosolic, the remaining MRs in hypoxic areas were mainly localized in the nuclei, indicating activation followed by translocation and degradation. Accordingly, eplerenone treatment prevented nuclear MR translocation and the worsening of cirrhosis. Exposing hepatocytes ex vivo to hypoxia induced nuclear MR translocation and enhanced transcriptional MR activity at response elements of the NF-κB pathway. We showed for the first time that hypoxia leads to a pathogenetic ligand-independent activation of hepatic MRs during cirrhosis resulting in their nuclear translocation and transcriptional activation of the NF-κB pathway. Treatment with eplerenone prevented the worsening of cirrhosis by blocking this ligand-independent activation of the MR.

A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROL PILOT STUDY OF EPLERENONE FOR THE TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY (ECSELSIOR).

To evaluate the safety and effects of oral eplerenone in chronic central serous chorioretinopathy. Prospective, randomized, double-blind, placebo-control study at a tertiary referral academic private practice. For a diagnosis of chronic central serous chorioretinopathy, patients must have had at least 3 months clinical follow-up demonstrating persistent symptoms, subfoveal fluid on spectral-domain optical coherence tomography, and <50% reduction in fluid thickness. Patients were randomized 2:1 (treatment:placebo) to receive eplerenone (25 mg daily for 1 week, then up to 50 mg daily for 8 weeks) or placebo once daily. Fifteen patients completed the study. Ten patients (15 eyes) were randomized into the eplerenone treatment arm, while the remaining 5 patients (6 eyes) received placebo. After 9 weeks of eplerenone therapy, mean logarithm of the minimal angle of resolution visual acuity improved from 0.394 (Snellen equivalent: 20/50) to 0.330 (20/43, P = 0.04). In the placebo group, the mean logarithm of the minimal angle of resolution visual acuity slightly decreased from 0.313 (20/41) to 0.342 (20/44) during the same period (P = 0.21). With respect to anatomic changes, mean maximal subretinal fluid height in the eplerenone group improved from 139.3 μm at baseline to 51.8 μm (P = 0.02), mean subfoveal fluid height improved from 121.4 μm to 29.4 μm (P = 0.01), and mean central subfield thickness improved from 366.2 μm to 283.7 μm (P = 0.02). In comparison with the placebo group, mean maximal subretinal fluid height worsened from 135.9 μm to 172.3 μm (P = 0.32), mean subfoveal fluid height worsened from 92.1 μm to 134.0 μm (P = 0.54), and mean central subfield thickness worsened from 345.0 μm to 380.0 μm (P = 0.37). No patients in either group experienced serious adverse events to result in treatment discontinuation. These findings suggest that oral eplerenone therapy is safe and potentially effective in the treatment of chronic central serous chorioretinopathy with persistent subretinal fluid.

Effect of Eplerenone on the Glomerular Filtration Rate (GFR) in Primary Aldosteronism: Sequential Changes in the GFR During Preoperative Eplerenone Treatment to Subsequent Adrenalectomy.

Objective Eplerenone (EPL) is a mineralo-corticoid receptor antagonist that is highly selective and has few side effects. This study was conducted to examine whether or not EPL treatment was able to reverse glomerular hyperfiltration, as an indicator of aldosterone renal action, in primary aldosteronism (PA) patients. Methods Changes in the estimated glomerular filtration rate (ΔGFR) were examined in 102 PA patients with EPL treatment. Furthermore, the sequential ΔGFR in 40 patients initially treated with EPL followed by adrenalectomy was examined in order to evaluate the extent of the remaining glomerular hyperfiltration in the patients treated with EPL. Results EPL decreased the GFR at 1 month after treatment. The GFR at baseline was the sole significant predictor for the ΔGFR. Patients initially treated by EPL followed by adrenalectomy showed three different ΔGFR patterns during the treatment, despite having comparable doses of EPL and comparable control of blood pressure and serum potassium levels. The urinary aldosterone excretion was significantly different among these three groups, and the group with no decrease in the GFR after EPL treatment showed greater urinary aldosterone excretion. Glomerular hyperfiltration was completely restored only in 17.5% of our unilateral PA patients after EPL treatment. Conclusion The present study revealed that blockade of aldosterone action by EPL could, at least partially, reverse glomerular hyperfiltration in PA. Whether or not these differential effects on the GFR affect the long-term outcome needs to be investigated, especially in patients with unilateral PA who do not want adrenalectomy and choose the EPL treatment option.

Is there a blood pressure lowering effect of MRAs in heart failure? An overview and meta-analysis.

Although mineralocorticoid antagonists (MRAs) have been proposed as effective fourth-line blood pressure (BP) lowering agents in resistant hypertension, this effect in heart failure is undetermined. In this synthesis of heart failure randomized controlled trials (RCTs), we evaluated the extent of BP lowering following MRA treatment against placebo. We searched Medline and the Cochrane Collaboration Library databases from 1991 to September 2016 for RCTs, in which MRAs were compared with placebo. The quality of RCTs was assessed with Cochrane risk of bias tool. Outcomes were the extent of systolic and diastolic BP lowering. We included seven studies (13,354 patients, 65.8% males, mean age of 66.3years, mean follow-up period of 9.4months, mean baseline BP of 123.5/75.0mmHg) of MRAs compared with placebo. MRAs were not significantly associated with systolic - 1.8 (95% CI: - 8.0, 4.4) mmHg or diastolic - 0.3 (95% CI: - 3.4, 2.7) mmHg, BP reduction. Although systolic BP was not lowered by spironolactone, diastolic BP was lowered by - 3.0 (95% CI: - 3.4, - 2.6) mmHg. Eplerenone treatment did not significantly lowered systolic [- 0.04 (95% CI: - 4.4, 4.3) mmHg], but it was associated with minimal diastolic BP increase [1.0 (95% CI: 0.5, 1.53) mmHg]. MRAs were not associated with systolic and diastolic BP reduction in heart failure patients. This finding suggests that MRAs should be used according to their indications in heart failure independently of initial BP levels.

Multimodal retinal imaging in central serous chorioretinopathy treated with oral eplerenone or photodynamic therapy.

PurposeTo correlate function and structural optical coherence tomography (OCT) to optical coherence tomography angiography (OCT-A) measures in patients affected by central serous chorioretinopathy (CSC) and to describe their changes after treatments (ie oral eplerenone, half-fluence photodynamic therapy (PDT)).Patients and methodsTwenty eyes of 16 consecutive patients with treatment-naïve CSC undergoing either eplerenone or PDT were enrolled in this prospective, observational study. All patients underwent structural OCT and OCT-A at baseline and after therapy at months 1 and 3.ResultsEleven eyes of nine patients and nine eyes of seven patients underwent eplerenone or PDT treatment, respectively. Central macular thickness (CMT) and subretinal fluid (SRF) correlated to fovea avascular zone (FAZ) area (r=0.74 and r=0.71, P=0.01) and vessel density (r=0.77 and r=0.68, P=0.01) at deep capillary plexus (DCP). CMT (P=0.0011), SRF (P=0.0005), SFCT (P=0.0016), FAZ area at DCP (P=0.0334) improved at 3-month visit. A significant reduction of deep FAZ area was appreciated in eplerenone (P=0.0204) but not in PDT (P=0.5) group. SFCT reduction was significantly higher in PDT than eplerenone group (P=0.0347).ConclusionStructural and vascular parameters are correlated in CSC and they improve after different treatments. Both half-fluence PDT and oral eplerenone do not permanently damage choriocapillaris or other choroidal layers as evaluated by OCT-A.