Showing papers on "Spironolactone published in 2001"
TL;DR: A review article gives an in-depth update on the mechanisms of action of aldosterone and their implications for therapy and underscores the value of a Aldosterone-receptor antagonists, such as spironolactone, in the treatment of chronic heart failure.
Abstract: The potent mineralocorticoid aldosterone has a multifaceted role in the pathogenesis of congestive heart failure. In addition to its contribution to salt and water retention, it also promotes organ fibrosis. Although angiotensin-converting–enzyme inhibitors have important therapeutic benefit in heart failure, they do not eliminate the effects of aldosterone. Thus, recent studies have underscored the value of aldosterone-receptor antagonists, such as spironolactone, in the treatment of chronic heart failure. This review article gives an in-depth update on the mechanisms of action of aldosterone and their implications for therapy.
660 citations
TL;DR: Findings indicate that four months of treatment with spironolactone improved the left ventricular volume and mass, as well as decreased plasma level of BNP, a biochemical marker of prognosis and/or ventricular hypertrophy, suggesting that endogenous aldosterone has an important role in the process ofleft ventricular remodeling in nonischemic patients with CHF.
358 citations
TL;DR: If the hypothesis being tested in the EPHESUS trial proves correct, eplerenone has the potential to be used in a broad population to prevent progressive left ventricular remodeling, ventricular fibrosis, malignant arrhythmias, non-fatal AMI, and sudden cardiac death.
Abstract: The importance of aldosterone in the pathophysiology of chronic heart failure (HF) has been established in previous studies [1–4] and is emphasized by the findings of the RALES trial [5]. In this study, aldosterone blockade with spironolactone resulted in a 30% reduction in total mortality and a 35% reduction in hospitalizations for HF in patients with pre-existing chronic severe HF. Patients in the RALES trial also received standard therapy including an ACE inhibitor (if tolerated), a loop diuretic, and digoxin. While aldosterone receptor blockade has been proven beneficial in severe chronic HF due to systolic left ventricular (LV) dysfunction, its effects in patients with acute myocardial infarction (AMI) complicated by HF due to systolic left ventricular dysfunction are unknown. The pathophysiology of HF complicating AMI is complex. Factors such as the acute release of catecholamines, activation of the renin angiotensin aldosterone system, degree of ventricular remodeling, myocardial scar formation, extent of coronary artery disease, and residual ischemia may differ both quantitatively and qualitatively in patients with acute infarction compared to patients with chronic HF. Additionally, the extent of activation of cytokines, fibrinolytic balance, and activity of clotting factors may differ. Eplerenone was chosen for this study because of its demonstrated efficacy in an experimental model of AMI [6]. In clinical trials, eplerenone demonstrated efficacy similar to spironolactone in blocking aldosterone receptors, lowering blood pressure, and moderating hormonal and neurohormonal markers of HF [7,8]. However, eplerenone has significantly less affinity for androgen and progesterone receptors and should therefore be associated with a lower incidence of gynecomastia, breast pain and impotency in males, and diminished libido and menstrual irregularities in females [9–11]. While older patients suffering from refractory HF may tolerate these androgenic and progestational side effects, they may preclude widespread use of a nonspecific aldosterone antagonist in younger patients or in patients with less severe cardiac compromise. Since eplerenone is at least 100 times more specific in its affinity for aldosterone receptors than is spironolactone, if the hypothesis being tested in the EPHESUS trial proves correct, eplerenone has the potential to be used in a broad population to prevent progressive left ventricular remodeling, ventricular fibrosis, malignant arrhythmias, non-fatal AMI, and sudden cardiac death. We hypothesize that selective aldosterone receptor blockade with eplerenone will have a beneficial effect on survival and morbidity in patients with AMI complicated by HF due to systolic left ventricular dysfunction. This paper describes the background, design, and organization of a trial to test this hypothesis—the EPHESUS trial (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study).
349 citations
TL;DR: A combination of ACE inhibitors and spironolactone should be considered with caution and monitored closely in patients with renal insufficiency, diabetes, older age, worsening heart failure, a risk for dehydration, and in combination with other medications that may cause hyperkalemia.
246 citations
TL;DR: To the Editor: Angiotensin-converting–enzyme (ACE) inhibitors have been shown to reduce proteinuria and slow the progression of renal disease.
Abstract: To the Editor: Angiotensin-converting–enzyme (ACE) inhibitors have been shown to reduce proteinuria and slow the progression of renal disease.1 Although to date angiotensin II has been the focus of...
239 citations
TL;DR: This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome and demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifEPristone-treated Cushing’s disease.
Abstract: An extremely ill patient, with Cushing’s syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg·d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient’s heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with...
219 citations
TL;DR: Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes, and spironOLactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II.
Abstract: Background — The cardiac renin-angiotensin-aldosterone system is activated in failing hearts in proportion to the severity of the disease. We hypothesized that a positive feedback mechanism might exist within this system and contribute to the progression of the heart failure.
Methods and Results — To test this hypothesis, we examined whether angiotensin II or aldosterone induces the expression of angiotensin-converting-enzyme (ACE) mRNA in cultured neonatal rat ventricular cardiocytes. Expression of ACE mRNA was detected and quantified using real-time reverse transcription-polymerase chain reaction. Exposure to angiotensin II (10−5 mol/L) for 24 hours had no significant effect on the expression of ACE mRNA (0.7±0.5-fold versus control, P =NS), but similar treatment with aldosterone (10−5 mol/L) induced a 23.3±7.9-fold increase ( P <0.01) in ACE mRNA expression. The effect of aldosterone was both time- (maximal effect, 24 hours) and dose-dependent (EC50, 4×10−7 mol/L), and it was significantly ( P <0.01) inhibited by spironolactone, a specific mineralocorticoid receptor antagonist.
Conclusions — Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. Thus, spironolactone may suppress the progression of heart failure by blocking the effects of aldosterone and angiotensin II.
Received February 23, 2001; revision received May 1, 2001; accepted May 15, 2001.
212 citations
TL;DR: Spironolactone is a safe, effective therapy for patients with refractory hypertension and the mean number of antihypertensive drugs required per patient was significantly reduced by 3 months after the introduction of the drug.
208 citations
TL;DR: Short‐term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ‐diabetic rats.
Abstract: Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. Streptozotocin (65 mg kg(-1) i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg(-1) day(-1) as 0.2 - 2g 1(-1) drinking water) or spironolactone (50 mg kg(-1) day(-1) s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ-diabetic rats. Passive diastolic stiffness increased in isolated hearts from STZ-diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dt(max) of STZ-diabetic hearts. Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ-treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ-diabetic rats.
195 citations
TL;DR: Limiting the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.
Abstract: Cardiac extracellular matrix undergoes extensive and continuous turnover involved in the lesion-reparation process, such as in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, after myocardial infarction in the transition to heart failure, and during the progression of left ventricular dysfunction. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenicity, thus potentially contributing the to progression of heart failure and sudden death. Aldosterone was shown to promote cardiac fibrosis in various experimental models. It was demonstrated that spironolactone may oppose the effect of aldosterone in promoting cardiac fibrosis. Measurement of cardiac collagen turnover by use of serological markers is a useful tool for monitoring cardiac tissue repair and fibrosis in experimental models or clinical conditions. We found that high serum levels of a marker of collagen turnover (procollagen type III N-terminal peptide ) in patients with chronic heart failure receiving conventional therapy, including ACE inhibitors, was associated with high mortality and hospitalization rates. In RALES (Randomized Aldactone Evaluation Study), in patients randomized to placebo, markers continued to increase or remained unchanged after 6-month follow-up. On the contrary, adding spironolactone 25 mg daily significantly decreased the levels of these serum markers during the same period. Most importantly, the spironolactone-related morbidity and mortality benefit was most predominant in subgroups with highest baseline levels of serum markers. These results suggest that limitation of the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.
168 citations
TL;DR: Spironolactone reduced heart rate and improved HRV and QT dispersion in CHF and had favorable autonomic effects, which were limited to the morning, including heart rate reduction and an improvement in HRV.
TL;DR: Support of patients with acute left ventricular failure caused by myocarditis should be aggressive, to allow for the possibility of spontaneous recovery, and contemporary trials of treatment in chronic heart failure secondary to dilated cardiomyopathy support the use of angiotensin converting enzyme inhibitors, β adrenoceptor blockers, and spironolactone in such patients.
Abstract: 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, β adrenoceptor blockers, and spironolactone in such patients.
TL;DR: It is suggested that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.
Abstract: The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.
TL;DR: Eplerenone attenuates constrictive remodeling after coronary artery angioplasty by mechanisms involving reduction in collagen accumulation, which thus appears to be an important contributor to constrictives remodeling of angioplastied coronary arteries.
Abstract: Background Coronary artery angioplasty triggers healing that causes constrictive remodeling. Because collagen accumulation correlates with constrictive remodeling and aldosterone has been implicated in collagen accumulation, we examined how aldosterone and the mineralocorticoid receptor antagonists spironolactone and eplerenone affect remodeling and collagen in porcine coronary and iliac arteries after angioplasty. Methods and Results Twenty-four pigs were allocated into 4 treatment groups: oral eplerenone (100 mg/d), oral spironolactone (200 mg/d), subcutaneous aldosterone (400 μg/d), or no treatment. Twenty-eight days after angioplasty of the coronary arteries, eplerenone increased total vessel area by 30% (P<0.05) and luminal area by nearly 60% (P<0.05) compared with the no-treatment group, without affecting neointima size. These effects were accompanied by a 65% reduction in neointimal and medial collagen density (both P<0.05). Spironolactone was less effective, and aldosterone tended to exert opposit...
TL;DR: Results show that in old normotensive rats, spironolactone can markedly prevent cardiac and, to a lesser extent, arterial fibrosis and improve arterial stiffness, despite a lack of hypotensive effect.
TL;DR: A variety of biochemical, hemodynamic, functional, electrophysiologic, and demographic risk factors are examined and their relative value for predicting the outcome in patients with heart failure is assessed.
TL;DR: This study investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF, finding that at 6 months, markers decreased in the spironOLactone group but remained unchanged in the placebo group.
Abstract: Background—In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF. Methods and Results—A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP >3.85 μg/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome...
TL;DR: Spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.
Abstract: Remodeling of the cerebral vasculature contributes to the pathogenesis of cerebral ischemia. Remodeling is caused by increased smooth muscle proliferation and may be due to an increase in the responsiveness of vascular cells to epidermal growth factor (EGF). Aldosterone is a risk factor for stroke, and the literature suggests it may play a role in increasing the expression of the receptor for EGF (EGFR). We hypothesized that mRNA for the EGF-stimulated pathway would be elevated in the vasculature of stroke-prone spontaneously hypertensive rats (SHRSP) and that this and experimental ischemic cerebral infract size would be reduced by aldosterone inhibition with spironolactone. We found that spironolactone treatment reduced the size of cerebral infarcts after middle cerebral artery occlusion in SHRSP (51.69 ± 3.60 vs. 22.00 ± 6.69% of hemisphere-infarcted SHRSP vs. SHRSP + spironolactone P < 0.05). Expression of EGF and EGFR mRNA was higher in cerebral vessels and aorta from adult SHRSP compared with Wistar-Kyoto rats. Only the expression of EGFR mRNA was elevated in the young SHRSP. Spironolactone reduced the EGFR mRNA expression in the aorta (1.09 ± 0.25 vs. 0.56 ± 0.11 phosphorimage units SHRSP vs. SHRSP + spironolactone P < 0.05) but had no effect on EGF mRNA. In vitro incubation of aorta with aldosterone ± spironolactone produced similar results, suggesting a direct effect of aldosterone. Thus spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.
TL;DR: Aldosterone receptor antagonism does not retard infarct healing but rather protects against maladaptive responses after MI, where reactive fibrosis in the viable myocardium was reduced in eplerenone-treated animals compared with vehicle- treated animals.
Abstract: Myocardial infarction (MI) initiates adaptive tissue remodeling, which is essential for heart function (such as infarct healing) but is also important for maladaptive remodeling (for example, reactive fibrosis and left ventricular dilation). The effect of aldosterone receptor antagonism on these processes was evaluated in Sprague-Dawley rats using eplerenone, a selective aldosterone receptor antagonist. Infarct healing and left ventricular remodeling were evaluated at 3, 7, and 28 days after MI by determination of the diastolic pressure-volume relationship of the left ventricle, the infarct-thinning ratio, and the collagen-volume fraction. Eplerenone did not affect reparative collagen deposition as was evidenced by a similar collagen volume fraction in the infarcted myocardium between eplerenone and vehicle-treated groups at 7 and 28 days post-MI. In addition, the thinning ratio, which is an index of infarct expansion, was comparable between the eplerenone and vehicle-treated animals at 7 and 28 days post-MI. A protective effect of eplerenone was demonstrated at 28 days post-MI, where reactive fibrosis in the viable myocardium was reduced in eplerenone-treated animals compared with vehicle-treated animals. Thus aldosterone receptor antagonism does not retard infarct healing but rather protects against maladaptive responses after MI.
TL;DR: The results of the present study provide further evidence for the mineralocorticoid actions of cortisol in freshwater fish, specifically in eliciting chloride cell proliferation, and support the hypothesis that distinct glucocortioid and mineraloc Corticoid receptor populations are present in teleost fish, despite the apparent absence of the classic mineralocortsicoid hormone, aldosterone.
Abstract: Fish acclimated to ion-deficient water exhibit proliferation of branchial chloride cells. The objective of the present study was to investigate the role of cortisol in this response using the corticosteroid receptor antagonists RU486 and spironolactone. RU486 is a potent antagonist of the glucocorticoid actions of cortisol, whereas spironolactone exhibits high-affinity binding to mineralocorticoid receptors, with a resulting blockade of mineralocorticoid properties in mammals. Untreated rainbow trout, as well as rainbow trout given a single intraperitoneal implant of coconut oil alone, coconut oil containing RU486 (0.5 mg g(-1)) or coconut oil containing spironolactone (0.1 mg g(-1)), were exposed to either dechlorinated city-of-Ottawa tapwater or artificial softwater for 7 days. Neither corticosteroid antagonist nor acclimation condition affected circulating plasma cortisol levels, plasma ion concentrations or gill Na(+)-K(+)-ATPase activity. Kidney Na(+)-K(+)-ATPase activity was significantly higher in softwater-acclimated fish than in fish held in dechlorinated tapwater. In addition, whereas RU486 treatment was found to be without effect on gill morphometrics, treatment with spironolactone inhibited the proliferation of chloride cells normally associated with acclimation to ion-deficient water. The results of the present study provide further evidence for the mineralocorticoid actions of cortisol in freshwater fish, specifically in eliciting chloride cell proliferation. Furthermore, these results support the hypothesis that distinct glucocorticoid and mineralocorticoid receptor populations are present in teleost fish, despite the apparent absence of the classic mineralocorticoid hormone, aldosterone.
TL;DR: This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11&bgr;-HSD2–deficient hypertension.
Abstract: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11beta-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days. From days 8 to 21, spironolactone (5.8+/-0.6 mg. kg(-1). d(-1)), eplerenone (182+/-13 mg. kg(-1). d(-1)), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142+/-8 to 185+/-9 mm Hg (P<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73+/-6% versus 99+/-5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11beta-HSD2-deficient rats, eNOS protein content and nitrate tissue levels decreased (1114+/-128 versus 518+/-77 microgram/g protein, P<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308+/-38 versus 497+/-47 pg/mg tissue, P<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142+/-9 and 143+/-9 mm Hg, respectively, versus 189+/-8 mm Hg in the placebo group; P<0.01), restored endothelium-dependent relaxation (96+/-3% and 97+/-3%, respectively, P<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11beta-HSD2-deficient hypertension.
TL;DR: Experimental studies on uninephrectomized rats given 0.9% NaCl solution to drink show blood pressure elevation via activation of circumventricular mineralocorticoid receptors in the central nervous system and production of pressure‐independent cardiac hypertrophy and fibrosis by a direct effect on the heart.
Abstract: 1. Over the past decade, aldosterone has been shown to have direct extra-epithelial actions and substantial (patho)physiological roles in the cardiovascular system in the context of inappropriate salt status. In experimental studies on uninephrectomized rats given 0.9% NaCl solution to drink, these include blood pressure elevation via activation of circumventricular mineralocorticoid receptors in the central nervous system and production of pressure-independent cardiac hypertrophy and fibrosis by a direct effect on the heart. 2. In the Randomized Aldactone Evaluation Study (RALES) trial, patients with severe congestive heart failure (CHF) were continued on their current therapy (angiotensin-converting enzyme inhibitor, diuretic etc.) and given either placebo or spironolactone at an average dose of 26 mg/day. Mineralocorticoid receptor inhibition was accompanied by a 30% improvement in mortality and 35% less hospitalization, striking confirmation of a pathophysiological role for aldosterone in CHF. 3. Although the current basic and clinical studies are conflicting, there is evidence both for aldosterone synthesis by the failing human heart and for substantial cardiac metabolism of aldosterone. The extent to which this potential paracrine source for aldosterone may be involved in cardiac hypertrophy and cardiac fibrosis remains to be established. 4. Belatedly, aldosterone-induced proteins (e.g. serum and glucocorticoid-regulated kinase (SGK)) have been identified in epithelial mineralocorticoid target tissue. Studies are currently in progress on the cellular and molecular mechanisms involved in the coronary vasculitis provoked early in the mineralocorticoid/salt model, which, in turn, appears to trigger the subsequent perivascular and interstitial fibrotic response.
TL;DR: New preclinical data generated over the past few years strongly support the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells.
TL;DR: Four cases involving men with New York Heart Association functional class III heart failure are presented, and close monitoring of blood chemistry is mandatory after starting spironolactone, and patients should be advised to stop spironOLactone immediately if diarrhoea develops.
Abstract: In patients with chronic heart failure, spironolactone added to conventional treatment may lead to serious and, occasionally, fatal hyperkalaemia. In some cases this seems to happen because spironolactone causes diarrhoea. Four cases involving men with New York Heart Association functional class III heart failure are presented. As these cases revealed, close monitoring of blood chemistry is mandatory after starting spironolactone, and patients should be advised to stop spironolactone immediately if diarrhoea develops.
TL;DR: Among the most intriguing effects of aldosterone are its impact on fibrosis and activity associated with a cell surface receptor in certain target tissues, including endothelial cells, which contribute substantially to the pathophysiology of congestive heart failure, as well as progressive renal dysfunction.
Abstract: Aldosterone is a major regulator of extracellular fluid volume and the principal determinant of potassium metabolism 1,2,3,4,5. These effects are mediated by the binding of aldosterone to the mineralocorticoid receptor in target tissues, primarily the kidney. Volume is regulated through a direct effect on the collecting duct, where aldosterone promotes sodium retention and potassium excretion. The reabsorption of sodium ions produces a fall in the transmembrane potential, thus enhancing the flow of positive ions (such as potassium) out of the cell into the lumen. The reabsorbed sodium ions are transported out of the tubular epithellium into the renal interstitial fluid and from there into the renal capillary circulation.
Three primary mechanisms control aldosterone release—the renin-angiotensin system, potassium, and adrenocorticotropic hormone. The renin-angiotensin system controls extracellular fluid volume via regulation of aldosterone secretion. In effect, the renin-angiotensin system keeps the circulating blood volume constant by causing aldosterone-induced sodium retention during volume deficiency and by decreasing aldosterone-dependent sodium retention when volume is ample.
In recent years there has been a radical shift in our view of aldosterone's effects on the heart, the vasculature and the kidney6,7,8,9. Aldosterone's endocrine properties have taken on a broader perspective, involving non-classic actions in non-epithelial cells found in non-classic target tissues6, 10,11,12,13,14,15. The traditional concept, that aldosterone is synthesized only in the adrenal glomerulosa cell and acts almost exclusively on the kidney to modify sodium and potassium homoeostasis, needs to be expanded. There is increasing evidence that aldosterone can have an effect on vascular remodelling and collagen formation, and a non-genomic action to modify endothelial function. Among the most intriguing effects of aldosterone are its impact on fibrosis and activity associated with a cell surface receptor in certain target tissues, including endothelial cells 6, 7, 16,17,18,19. These actions contribute substantially to the pathophysiology of congestive heart failure (CHF), as well as progressive renal dysfunction. This new information has increased interest in the development of an antagonist to block aldosterone's effect, not just because of its diuretic action but primarily because of its potential cardiovascular and renal protective effects.
In this review I consider the broad spectrum of non-genomic effects of aldosterone. It is becoming increasingly evident that these effects, occurring independently of haemodynamic factors, contribute to enhanced cardiovascular risk manifested by congestive heart failure and progressive renal disease. I also discuss the clinical trials with selective aldosterone receptor antagonists that are currently underway in patients with left ventricular hypertrophy, essential hypertension and systolic hypertension, and in those who have experienced myocardial infarction. Such trials will enhance our understanding of the role of aldosterone in the pathophysiology of cardiovascular disease. Also, selective aldosterone receptor antagonism holds promise for a reduction in cardiovascular and renal disease morbidity and mortality, and for enhancement of patient wellbeing.
TL;DR: Management is directed at prevention, retarding disease progression, relief of symptoms and prolonging survival, and surgical approaches in highly selected patients may include myocardial revascularisation, insertion of devices and cardiac transplantation.
Abstract: Chronic heart failure (CHF) affects approximately 1% of people aged 50-59 years, and this high prevalence increases dramatically with age. CHF is a common reason for hospital admission and general practitioner consultation in the elderly. Common causes of CHF are ischaemic heart disease, hypertension and idiopathic dilated cardiomyopathy. Diagnosis of CHF is based on clinical features and objective measurement of ventricular function (eg, echocardiography). Management is directed at prevention, retarding disease progression, relief of symptoms and prolonging survival. Non-pharmacological approaches include exercise, home-based support and risk-factor modification. Angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of pharmacological therapy to prevent disease progression and prolong survival. beta-Blockers prolong survival when added to ACE inhibitors in symptomatic patients. Diuretics provide symptom relief and restoration or maintenance of euvolaemia. Spironolactone, angiotensin II receptor antagonists and digoxin may be useful in some patients. Surgical approaches in highly selected patients may include myocardial revascularisation, insertion of devices and cardiac transplantation.
TL;DR: Clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure.
Abstract: Until recently, spironolactone was considered only as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was used clinically in the treatment of hyperaldosteronism and, occasionally, as a K(+)-sparing diuretic. The spironolactone renaissance started with the experimental finding that spironolactone reversed aldosterone-induced cardiac fibrosis by a cardiac action. Experimentally, spironolactone also has direct effects on blood vessels. Spironolactone reduces vascular fibrosis and injury, inhibits angiogenesis, reduces vascular tone and reduces portal hypertension. The rationale for the Randomized Aldactone Evaluation Study (RALES) of spironolactone in heart failure was that 'aldosterone escape' occurred through non-angiotensin II mechanisms. The RALES clinical trial was stopped early when it was shown that there was a 30% reduction in risk of death among the spironolactone patients. In RALES, spironolactone also reduced hospitalisation for worsening heart failure and improved the symptoms of heart failure. Other recent clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure. Spironolactone may also be useful in the treatment of left ventricular hypertrophy, portal hypertension and cirrhosis. There have also been some recent small clinical trials of spironolactone as an anti-androgen showing potential in acne, hirsutism and precocious puberty.
TL;DR: A combination of ACE inhibitors and spironolactone should be considered with caution and monitored closely in patients with renal insufficiency, diabetes, older age, worsening heart failure, a risk for dehydration, and in combination with other medications that may cause hyperkalemia.
TL;DR: An unusual tumor associated with ectopic ACTH and CRH production is described and the pharmacodynamic relationship of plasma cortisol levels and urinary cortisol excretion with ketoconazole treatment is described.
TL;DR: The findings suggest that the 2 drugs with different modes of action—amiloride, a direct inhibitor of ENaC, and spironolactone, a mineralocorticoid receptor antagonist—may compliment each other’s ability to inhibit EN aC and thereby reduce sodium reabsorption to a point at which BP decreases.
Abstract: The epithelial sodium channel (ENaC) is a principal site for sodium reabsorption and as such may participate importantly in blood pressure (BP) regulation. Amiloride, a direct inhibitor of ENaC, characteristically has mild antihypertensive properties, consistent with ENaC having more minor influences on BP regulation. Counter-regulatory influences may, however, prevent amiloride from effectively lowering BP. Aldosterone secretion is known to increase in response to the reduced sodium reabsorption that follows amiloride inhibition of ENaC, and because aldosterone upregulates ENaC function, we considered the possibility that secondary hyperaldosteronism mitigates the ability of amiloride to reduce BP. In the present study, the BP responses to amiloride (5 mg per day), spironolactone (25 mg per day), the combination of the 2 drugs, and placebo were studied in healthy normotensive subjects. Over 4 weeks of treatment, the combination of amiloride and spironolactone lowered systolic BP by 4.6±1.6 (mean±SEM) mm Hg ( P =0.022) and diastolic BP by 2.2±1.2 mm Hg ( P =0.30), whereas either drug alone had no significant effect on BP. The findings suggest that the 2 drugs with different modes of action—amiloride, a direct inhibitor of ENaC, and spironolactone, a mineralocorticoid receptor antagonist—may compliment each other’s ability to inhibit ENaC and thereby reduce sodium reabsorption to a point at which BP decreases. On the other hand, we cannot rule out that the BP response resulted from the greater dose of total drug. The lowering of BP with small doses of inhibitors of ENaC serves as additional evidence for the importance of ENaC to the tonic maintenance of BP.