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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In clinical trials of heart failure, spironolactone, an antagonist of the mineralocorticoid receptor (MR), reduced mortality rates by unknown mechanisms. We hypothesized that spironolactone functions by upregulating expression of certain cardiovascular genes. An RNA differential display technique was used to identify genes whose expression was increased by spironolactone in an Xenopus kidney epithelial cell line (A6), a known target of aldosterone. We found that integrin beta3 gene expression was increased by spironolactone, and reversed by aldosterone or dexamethasone in a dose dependent manner. Competition binding studies and RT-PCR indicate the presence of MR in A6 cells, suggesting that regulation of expression occurred primarily through MR. Spironolactone also increased integrin beta3 expression in rat neonatal cardiomyocytes. In summary, spironolactone increases integrin beta3 gene expression in kidney epithelial cells and cardiomyocytes. The findings suggest new mechanisms for spironolactone actions with possible relevance to treatment of heart disease.
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PMID:Spironolactone increases integrin beta3 gene expression in kidney and heart muscle cells. 1224 40

We review the macroscopic and microscopic anatomy of myocardial disease associated with heart failure (HF) and sudden cardiac death (SCD) and focus on the prevention of SCD in light of its structural pathways. Compared to patients without SCD, patients with SCD exhibit 5- to 6-fold increases in the risks of ventricular arrhythmias and SCD. Epidemiologically, left ventricular hypertrophy by ECG or echocardiography acts as a potent dose-dependent SCD predictor. Dyslipidemia, a coronary disease risk factor, independently predicts echocardiographic hypertrophy. In adult SCD autopsy studies, increases in heart weight and severe coronary disease are constant findings, whereas rates of acute coronary thrombi vary remarkably. The microscopic myocardial anatomy of SCD is incompletely defined but may include prevalent changes of advanced myocardial disease, including cardiomyocyte hypertrophy, cardiomyocyte apoptosis, fibroblast hyperplasia, diffuse and focal matrix protein accumulation, and recruitment of inflammatory cells. Hypertrophied cardiomyocytes express "fetospecific" genetic programs that can account for acquired long QT physiology with risk for polymorphic ventricular arrhythmias. Structural heart disease associated with HF and high SCD risk is causally related to an up-regulation of the adrenergic renin-angiotensin-aldosterone pathway. In outcome trials, suppression of this pathway with combinations of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, and mineralocorticoid receptor blockers have achieved substantial total mortality and SCD reductions. Contrarily, trials with ion channel-active agents that are not known to reduce structural heart disease have failed to reduce these risks. Device therapy effectively prevents SCD, but whether biventricular pacing-induced remodeling decreases left ventricular mass remains uncertain.
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PMID:Structural pathways and prevention of heart failure and sudden death. 1293 Feb 59

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.
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PMID:Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. 1450 34

Excessive collagen deposition is a common complication of myocardial infarction that causes progressive heart disease. Several pro-fibrotic cytokines and hormones, including aldosterone, control this process. Procollagen processing by procollagen C-proteinase(s) is critical for collagen deposition and is potentiated by procollagen C-proteinase enhancer proteins (PCPEs). We have shown previously that, in addition to stimulation of collagen I expression, aldosterone increases PCPE-1 expression in cultured heart fibroblasts. The present study was designed to examine whether aldosterone acts similarly in vivo. Rats underwent coronary artery ligation to induce myocardial infarction. They were then left either untreated (control) or treated with spironolactone (an aldosterone receptor antagonist) for 5 weeks when they were sacrificed and their hearts removed for analysis. In situ hybridization co-localized PCPE-1 and collagen I mRNAs to fibroblasts surrounding the scar region and adjacent blood vessels. The levels of both transcripts in the remodeling myocardium of untreated rats increased twofold as compared to sham-operated controls, an increase greatly reduced by spironolactone. Correspondingly, a 2-5 fold increase in PCPE-1 and collagen I was observed in the hearts of untreated rats as compared to both the spironolactone-treated and sham-operated controls. The results establish aldosterone as a physiological stimulator of PCPE-1 expression in the remodeling myocardium after infarction. Since PCPE-1 itself is a positive regulator of collagen deposition, this finding suggests PCPE-1 as a new potential target for intervention with cardiac fibrosis.
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PMID:Expression of procollagen C-proteinase enhancer-1 in the remodeling rat heart is stimulated by aldosterone. 1630 Sep 90

The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathophysiology of salt-induced hypertension. Angiotensin converting enzyme inhibitors, angiotensin II-type 1 receptor blockers, and aldosterone receptor blockers are used to treat hypertension and congestive heart disease. In addition to their blood pressure lowering effects, they appear to protect against myocardial, renal, and vascular damage. In various models of hypertension, generation of reactive oxygen species is increased in the vasculature and that treatment with antioxidants or superoxide dismutase mimetics (e.g., tempol) improves vascular function and structure and reduces blood pressure. The purpose of this study was to examine the effects of enalapril, an angiotensin II converting enzyme inhibitor; eplerenone, a selective aldosterone receptor antagonist; and tempol, a superoxide dismutase mimetic, on salt-induced hypertension in Dahl Salt-Sensitive rats. The rats were placed on a high salt (HS; 8%) diet for 3 weeks prior to switching to a normal salt (0.3%) diet for an additional 3 weeks. While on the normal salt (NS) diet, rats were treated with enalapril (30 mg/kg/day in the drinking water), eplerenone (100 mg/kg/day by gavage), tempol (1 mM/day in the drinking water), eplerenone + enalapril, eplerenone + enalapril + tempol, or without drug treatment (control). After 3 weeks on HS diet, systolic blood pressure rose from 127 +/- 7 to 206 +/- 11 mm Hg and remained elevated when switched to NS diet. Subsequently, treatment with eplerenone alone or in combination with enalapril and tempol produced a stepwise reduction in systolic blood pressure reaching -80 mm Hg; however, enalapril and tempol alone produced more modest pressure reduction (approximately -35 mmHg). Plasma levels of prostacyclin and nitric oxide were elevated in rats treated with enalapril and eplerenone alone or in combination. Enalapril and eplerenone alone and in combination reduced heart and kidney levels of angiotensin II and aldosterone when compared with control. Renal and heart levels of reduced glutathione were diminished by eplerenone alone; however, enalapril tended to attenuate the effect of eplerenone on reduced glutathione levels in the heart. The findings from this study suggest that eplerenone reduces salt-induced hypertension by increasing endothelium-derived relaxing factors, inhibiting RAAS components and oxidative stress. (353words).
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PMID:Effects of enalapril, tempol, and eplerenone on salt-induced hypertension in dahl salt-sensitive rats. 1654 38

Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators have examined effects of Aldo receptor blockade in human subjects and various animal models using the two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA) Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor (MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR, it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction [Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the treatment of heart disease.
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PMID:Aldosterone receptor antagonists and cardiovascular disease: do we need a change of the guard? 1661 Oct 48

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.
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PMID:Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats. 1700 Sep 33

Amiloride was originally described in 1967 as a potassium-sparing diuretic, the mechanism of action of which is to block the epithelial sodium channel (ENaC) within the distal tubule of the kidney. In addition, higher doses of amiloride were found to be capable of inhibiting the Na(+)/H(+) exchangers (NHE) and the Na(+)/Ca(2+) exchangers. In time, several amiloride analogs have been synthesized to have a marked increase in their specificity to inhibit the ENaC, the NHE or the Na(+)/Ca(2+) exchangers. Although the NHE inhibitors have received the most recent attention, large-scale clinical trials using NHE inhibitors in ischemic cardiac states have shown them to be either ineffective or associated with an unacceptable risk profile. Aldosterone excess in animal models is known to cause cardiovascular injury, and blockade of mineralocorticoid receptors in human beings with heart disease improves outcomes. However, the exact mechanisms of aldosterone injury in animal models of hypertensive disease and protection with mineralocorticoid receptor antagonists in human trials of heart failure remain unknown. These effects are unexplained by changes in BP, potassium, or sodium balance. An additional possibility is that aldosterone action and mineralocorticoid receptor blockade is conferred by alterations in ENaC activity. Emerging experimental evidence suggests the possibility that systemic or central ENaC inhibition or both may be an alternative to the treatment of hypertension and cardiovascular disease states. Clinical trials to evaluate further the potential beneficial cardiovascular effects of ENaC blockade are needed. This article reviews the case for ENaC inhibition as a potential target for cardiovascular and renal protection in human beings.
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PMID:Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride. 1719 22

An historical perspective on the role of aldosterone in the pathophysiology of hypertension and heart disease, and data supporting the advantages of blocking the mineralocorticoid receptor with anti-aldosterone agents.
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PMID:A primer on aldosterone for gynecologists/obstetricians. 1747 9

In 1955, Dr. Jerome Conn described a patient with severe hypertension and hypokalemia and an aldosterone-secreting adenoma. The prevalence of hyperaldosteronism is increased among patients with obesity or resistant hypertension. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce the secretion of aldosterone, but with chronic treatment aldosterone concentrations "escape" back to baseline values. Mineralocorticoid receptor (MR) antagonism reduces mortality in patients with heart disease who are already taking an ACE inhibitor and diuretic. In addition to affecting sodium and potassium homeostasis via classical MR-dependent pathways, aldosterone induces inflammation and causes cardiovascular remodeling and renal injury. Some of these effects involve MR-independent pathways. At the same time, ligands other than aldosterone can activate the MR. This paper reviews mechanism(s) for the proinflammatory and profibrotic effects of aldosterone and presents data indicating that endogenous aldosterone, acting at the MR, contributes to many of the pro-inflammatory and pro-fibrotic effects of angiotensin II in vivo.
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PMID:This is not Dr. Conn's aldosterone anymore. 2168 29


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