Eplerenone reduces lymphangiogenesis in the contralateral kidneys of UUO rats.

Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. Methods: We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. Results: We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. Conclusions: These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

OBJECTIVE: To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. ANIMALS: Ten healthy purpose-bred Beagle dogs. PROCEDURES: Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. RESULTS: Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. CONCLUSIONS: Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

Gene expression analysis to identify mechanisms underlying improvement of myocardial fibrosis by finerenone in SHR.

Both spironolactone and finerenone treatments significantly reduced SBP and there was no statistical difference in their antihypertensive effects. The differences in body weight (at the end of 1/2/3/4 week) to pre-dose body weight ratio and heart rate (at the end of 1/2/3/4 week) to pre-dose heart rate ratio were not statistically significant in the vehicle, spironolactone, finerenone, and control groups.There was no statistically significant difference in mortality among the vehicle, spironolactone, and finerenone groups. The relative heart mass, ANP, BNP, CVF, Col I, TGF-ß, and Casp-3 were gradually decreased in vehicle group, spironolactone group, and finerenone group. Among them, BNP, CVF, TGF-ß, and Casp-3 were significantly decreased in the finerenone group compared with the vehicle group. HE and Masson staining showed that the cardiomyocytes of rats in the vehicle group and spironolactone group were disorganized, with cell hypertrophy, significantly enlarged cell gaps and a large amount of collagen deposition, whereas the cardiomyocytes of rats in the finerenone group and the control group were more neatly arranged, with smaller cell gaps and a small amount of collagen tissue deposition. RNA sequencing (RNA-seq) showed that there was a total of 119 differentially expressed genes (DEGs) between finerenone treatment and vehicle treatment. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the signaling pathways involved were mainly in drug metabolism-cytochrome P450, chemical carcinogenesis, IL-17 signaling pathway, axon guidance, and hematopoietic cell lineage. Protein-protein interaction (PPI) analysis showed that the core genes were Oaslf, Nos2, LOC687780, Rhobtb1, Ephb3, and Rps27a.

Efficacy of pharmacological and interventional treatment for resistant hypertension: a network meta-analysis.

AIMS: Resistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease, and mortality. Yet, its management is challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis. METHODS AND RESULTS: MEDLINE, Cochrane Register of Controlled Trials, and Web of Science Core Collection were systematically searched in March 2022. Randomized controlled trials comparing treatment options for management of resistant hypertension were included. Outcomes were blood pressure (BP) changes, measured in the office and in 24 h ambulatory BP measurement. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator. From 4771 records, 24 studies met the inclusion criteria with 3458 included patients in total. Twelve active treatment alternatives [spironolactone, doxazosin, ß-blocker, clonidine, darusentan, guanfacine, various types of renal sympathetic denervation, lifestyle intervention, continuous positive airway pressure, and baroreflex activation therapy (BAT)] were analysed. Among all comparators, spironolactone had the highest ranking probability and was considered the most effective treatment to reduce office systolic blood pressure (sBP) [-13.30 mmHg (-17.89; -8.72); P < 0.0001] and 24 h sBP [-8.46 mmHg (-12.54; -4.38); P < 0.0001] in patients with resistant hypertension. Lifestyle interventions were the most effective non-pharmacological treatment, lowering office sBP by -7.26 mmHg (-13.73; -0.8), whereas BAT lowered office sBP by -7.0 (-18.59; 4.59). Renal denervation lowered office sBP by -5.64 mmHg (-12.95; 1.66) and -3.79 mmHg (-11.39; 3.8) depending on the type of the procedure. CONCLUSION: Among all pharmacologic and interventional treatments, spironolactone is the most effective treatment in reducing BP in patients with resistant hypertension. More comparative trials and especially trials with long-term follow-up are needed. In the meanwhile, we have to conclude that a combination of spironolactone and lifestyle modification are the most effective treatments in resistant hypertension.

The influence of pharmacological mineralocorticoid and glucocorticoid receptor blockade on the cortisol response to psychological stress.

The glucocorticoid cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis and crucial for the stress response in humans. Cortisol regulates numerous biological functions by binding to two different types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are found in the brain where they are crucially involved in various mental functions and in feedback inhibition of cortisol release. The precise role of both receptors in the human stress response is not completely understood. In this study, we examined the effects of pharmacological blockade of the MR or the GR on stress-induced cortisol release in a sample of 318 healthy young men (M = 25.42, SD = 5.01). Participants received the MR antagonist spironolactone (300 mg), the GR antagonist mifepristone (600 mg), or a placebo and were subjected 90 min later to a social-evaluative stressor (Trier Social Stress Test) or a non-stressful control condition. We found significantly higher stress-induced cortisol release in the spironolactone group, whereas participants after mifepristone administration did not differ from the control groups. These results suggest that MR blockade results in attenuated fast negative feedback processes and emphasize the important role of the MR during the early phase of the stress response.

Resistant hypertension: challenges in everyday practice.

Resistant hypertension is defined as not achieving sufficient control of blood pressure (BP), that is, maintaining BP values equal to or above 140/90 mm Hg when using 3 antihypertensive drugs, including diuretics, properly combined and at maximum doses. The uncontrolled treated hypertension should be confirmed in out­of­office BP measurements, preferably with 24­hour ambulatory BP monitoring. Demographic and clinical characteristics indicate that patients with resistant hypertension are older than the general population of patients with arterial hypertension and more often suffer from comorbidities. When resistant hypertension is suspected, it is necessary to assess whether optimal pharmacotherapy has been prescribed, including appropriate combinations of antihypertensive drugs and diuretics at appropriate doses. It is also important to exclude parallel use of drugs that may have unfavorable interactions leading to an increase in BP. A common cause of pseudoresistant hypertension is a patient's failure to comply with therapeutic recommendations, including a lack of lifestyle changes and nonadherence to the prescribed medication regimen. An important step in management of resistant hypertension is targeted screening with diagnostic tests for secondary hypertension. Expanding of the drug therapy beyond a 3­drug regimen should include a mineralocorticoid receptor antagonist, in particular spironolactone. In selected patients, device­based hypertension treatment might be considered.

Mineralocorticoid Receptor Antagonism Prevents Type 2 Familial Partial Lipodystrophy Brown Adipocyte Dysfunction.

Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by LMNA mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.

Role of aldosterone and mineralocorticoid receptor (MR) in addiction: A scoping review.

Preclinical and human studies suggest a role of aldosterone and mineralocorticoid receptor (MR) in addiction. This scoping review aimed to summarize (1) the relationship between alcohol and other substance use disorders (ASUDs) and dysfunctions of the aldosterone and MR, and (2) how pharmacological manipulations of MR may affect ASUD-related outcomes. Our search in four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) indicated that most studies focused on the relationship between aldosterone, MR, and alcohol (n = 30), with the rest focused on opioids (n = 5), nicotine (n = 9), and other addictive substances (n = 9). Despite some inconsistencies, the overall results suggest peripheral and central dysregulations of aldosterone and MR in several species and that these dysregulations depended on the pattern of drug exposure and genetic factors. We conclude that MR antagonism may be a promising target in ASUD, yet future studies are warranted.

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.

We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.

Effect of pharmacological heart failure drugs and gene therapy on Danon's cardiomyopathy.

Danon disease is a rare X-linked genetic disease resulting from LAMP2 mutations leading to defective lysosomal function. Heart failure is the main causes of morbidity and mortality. Mice with an LAMP2-exon-6-deletion (L2Δ6), develop cardiac hypertrophy followed by dilated cardiomyopathy, in association with accumulation of autophagosomes, fibrosis and oxidative stress. We investigated the effect of drugs used to treat heart failure and of LAMP2 gene therapy on the phenotype, molecular markers and ROS in LAMP2 cardiomyopathy. L2Δ6 mice were treated with Angiotensin II, Ramipril, Metoprolol or Spironolactone. Gene therapy was delivered by IP injection of Adeno-associated-virus (AAV9) -LAMP2 vector to neonates ("AAVLAMP2-Prevention"), or at 15 weeks of age ("AAVLAMP2-Treatment"). Angiotensin II markedly aggravated the cardiac phenotype. Ramipril and Spironolactone were effective in attenuating left ventricular hypertrophy and preserving the systolic function. Cardiac protection was associated with decreased autophagosome accumulation, reduced fibrosis and oxidative stress. Gene therapy effectively attenuated autophagosome accumulation and ROS in L2Δ6 hearts, lowering troponin release to nearly normal levels. AAVLAMP2-Prevention protected against systolic dysfunction and decreased hypertrophy. AAVLAMP2-Treatment prevented ventricular dilatation and dysfunction but had no effect on wall thickness. We conclude that RAAS inhibitors are highly effective against cardiomyopathy progression in an experimental mouse model of Danon's and shall be considered in human patients for this purpose until novel therapies become clinically available.

Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels.

Decaying kidney function during cirrhosis correlates with remodeling of distal colon aldosterone target gene expression.

Liver cirrhosis is associated to circulatory abnormalities leading to hypovolemia and stimulation of the renin-angiotensin-aldosterone system (RAAS). Advanced stages of the disease cause renal failure, impairing K+ and Na+ homeostasis. It has been proposed that the distal colon undergoes functional remodeling during renal failure, in particular by aldosterone-driven increased K+ excretion. In this study, we compared the transcriptional response of aldosterone target genes in the rat distal colon under two models of increased circulating aldosterone (one with concomitant RAAS activation) and in a model of secondary hyperaldosteronism induced by cirrhosis. The expression of a subset of these genes was also tested in distal colon biopsies from control subjects or patients with cirrhosis with varying levels of disease progression and treated or not with mineralocorticoid receptor inhibitor spironolactone. We examined known aldosterone-regulated transcripts involved in corticosteroid signaling and transepithelial ion transport. In addition, we included aldosterone-regulated genes related to cell proliferation. Our comparison revealed multiple aldosterone target genes upregulated in the rat distal colon during decompensated cirrhosis. Epithelial Na+ channel ß and γ subunit expression correlated positively with plasma aldosterone concentration and negatively with glomerular filtration rate. Patients with cirrhosis showed increased expression of 11-ß-hydroxysteroid-dehydrogenase 2 (11ßHSD2), which was reverted by spironolactone treatment, suggesting a sensitization of the distal colon to aldosterone action. In summary, our data show that decaying kidney function during cirrhosis progression toward a decompensated state with hypovolemia correlates with remodeling of distal colon ion transporter expression, supporting a role for aldosterone in the process.NEW & NOTEWORTHY Liver cirrhosis progression significantly alters ion transporter subunit expression in the rat distal colon, a change that correlated well with declining kidney function and the severity of the disease. Our data suggest that the steroid hormone aldosterone participates in this homeostatic response to maintain electrolyte balance.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The Effectiveness of Eplerenone vs Spironolactone on Left Ventricular Systolic Function, Hospitalization and Cardiovascular Death in Patients With Chronic Heart Failure-HFrEF.

Background: Heart failure remains one of the most prevalent clinical syndromes associated with significant morbidity and mortality. According to current guidelines, the prescription of a MRA is recommended to reduce the risk of HF hospitalization and death in all patients with symptomatic heart failure and no contraindications for this therapy. Objective: The aim of our study was to determine the efficacy of eplerenone vs. spironolactone on left ventricular systolic function by measuring left ventricle ejection fraction (LVEF) in patients with chronic heart failure, especially their effect on preventing hospitalization, reducing mortality, and improving clinical status among patients with chronic HF. Methods: From June 2021 to June 2022, the study was a randomized, prospective clinical trial single blind study. A total of 142 patients of chronic heart failure with reduced ejection fraction were selected by random sampling. Each patient was randomly allocated into either of the two groups and was continued receiving treatment with either spironolactone (Spiron-HF group) or eplerenone (Epler-HF group). Patients in Epler-HF group were compared with an arm of the same size and matched by age and gender patients in Spiron-HF group for management of chronic HFrEF. Each patient was evaluated clinically, biochemically, and echocardiographically at the beginning of treatment (baseline) after 6 months and at the end of 12th month. Echocardiography was performed to find out change in left ventricular systolic function. Results: After 12 months of treatment, significant improvement of left ventricular ejection fraction was observed in eplerenone treated arm (37.9 ± 3.8 ± 4.6 in Spiron-HF group versus 40.1 ± 5.7 in Epler-HF group; P < 0.05). A significant reduction in left ventricular end-systolic volume (6.3 ± 2.5ml in Spiron-HF versus 17.8± 4.4ml in Epler-HF group; P < 0.05) and left ventricular systolic diameter volume (2.7 ± 0.5ml in Spiron-HF versus 6.7 ± 0.2ml in Epler-HF group; P < 0.05), occurred after 12 months of treatment. Left ventricular global longitudinal strain (LV GLS) was significantly improved in Epler-HF group compared with Spiron-HF group (0.6 ± 0.4 versus 3.4 ± 0.9; P < 0.05). There were no significant differences observed in reduction of left ventricular end-diastolic volume (2.2 ± 0.5 ml versus 4.7 ± 1.1ml; P =0.103) and left ventricular diastolic diameter (1.2 ± 0.6 versus 1.7 ± 0.3; P=0.082) in both arms. The effects of both MRA agents spironolactone and eplerenone on the primary composite outcome, each of the individual mortality and hospital admission outcomes are shown in Figure 1 and 2. Patients of the Epler-HF group showed statistically significant lower cardiovascular mortality (HR 0.53; 95% CI 0.34-0.82; p= 0.007) and all-cause mortality (HR 0.64; 95% CI 0.44-0.93; p= 0.022) than patients of the Spiron-HF group. The statistical analysis did not show a statistically significant difference between Epler -HF and Spiron-HF study groups regarding the risk of the primary composite outcome; cardiovascular death or hospitalization due to HF (Hazard Ratio (HR) eplerenone vs. spironolactone = 0.95; 95% Confidence Interval (CI) 0.73- 1.27; p= 0.675). Conclusion: Our study has demonstrated favorable effects of eplerenone on cardiac remodeling parameters and reduction of cardiovascular mortality and all-cause mortality compared with spironolactone in the treatment of HFrEF. The ability of eplerenone to effectively block the mineralocorticoid receptor while minimizing side effects and a significant reduction in the risk of hospitalization and cardiovascular death confirms its key role in the treatment of patients with chronic HFrEF.

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study.

BACKGROUND: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. METHODS: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI. RESULTS: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/µL; P = .02) increased in the eplerenone- versus placebo-treated groups. CONCLUSIONS: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. CLINICAL TRIALS REGISTRATION: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

Mineralocorticoid receptor blockade protects the kidneys but does not affect inverted blood pressure rhythm in hypertensive transgenic (mRen-2)27 rats.

Aldosterone regulates blood pressure (BP) through water and sodium balance. In our study, we studied if continuous treatment with a mineralocorticoid receptor antagonist, spironolactone (30 mg/kg/day) for 20 days can: 1) attenuate hypertension development and restore inverted 24-h BP rhythm in hypertensive transgenic (mRen-2)27 rats (TGR) measured by telemetry; 2) improve function of the kidneys and heart; 3) be protective against high salt load (1% in water) by mitigating oxidative injury and improving kidney function. Spironolactone decreased albuminuria and 8-isoprostane in normal and salt load conditions in BP-independent effects. Salt load increased BP, impaired autonomic balance, suppressed plasma aldosterone level and increased natriuresis, albuminuria and oxidative injury in TGR. Spironolactone did not restore the inverted 24-h rhythm of BP in TGR, therefore, mineralocorticoids are not crucial in regulation of BP daily profile. Spironolactone improved kidney function, decreased oxidative stress and was protective against high salt load in the BP-independent manner.

Corticosterone injection into the dorsal and ventral hippocampus impairs fear memory reconsolidation in a time-dependent manner in rats.

Reconsolidation is an active process induced following the reactivation of previously consolidated memories. Recent studies suggest brain corticosteroid receptors may participate in the modulation of fear memory reconsolidation. Glucocorticoid receptors (GRs), with 10-fold lower affinity than mineralocorticoid receptors (MRs), are mainly occupied during the peak of the circadian rhythm, and after stress, so they probably have a more critical role than MRs in memory phases during stressful situations. This study investigated the role of dorsal and ventral hippocampal (DH and VH) GRs and MRs on fear memory reconsolidation in rats. Male Wistar rats with surgically implanted bilaterally cannulae at the DH and VH were trained and tested in an inhibitory avoidance task. The animals received bilateral microinjections of vehicle (0.3 µl/side), corticosterone (3 ng/0.3 µl/side), the GRs antagonist RU38486 (3 ng/0.3 µl/side), or the MRs antagonist spironolactone (3 ng/0.3 µl/side) immediately after memory reactivation. Moreover, drugs were injected into VH 90 min after memory reactivation. Memory tests were performed 2, 9, 11, and 13 days after memory reactivation. Results indicated that injection of corticosterone into the DH but not VH immediately after memory reactivation significantly impaired fear memory reconsolidation. Moreover, corticosterone injection into VH 90 min after memory reactivation impaired fear memory reconsolidation. RU38486, but not spironolactone reversed these effects. These findings indicate that corticosterone injection into the DH and VH via GRs activation impairs the reconsolidation of fear memory in a time-dependent manner.

Betahistine prevents development of endolymphatic hydrops in a mouse model of insulin resistance and diabetes.

BACKGROUND: Diabetes is associated with inner ear dysfunction. Furthermore, C57BL/6J mice fed high fat diet (HFD), a model for insulin resistance and diabetes, develop endolymphatic hydrops (EH). AIM: Evaluate if betahistine, spironolactone (aldosterone antagonist) and empagliflozin (sodium -glucose cotransporter2 inhibitor) can prevent EH induced by HFD and explore potential mechanisms. METHODS: C57BL/6J mice fed HFD were treated with respective drug. The size of the endolymphatic fluid compartment was measured using contrast enhanced MRI. Secondarily, mice treated with cilostamide, a phosphodiesterase3 inhibitor, to induce EH and HEI-OC1 auditory cells were used to study potential cellular mechanisms of betahistine. RESULTS: HFD-induced EH was prevented by betahistine but not by spironolactone and empagliflozin. Betahistine induced phosphorylation of protein kinaseA substrates but did not prevent cilostamide-induced EH. CONCLUSIONS: Betahistine prevents the development of EH in mice fed HFD, most likely not involving pathways downstream of phosphodiesterase3, an enzyme with implications for dysfunction in diabetes. The finding that spironolactone did not prevent HFD-induced EH suggests different mechanisms for EH induction/treatment since spironolactone prevents EH induced by vasopressin, as previously observed. SIGNIFICANCE: This further demonstrates that independent mechanisms can cause hydropic inner ear diseases which suggests different therapeutic approaches and emphazises the need for personalized medicine.