Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Appreciation of the role of aldosterone in cardiovascular and renal disease has increased in the last 50 years. The use of spironolactone was limited by adverse sexual effects, including gynaecomastia. Eplerenone is a newer aldosterone antagonist that is much more selective, with minimal affinity for progesterone and androgenic receptors; therefore, there are very few reports of adverse sexual effects. A review of published trials shows that eplerenone reduces blood pressure (BP) in a dose-dependent manner, from 50 to 200 mg/day, and to a similar degree as enalapril. It has an additive effect when given to patients inadequately controlled on an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. Eplerenone performs better than losartan in African-American patients and lowers BP regardless of initial plasma renin activity. The risk of hyperkalaemia is low, similar to that of enalapril, and < 1% of patients have had to be withdrawn from studies because of elevated serum potassium levels. Eplerenone is an effective, well-tolerated antihypertensive agent that may be used alone or in conjunction with other agents; apart from the risk of hyperkalaemia, adverse effects are similar to placebo.
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PMID:Eplerenone in hypertension. 1557 74

Aldosterone antagonists have been available for many decades for the treatment of hypertension, but their use has been mostly limited to patients with classic primary aldosteronism or to combination products with hydrochlorothiazide to minimize risk for hypokalemia. Recently, indications for aldosterone antagonists have been expanded to include congestive heart failure and first-line treatment of mild-to-moderate hypertension. In addition, we have reported that spironolactone has significant antihypertensive benefit when added to existing regimens in patients with resistant hypertension. This benefit was present in patients with and without hyperaldosteronism and was additive to chronic renin-angiotensin blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Eplerenone, a selective aldosterone antagonist, avoids the androgen and progesterone receptor-related adverse events that sometimes occur with spironolactone, such as breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. In clinical trials, eplerenone has been shown to have antihypertensive benefit in treating mild-to-moderate hypertension similar to other widely used classes of agents. With recent demonstrations of benefit in multiple segments of the hypertensive population, aldosterone antagonists represent emerging opportunity for controlling high blood pressure.
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PMID:Aldosterone antagonism: an emerging strategy for effective blood pressure lowering. 1591 92

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.
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PMID:Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure. 1636 59

There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). These studies also showed that when using MR antagonist as an "organ protecting" drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The long-term effect of aldosterone was not inhibited in some subjects, so the possibility of organ damage due to so-called "breakthrough" aldosterone cannot be ignored. Nonepithelial MR-mediated effects played a major role in this aldosterone effect. These effects can be inhibited by MR antagonist at a small dose, not lower blood pressure. Therefore, the idea is now to combine a small dose of MR antagonist with an ACE inhibitor or ARB. However, warnings have been given recently due to the emergence of hyperkalemia and other adverse effects associated with inappropriate combination therapy. It is important to note that, if the eligibility criteria of RALES and EPHESUS are fulfilled, the potassium level will rarely become problematic. Therefore, the recent increase in the incidence of adverse effects can be attributed to the incorrect application of combination therapy. Elderly patients or those with dehydration, renal dysfunction, and aggravated heart failure require further close monitoring or termination of spironolactone administration. The combination of an MR antagonist and renin-angiotensin inhibitors should be a useful strategy if subjects are carefully selected, and carefully monitored. Adverse effects will occur only if the usage recommendations based on previous researches are not followed.
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PMID:Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. 1677 27

Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure. There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/vascular function and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris. Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.
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PMID:Aldosterone blockade over and above ACE-inhibitors in patients with coronary artery disease but without heart failure. 1708 70

The presence of heart failure or left ventricular systolic dysfunction in the setting of acute myocardial infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the renin-angiotensin-aldosterone system that promotes myocardial collagen deposition, myocardial fibrosis, apoptosis, ventricular remodeling, and endothelial dysfunction. It may play an important role in the increased morbidity and mortality and the development and progression of heart failure after acute myocardial infarction. Extending the findings from the Randomized Aldactone Evaluation Study (RALES) in patients with chronic heart failure, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone offered a significant survival benefit, attenuation of progression of heart failure, and prevention of sudden cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines now suggest that aldosterone blockade should be an integral component of heart failure therapy to improve outcomes in this high-risk population.
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PMID:Optimizing care of heart failure after acute MI with an aldosterone receptor antagonist. 1822 14

Activation of the renin-angiotensin (Ang)-aldosterone system is involved in the pathology of vascular diseases. Although the blockade of the mineralocorticoid receptor protects against vascular diseases, its role in cerebral aneurysms remains to be elucidated. We treated female rats subjected to renal hypertension, increased hemodynamic stress, and estrogen deficiency for 3 months with the mineralocorticoid receptor blocker eplerenone (30 or 100 mg/kg per day) or vehicle (vehicle control). Eplerenone reduced the incidence of cerebral aneurysms and saline intake without lowering of the blood pressure. In the aneurysmal wall, the production of Ang II and nitrotyrosine was increased. The mRNA levels of Ang-converting enzyme 1 and NADPH oxidase subunits NOX4, Rac1, monocyte chemoattractant protein 1, and matrix metalloproteinase 9 were increased. Eplerenone brought about a reduction in these molecules, suggesting that mineralocorticoid receptor blockade suppresses cerebral aneurysm formation by inhibiting oxidative stress, inflammatory factors, local renin-Ang system activation, and saline intake. Other female rats implanted with pellets of the mineralocorticoid receptor agonist deoxycorticosterone acetate manifested a high incidence of cerebral aneurysm formation and the upregulation of molecules related to oxidative stress, inflammatory factors, and the local renin-Ang system; their saline intake was increased. We demonstrate that mineralocorticoid receptor activation at least partly contributes to the pathogenesis of cerebral aneurysms.
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PMID:Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats. 1962 May 12

Recent interest in mineralocorticoid receptor (MR) antagonism in cardiovascular disease reflects recognition that blockade of the renin-angiotensin system may be followed by a breakthrough in aldosterone levels to or above the normal range. The Randomized Aldactone Evaluation Study (RALES) trial in progressive heart failure, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) in post-infarct heart failure, and the 4E trial in essential hypertension demonstrated the efficacy of MR blockade in addition to standard therapy. In all three trials, plasma aldosterone levels were low and sodium status unremarkable; this finding, and those of various preclinical studies, point squarely at pathophysiological MR activation by ligands other than aldosterone, most likely normal levels of cortisol, and provide clear evidence for the therapeutic utility of MR blockade in conditions of tissue and organ damage with normal aldosterone levels.
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PMID:Eplerenone: hypertension, heart failure and the importance of mineralocorticoid receptor blockade. 1980 89

Eplerenone, a selective aldosterone blocker, has become clinically available in Japan since 2007. It has been reported that eplerenone has a potential antihypertensive effect, with a profile slightly different from that of spironolactone, and has fewer adverse reactions, suggesting that it may become a first-line treatment for hypertension. However, clinical data on hypertensive patients in Japan are lacking for eplerenone. In this study, we explored the clinical efficacy of eplerenone when it is added to an angiotensin-converting enzyme (ACE) inhibitor or a long-acting calcium channel blocker (CCB) in 68 (31 males, 37 females) Japanese patients with essential hypertension. After adding 50 mg of eplerenone to their basal treatment, blood pressure was significantly reduced at 4 weeks, and further reduced after 24 weeks of eplerenone treatment. Urinary albumin excretion decreased significantly after 24 weeks. There were no significant differences in general biochemical test values or electrolytes, but fasting serum triglycerides were significantly decreased after eplerenone treatment. The serum potassium level showed no significant change during treatment. There were no significant correlations between plasma renin activity or plasma aldosterone concentration (PAC) before eplerenone treatment and blood pressure after eplerenone treatment, showing that the antihypertensive effect of eplerenone is not affected by the patient's renin profile or pretreatment PAC values. Eplerenone was also effective in hypertensive patients with metabolic syndrome. In conclusion, eplerenone, when coadministered with an ACE inhibitor or a long-acting CCB, caused an extremely beneficial antihypertensive effect in Japanese patients with essential hypertension, without few clinically important adverse events.
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PMID:Clinical effects of eplerenone, a selective aldosterone blocker, in Japanese patients with essential hypertension. 1986 6

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in spontaneously hypertensive rats (SHR) given salt excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-wk SHR were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, group 2 was given placebo, group 3 the mineralocorticoid receptor blocker eplerenone (100 mg.kg(-1).day(-1)), group 4 the angiotensin converting enzyme inhibitor quinapril (3 mg.kg(-1).day(-1)), group 5 the angiotensin II type 1 receptor blocker candesartan (10 mg.kg(-1).day(-1)), and groups 6 and 7 eplerenone and either quinapril or candesartan. The treatments lasted 8 wk. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indexes except MAP. Combination therapy also normalized all indexes, including MAP. These data suggest that 1) cardiovascular and renal damage induced by salt excess in the SHR were not pressure dependent; 2) mineralocorticoids were only marginally involved in this model; and 3) local tissue generation of angiotensin II may be, at least in part, responsible for the other adverse effects.
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PMID:Cardiovascular effects of inhibition of renin-angiotensin-aldosterone system components in hypertensive rats given salt excess. 2011 10


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