Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure
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Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.Keywords:
Eplerenone
Mineralocorticoid
Mineralocorticoid receptor (MR) antagonists of aldosterone (spironolactone and eplerenone) display beneficial effects in the treatment of cardiopathies; however, many of these responses are independent of this antagonism. The mechanisms of action of these drugs are not well known; few studies have comparatively evaluated whether eplerenone as well as spironolactone display cardioprotective effects independent of the blockade of aldosterone. To study these mechanisms, which lead to cardioprotective responses, and to evaluate comparatively their effects in vitro, we have evaluated the proliferative effect of spironolactone and eplerenone in primary culture of cardiomyocytes and fibroblasts of neonatal Wistar rats in the presence and absence of aldosterone. Spironolactone and eplerenone promoted proliferation of cardiomyocyte even in the absence of aldosterone, suggesting a signaling pathway independent of the antagonism over aldosterone. Spironolactone was able to reduce the proliferation of fibroblasts and to reverse the proliferation promoted by aldosterone, which was also displayed by eplerenone. To elucidate the biochemical pathways evoked by these drugs, we sought to analyze Ca 2+ , cAMP, and cGMP, and the activity of PKC and ERK1/2. Spironolactone and eplerenone increased the levels of Ca 2+ , cGMP and activity of ERK 1/2, and reversed the action of aldosterone on the activity of PKC and ERK1/2. Interestingly, only spironolactone increased the levels of cAMP. Our data support the fact that in addition to aldosterone, both spironolactone and eplerenone display rapid responses (non-genomic) such as an increase on cAMP, Ca 2+ , and cGMP by spironolactone, and Ca 2+ and cGMP by eplerenone. We have observed a more consistent cardioprotection promoted by spironolactone; however, these effects have yet to be tested clinically. Therefore, our data show that these drugs do not only act as an antagonist of MR, but could lead to a new pharmacological classification of these drugs.
Eplerenone
Mineralocorticoid
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Spironolacotone and eplerenone are mineralocorticoid-blocking agents. These compounds block both the epithelial and non-epithelial actions of aldosterone with the latter assuming increasing clinical importance. Spironolactone and eplerenone both effectively reduce blood pressure either as mono- or add-on therapy; moreover, they each offer survival benefits in diverse circumstances of heart failure and the potential for renal protection in proteinuric chronic kidney disease. However, as the use of mineralocorticoid-blocking agents has increased the hazards inherent to use of such drugs has become more apparent. Whereas; the endocrine side-effects of spironolactone are in most cases little more than a cosmetic annoyance the potassium-sparing effects of both spironolactone and eplerenone can prove fatal if sufficient degrees of hyperkalemia develop. However, for most patients the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered as a possibility in any patient receiving one or the other of these medications. As such, steps should be taken to lessen the likelihood of its occurring if therapy is being contemplated with agents in this class.
Eplerenone
Mineralocorticoid
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The mineralocorticoid receptor antagonists spironolactone and eplerenone have become part of standard medical therapy for heart failure (HF). Randomized clinical trials have shown the clinical efficacy of spironolactone and eplerenone, which lead to lower death rates in patients with systolic HF. Whether these two drugs are equivalent and able to exert a positive effect in patients with clinical HF, including chronic HF with retained left ventricular systolic function remains to be answered.
Eplerenone
Mineralocorticoid
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Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRATM), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.
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Abstract Aims The selective mineralocorticoid receptor (MR) antagonist eplerenone given early in patients with acute myocardial infarction (MI) improves clinical outcome, whereas little is known about the effectiveness of early spironolactone therapy. We aimed to compare the ability of eplerenone and spironolactone to promote cardiac repair after experimental MI. Methods and results Starting immediately after coronary artery ligation, C57BL/6J mice were treated with placebo, eplerenone, or spironolactone. At 7 days, treatment with eplerenone or spironolactone reduced thinning and expansion of healing infarct and improved early left ventricular chamber enlargement. Remarkably, eplerenone therapy resulted in significantly greater improvement than spironolactone of left ventricular contractile function and relaxation, associated with a more considerable leftward and downward shift of the pressure volume curve. Seven‐day survival rate was significantly increased only in eplerenone treated mice. Moreover, eplerenone was superior to spironolactone in ameliorating neovessel formation in the injured myocardium. Optimized flow cytometry analysis of the monocyte differentiation marker Ly6C revealed predominant accumulation of Ly6C high monocytes/macrophages at the site of ischemic injury during the early inflammatory phase in placebo‐treated mice. In contrast, MR antagonism, especially by eplerenone, led to a skewing of the monocyte/macrophage population toward a higher frequency of healing promoting Ly6C low cells. Conclusion The MR antagonist eplerenone versus spironolactone showed superior efficacy during the acute MI phase with more beneficial effects on survival, early cardiac dilation, and functional decline. Modulation of monocyte maturation and enhanced infarct neovessel formation appears to play a pivotal role.
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Background: heart is the target organ for Aldosterone, spironolactone and eplerenone (mineralocorticoid receptor antagonists) inhibits the aldosterone extraction through the heart in patients with congestive heart failure (CHF).Objective: to evaluate prognostic impact of both MRA (spironolactone and eplerenone) on heart failure and compare between both agents in incidence of side effect (gynecomastia and hyperkalemia).Patients and Methods: the study was conducted from March 2016 to September 2016 at Aswan University hospital.Our study population consisted of 100 adult patients, who were proved to have heart failure symptoms, with reduced ejection fraction heart failure divided in two groups.Group A contains 50 patients on spironolactone in addition to other anti-failure treatments according to ESC guidelines.Group B is 50 patients on eplerenone in addition to other anti-failure treatments according to ESC guidelines.Results: follow up had been done after one month for patient clinical status and serum potassium level and development of gynecomastia.Another Follow up was done after 3 months for BNP level, gynecomastia, NYHA classification and body weight.Conclusion: MRA are important line of treatment in HF patients, eplerenone and spironolactone are both have good result in improving BNP level and improving NYHA classifications and patients weight loss.
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Gynecomastia
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Eplerenone
Primary Aldosteronism
Mineralocorticoid
Nefazodone
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Eplerenone
Mineralocorticoid
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