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In a substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which evaluated the effects of the selective aldosterone receptor antagonist eplerenone versus placebo, serum levels of collagen biomarkers were measured in 476 patients with congestive heart failure after acute myocardial infarction complicated with left ventricular systolic dysfunction. The combination of the type I collagen telopeptide and brain natriuretic peptide levels above median at baseline was associated with all-cause mortality and the composite end point of cardiovascular death or heart failure hospitalization, with hazard ratios of 2.49 (P=0.039) and 3.03 (P=0.002), respectively. During follow-up, levels of aminoterminal propeptide of type I and type III procollagen were found to be consistently lower in the eplerenone group and significantly lower beginning at 6 months.
Cushing syndrome was diagnosed on the basis of a markedly elevated 24-hour urine free cortisol level and classic cushingoid features. The etiology of Cushing syndrome was determined to be an adrenocortical carcinoma arising from testicular adrenal rest cells. Nevertheless, the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be excluded.
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The aim of the study was to determine risk mortality factors in a 3-year follow-up of patients with CHF due to hypertension.
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Atherosclerosis is a chronic inflammatory disease in the vessel. As a representative inflammatory cytokine, C-reactive protein (CRP) participates in atherogenesis. Although hyperaldosteronism is known to evoke inflammatory response in several tissues and cell types, there is no direct evidence to demonstrate the proinflammatory effect of aldosterone on vascular smooth muscle cells (VSMCs) through CRP. In this study, we observed the effect of aldosterone on CRP expression and the molecular mechanisms in rat VSMCs. The results showed that aldosterone induced CRP expression in VSMCs in vitro and in vivo. Mineralocorticoid receptor (MR) antagonist spironolactone abolished aldosterone-induced CRP expression. In addition, aldosterone stimulated generation of reactive oxygen species (ROS) and activated ERK1/2 phosphorylation, whereas spironolactone inhibited aldosterone-stimulated ROS generation and ERK1/2 phosphorylation. Antioxidant NAC decreased aldosterone-induced CRP expression and ERK1/2 phosphorylation. The further study confirmed that ERK1/2 inhibitor PD98059 and NF-κB inhibitor pyrrolidine dithiocarbamate both depressed aldosterone-induced CRP expression. These demonstrate that aldosterone is able to induce CRP expression via MR-ROS-ERK1/2-NF-κB signal pathway in VSMCs, which provides a new evidence for the proinflammatory and proatherosclerotic effects of aldosterone.
Glucocorticoids, not aldosterone, may regulate basal colonic NaCl transport. Aldosterone induces spironolactone-inhibitable, amiloride-inhibitable conductive Na absorption but basal transport is electroneutral and amiloride and spironolactone resistant. We examined in vivo the Na absorptive pathway induced by glucocorticoid receptor specific doses of glucocorticoid using various amiloride analogues. Doses of dexamethasone sufficient to co-occupy aldosterone receptors produced amiloride-sensitive Na absorption in proximal and distal colon. Low doses of dexamethasone or the specific glucocorticoid RU26988 markedly stimulated Na absorption but did so by an amiloride-resistant mechanism. The Na-H antiport inhibitor, 5-N-ethyl-N-isopropylamiloride (NENIA) eliminated glucocorticoid-induced Na and Cl absorption without changing transmural potential difference (PD) in proximal and distal colon (Ki = 0.7 x 10(-7) M). NENIA had no effect on aldosterone-induced transport. NENIA (10(-5) M) almost eliminated Na absorption in adrenal intact animals if infused early in the experimental protocol. With time, NENIA resistance developed, corresponding with the previously documented rise in endogenous aldosterone. Thus glucocorticoids induce an electroneutral Na absorptive pathway that may be the luminal Na-H antiport, suggesting that glucocorticoids regulate adrenal-dependent electroneutral Na absorption in rat colon.
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Besides the various androgenic activities actions in women, signs of androgenisation such as acne, seborrhoe, hirsutism and alopecia, play an important clinical role and require a proper diagnostic evaluation and individualised medical treatment. After development and thorough clinical evaluation of antiandrogen, a variety of therapeutic possibilities have become available. The main antiandrogens are: Cyproterone acetate, chlormadinone acetate and spironolactone. They are used in mono- or combination-therapy regimens. Means of application (oral, parenteral), dosages used and different forms of combination therapies are presented under practical aspects. The effects of such treatment modalities are outlined.
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Plasma epinephrine and heart rate are elevated in metabolic syndrome, suggesting enhanced catecholamine secretion from the adrenal medulla. Canonical transient receptor potential (TRPC) channels are implicated in mediating hormone-induced Ca(2+) influx and catecholamine secretion in adrenomedullary chromaffin cells. We studied the pattern of TRPC expression in the pig adrenal medulla and investigated whether adrenal TRPC expression is altered in prediabetic metabolic syndrome Ossabaw miniature pigs. We used a combination of molecular biological, biochemical, and fluorescence imaging techniques. We determined the sequence of pig TRPC1 and TRPC3-7 channels. We found that the pig adrenal medulla expressed predominantly TRPC1, TRPC5, and TRPC6 transcripts. The expression level of these TRPCs was significantly elevated in the adrenal medulla from pigs with metabolic syndrome. Interestingly, aldosterone, which is endogenously secreted in the adjacent adrenal cortex, increased TRPC1, TRPC5, and TRPC6 expression in adrenal chromaffin cells isolated from metabolic syndrome but not control pigs. Spironolactone, a blocker of mineralocorticoid receptors, inhibited the aldosterone effect. Dexamethasone also increased TRPC5 expression in metabolic syndrome chromaffin cells. The amplitude of hormone-induced divalent cation influx correlated with the level of TRPC expression in adrenal chromaffin cells. Orai1/Stim1 protein expression was not significantly altered in the metabolic syndrome adrenal medulla when compared with the control. We propose that in metabolic syndrome, abnormally elevated adrenal TRPC expression may underlie increased plasma epinephrine and heart rate. The excess of plasma catecholamines and increased heart rate are risk factors for cardiovascular disease. Thus, TRPCs are potential therapeutic targets in the fight against cardiovascular disease.
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Viral infection of the heart is relatively common and usually of little consequence. It can, however, lead to substantial cardiac damage and severe acute heart failure. It can also evolve into the progressive syndrome of chronic heart failure. Recent studies have gone some way towards unravelling the complex mechanisms underlying the heart muscle damage that occurs after viral infection. These studies have lent support to both immune and viral mediated (independent of an immune response) cardiac damage. Acute myocarditis can present in various ways, and it may be a cause of sudden death in an otherwise healthy young adult. New treatments for viral heart disease are awaited. In the meanwhile, the haemodynamic support of patients with acute left ventricular failure caused by myocarditis should be aggressive, to allow for the possibility of spontaneous recovery. Contemporary trials of treatment in chronic heart failure secondary to dilated cardiomyopathy support the use of angiotensin converting enzyme inhibitors, beta adrenoceptor blockers, and spironolactone in such patients.
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This study concerned 40 consecutive patients referred for HT evaluation who underwent a clinical assessment, including hemodynamic, echocardiographic, and brain natriuretic peptide determinations. Medical therapy was optimized according to the clinical assessment to improve neurohormonal and hemodynamic profiles. We analyzed the distribution of the different drugs between the first and the following evaluation to demonstrate whether a significant improvement of medical therapy could be achieved in advanced chronic heart failure (ACHF).
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This economic evaluation suggests that the addition of spironolactone to standard therapy for patients with severe chronic heart failure is not only safe and effective, but is highly cost-effective in the Irish healthcare setting.
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Excess fat intake causes obesity and renal injury in C57BL/6J mice, and these changes are mediated by an enhanced mineralocorticoid receptor/Rho/Rho-kinase pathway and inflammatory process. Mineralocorticoid receptor activation in the kidney tissue and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.
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The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 - March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation. BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well. On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (ABSTRACT TRUNCATED)
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Eight hemodialysis patients were administered either spironolactone, 50 mg, or placebo orally twice daily for 2 weeks, followed by a 3-week washout period, after which patients crossed over in their treatment arms for 2 more weeks.
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Agranulocytosis associated with spironolactone administration is described in a 57-year-old man. Four days after initiation of spironolactone, leukocyte counts decreased from 8.2 to 2.3 X 10(9)/L with 6% neutrophils. Spironolactone, domperidone, and prochlorperazine were discontinued. Domperidone and prochlorperazine were reintroduced and there was concomitant improvement of the leukocyte and neutrophil counts. Substitution of triamterene for spironolactone was not associated with recurrent leukopenia. The potential association of spironolactone with granulocytopenia warrants increased awareness of this rare but serious adverse drug reaction.
Ferriman-Gallwey scores were decreased significantly in both groups at the end of 9 months. The percent of change in hirsutism scores in flutamide and spironolactone group were as follows: 26.4% and 20.9% at 3 months; 39.5% and 32.9% at 6 months; and 46.4% and 39.6% at 9 months, respectively. There was a trend toward a better response with flutamide that did not achieve significance. None of the hormonal parameters changed significantly during this period of time. Irregular bleeding was observed in five patients (50%) of the spironolactone group, whereas none of the patients in the flutamide group experienced menstrual irregularity. Conversely, dry skin and increased appetite were experienced by two patients (20%) in the flutamide group but not in the spironolactone group.
Addison's disease may be complicated by hypertension and less commonly by heart failure. We review the pathophysiology of the renin-angiotensin-aldosterone axis in Addison's disease and how this is altered in the setting of hypertension and heart failure. An essential first step in management in both conditions is optimizing glucocorticoid replacement and considering dose reduction if excessive. Following this, if a patient with Addison's disease remains hypertensive, the fludrocortisone dose should be reviewed and reduced if there are clinical and/or biochemical signs of mineralocorticoid excess. In the absence of such signs, where the renin is towards the upper end of the normal range or elevated, an angiotensin II (AII) receptor antagonist or angiotensin converting enzyme (ACE) inhibitor is the treatment of choice, and the fludrocortisone dose should remain unchanged. Dihydropyridine calcium channel blockers are clinically useful as second line agents, but diuretics should be avoided. In the setting of heart failure, there is an increase in total body sodium and water; therefore, it is appropriate to reduce and rarely consider ceasing the fludrocortisone. Loop diuretics may be used, but not aldosterone antagonists such as spironolactone or eplerenone. Standard treatment with ACE inhibitors, or as an alternative, AII receptor antagonists, are appropriate. Measurements of renin are no longer helpful in heart failure to determine the volume status but plasma levels of brain natriuretic peptide (BNP/proBNP) may help guide therapy.
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Aldosterone is known to have multiple adverse cardiovascular effects that are reminiscent of but independent from angiotensin II. These effects include endothelial dysfunction, heightened thrombogenicity, inflammation, and reparative fibrosis, and have been described in experimental and human models of aldosterone excess. Recently a number of clinical investigations have demonstrated that mineralocorticoid receptor (MR) antagonism, even in conditions not traditionally associated with systemic activation of the renin-angiotensin II-aldosterone pathway, may provide additional benefits above and beyond angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockade. The Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS) with eplerenone in patients who were post-myocardial infarction underscores the additive benefit of such a strategy in post-infarction patients that typify an at-risk population for recurrent cardiovascular events. The mechanisms operative in acute coronary syndromes (ACS), including inflammation, altered hemostasis, and endothelial dysfunction, overlap significantly with those seen in the EPHESUS patient population. One may therefore hypothesize that MR antagonism with eplerenone may be beneficial in patients with ACS. Another advantage of using eplerenone is that it offers the advantages of MR antagonism without the side effects due to blockade of other nuclear receptors such as the androgen and progesterone receptors. If MR blockade is found to be beneficial in patients with ACS, the potential reduction in morbidity, mortality, and health care costs are profound.
Transcription from the HIV promoter is regulated by the combined activities of the host transcription machinery and the viral transactivator Tat protein. Here, we report that the drug spironolactone-an antagonist of aldosterone-blocks viral Tat-dependent transcription, thereby inhibiting both HIV-1 and HIV-2 infection of permissive T cells. This inhibition relies on the degradation of the cellular helicase XPB, a component of the TFIIH transcription factor complex. Consequently, XPB appears to be a novel HIV cofactor. Our discovery of the HIV-inhibitory activity of spironolactone opens the way for the development of novel anti-HIV strategies targeting a cellular cofactor without the limitations of antiretroviral therapy of drug resistance and high cost.
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A significant correlation was found between age and interstitial fibrosis. A significant inverse correlation was found between left ventricular diastolic diameter (LVDd) in echocardiographic data and interstitial fibrosis. There were no other significant relation between histopathological scores and clinical findings.
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A discharge prescription for spironolactone had no association with 30-day all-cause readmission among older, hospitalized Medicare beneficiaries with HFrEF eligible for spironolactone therapy.
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To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker.
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Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
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The purpose of revising the 1995 ACC/AHA guidelines was to incorporate recent advances in pharmacological and nonpharmacological approaches to HF treatment and to assist physicians in clinical decision-making in the management of HF.
Exposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 μmol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 μmol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 μmol/L HDC (15%, P = 0.04), 10 μmol/L DEX (53%, P < 0.01), 0.2 μmol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation.
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The subjects ranged in age from 11 to 52 years. The average daily KCl and spironolactone dose was 3.3 +/- 1.5 mEq/kg and 3.5 +/- 1.2 mg/kg, respectively, and this regimen resulted in an increase in serum K(+) from 4.0 +/- 0.3 to 5.2 +/- 0.3 mEq/l. There were no serious complications associated with therapy. The increase in serum K(+) resulted in a decrease in the corrected QT interval from 526 +/- 94 to 423 +/- 36 ms (mean +/- SD; lead V(2)). Both QT dispersion and T-wave morphology improved in most subjects.
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Results on the subcellular localization of the mineralocorticoid receptor (MR) have been controversial. To determine the subcellular distribution and trafficking of the MR in living cells after binding of agonists and antagonists, we expressed a MR-green fluorescent protein (GFP) chimera in mammalian cells lacking endogenous MR. The GFP-tagged MR (GFP-MR) remained transcriptionally active, as determined in cotransfection experiments with the MR-responsive reporter, TAT3-LUC. The subcellular localization of GFP-MR was monitored by fluorescence time-lapse microscopy. In the absence of hormone, MR was present both in the cytoplasm and nucleus. Aldosterone induced a rapid nuclear accumulation of the MR. Aldosterone-bound GFP-MR was concentrated in prominent clusters within the nucleus, whereas GFP-MR did not form clusters in the absence of hormone. Similar subnuclear distribution was observed with corticosterone, another MR agonist. In the presence of the MR antagonists spironolactone or ZK91587 the rate of nuclear translocation was significantly slower and the final nuclear-to-cytoplasmic ratio in steady state was significantly lower than with aldosterone. In addition, MR antagonists did not induce formation of nuclear GFP-MR clusters. MR antagonists also were able to disrupt pre-existing nuclear clusters formed in the presence of aldosterone. GFP-MR clusters were retained in nuclear matrix preparations after in vivo crosslinking. These data strongly suggest that hormone-activated MRs accumulate in dynamic discrete clusters in the cell nucleus, and this phenomenon occurs only with transcriptionally active mineralocorticoids.
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Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial Na(+) channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for beta- and gamma-ENaC, whereas alpha-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a glucocorticoid receptor antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA. We conclude that Na(+) movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the beta- and gamma-subunits of ENaC. ENaC expression and activity could account for the low Na(+) concentration that is typical of milk.
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Evaluate heart failure management in a Military Hospital in 2005.
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Our study showed that a guideline-based management program for patients with heart failure at discharge improves quality of life and reduces readmission for DRG 127 and total bed days, allowing relevant cost savings.
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Aldosterone antagonists inhibit the fibrosis-induced NOX4 protein expression in rat hepatic cells.