eplerenone and Cardiac-Output--Low

Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setting. However, lack of practical experience with aldosterone blockade may make clinicians hesitant to use these therapies. This review is based on a consensus cardiology conference that occurred in May 2005 (New York City) concerning these topics. Potential barriers to the use of aldosterone blockade are discussed and an algorithm for appropriate in-hospital pharmacologic management of AMI with LVSD and/or HF is presented.

Topics: Algorithms; Cardiac Output, Low; Eplerenone; Humans; Hyperkalemia; Hypotension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Risk Factors; Spironolactone; Systole; Ventricular Dysfunction, Left

Topics: Aldosterone; Animals; Cardiac Output, Low; Cardiovascular Diseases; Eplerenone; Humans; Inflammation; Metaphor; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Topics: Aged; Cardiac Output, Low; Clinical Trials as Topic; Eplerenone; Humans; Male; Mineralocorticoid Receptor Antagonists; Spironolactone

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiac Output, Low; Chronic Disease; Death, Sudden, Cardiac; Drug Therapy, Combination; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renin-Angiotensin System; Spironolactone; Treatment Outcome

Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).. Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl. The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Drug Synergism; Eplerenone; Hypertension; Indoles; Kidney; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Spironolactone; Superoxide Dismutase; Transforming Growth Factor beta

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11beta-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Topics: Aldosterone; Animals; Cardiac Output, Low; Cardiomegaly; Cardiotonic Agents; Coronary Vessels; Corticosterone; Echocardiography; Eplerenone; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Osmolar Concentration; Oxidative Stress; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; Renin; RNA, Messenger; Spironolactone; Vasculitis; Ventricular Function; Ventricular Remodeling

Topics: Aldosterone; Animals; Cardiac Output, Low; Cardiomegaly; Cardiotonic Agents; Corticosterone; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Renin; Spironolactone; Ultrasonography

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor kappaB (NF-kappaB) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-kappaB, protein kinase CbetaII, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca(2+)-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.

Topics: Animals; Cardiac Output, Low; Cardiotonic Agents; Drug Interactions; Echocardiography; Elasticity; Eplerenone; Heart; Male; Mineralocorticoid Receptor Antagonists; Mitogen-Activated Protein Kinases; Myocardial Contraction; Myocardium; NADPH Oxidases; NF-kappa B; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Dahl; Scavenger Receptors, Class E; Spironolactone; Superoxides; Systole; Ventricular Remodeling

Topics: Aldosterone; Cardiac Output, Low; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone