Showing papers on "Spironolactone published in 2009"

Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

Abstract: Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial.

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

Abstract: Myocardial ischemia-reperfusion leads to significant changes in redox state, decreased postischemic functional recovery, and cardiomyocyte apoptosis, with development and progression of heart failure. Ischemia-reperfusion in the isolated perfused rat heart has been used as a model of heart failure. Clinically, mineralocorticoid receptor blockade in heart failure decreases morbidity and mortality versus standard care alone. The effects of corticosteroids on infarct area and apoptosis were determined in rat hearts subjected to 30 minutes of ischemia and 2.5 hours of reperfusion. Both aldosterone and cortisol increased infarct area and apoptotic index, an effect half-maximal between 1 and 10 nM and reversed by spironolactone. Dexamethasone and mifepristone aggravated infarct area and apoptotic index, similarly reversed by spironolactone. Spironolactone alone reduced infarct area and apoptotic index below ischemia-reperfusion alone, in hearts from both intact and adrenalectomized rats. The present study shows that cardiac damage is aggravated by activation of mineralocorticoid receptors by aldosterone or cortisol or of glucocorticoid receptors by dexamethasone. Mifepristone unexpectedly acted as a glucocorticoid receptor agonist, for which there are several precedents. Spironolactone protected cardiomyocytes via inverse agonist activity at mineralocorticoid receptors, an effect near maximal at a relatively low dose (10 nM). Spironolactone acts not merely by excluding corticosteroids from mineralocorticoid receptors but as a protective inverse agonist at low concentration. Mineralocorticoid receptor antagonists may, thus, provide an additional therapeutic advantage in unstable angina and acute myocardial infarction.

Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne

Abstract: Background Hirsutism is the presence of excessive hair growth in women and is an important cosmetic condition often resulting in severe distress. The most common cause is by increased production of male sex hormones (androgens). It is also affected by increased sensitivity to androgens in the hair follicles, and secretory glands around hair follicles (sebaceous glands). Spironolactone is an antiandrogen and aldosterone antagonist used to treat hirsutism. Objectives The objective was to investigate the effectiveness of spironolactone and/or in combination with steroids (oral contraceptive pill included) in reducing excess hair growth and/or acne in women. Search methods The Cochrane Menstrual Disorders and Subfertility Group (MDSG) trials register was searched (April 2008). The Cochrane MDSG register is based on regular searches of MEDLINE, EMBASE, CINAHL, PsycINFO and CENTRAL, handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. In addition, all reference lists of relevant trials were searched and drug companies contacted for details of unpublished trials. Selection criteria All randomised controlled comparisons of spironolactone versus: placebo, steroids (oral contraceptive pill included), spironolactone of varying dosages, or spironolactone and steroids versus steroids alone when used to reduce hair growth and acne in women. Data collection and analysis Nine trials were included in the review, eight trials were excluded. Two other trials are awaiting assessment. Only one trial studied acne as an outcome, the remainder were concerned with hirsutism. Major outcome measures include the following: subjective observations, Ferriman and Gallwey hair scores, hormonal and biochemical parameters, side effects, sebum production measurement. Main results In the two trials that compared 100 mg of spironolactone with placebo significant differences were reported for subjective improvements in hair growth (OR 7.18, 95% CI 1.96 to 26.28), although not the Ferriman-Galwey score (MD 7.20, 95% CI -10.98 to -3.42)). Data could not be otherwise pooled as only one trial reported an outcome. Authors' conclusions From the studies included in this review, there is some evidence to show that spironolactone is an effective treatment to decrease the degree of hirsutism but there was no evidence for effectiveness for the treatment of acne vulgaris. Studies in this area are scarce and small. Individual study data indicates some superiority of spironolactone over other drugs but results cannot be generalised.

Predictors of hyperkalemia risk following hypertension control with aldosterone blockade.

Abstract: Background: Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction; however, they are not widely used due to risk of hyperka

Reconsidering the Roles of the Mineralocorticoid Receptor

Abstract: Translational research is usually taken to mean the application of laboratory discovery to clinical practice Like languages or enzymes, however, translation is a 2-way street, and in the field of aldosterone and mineralocorticoid receptors (MR), there are a number of examples where clinical studies have prompted reconsideration of the basic biology For example, in essential hypertensive subjects the distinction between the antihypertensive and electrolyte effects of the selective MR antagonist eplerenone has been interpreted as evidence against a primary renal role for aldosterone/MR activation in raising blood pressure1 Similarly, the finding of an S810L MR mutant receptor causing juvenile hypertension exacerbated by pregnancy2 prompted a reconsideration of the order of branching of the MR/glucocorticoid receptor (GR)/progesterone receptor (PR)/androgen receptor (AR) subfamily of steroid hormone receptors from a common primordial ancestral protein3 These studies and their implications for the basic biology of aldosterone action have been discussed elsewhere4 The present review focuses on the clinical study (Randomized ALdactone Evaluation Study [RALES]5) that prompted this process of re-examination almost a decade ago The rationale for this study, in patients with New York Heart Association class III heart failure, was that previous clinical studies had shown that plasma aldosterone levels could break through prolonged angiotensin-converting enzyme inhibition and angiotensin II type 1 blockade; in addition, early laboratory studies by Brilla and Weber6 had shown that exogenous aldosterone plus normal saline as drinking solution produced cardiac hypertrophy and fibrosis in uninephrectomized rats The outcomes of RALES were remarkable The trial was halted just more than half way through the projected period of recruitment on the basis of the divergence between the 2 groups: 1 treated with standard of care (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, etc) plus placebo and the other with standard of care plus spironolactone …

Sodium Retention in Heart Failure and Cirrhosis Potential Role of Natriuretic Doses of Mineralocorticoid Antagonist

Abstract: Patients with cirrhosis and heart failure (HF) share the pathophysiology of decreased effective arterial blood volume because of splanchnic vasodilatation in cirrhosis and decreased cardiac output in HF, with resultant stimulation of the renin-angiotensin-aldosterone system. Hyperaldosteronism plays a major role in the pathogenesis of ascites and contributes to resistance to loop diuretics. Therefore, the use of high doses of aldosterone antagonist (spironolactone up to 400 mg/day) is the main therapy to produce a negative sodium balance in cirrhotic patients with ascites. Hyperaldosteronism also has increasingly been recognized as a risk factor for myocardial and vascular fibrosis. Therefore, low-dose aldosterone antagonists are being used in patients with HF for cardioprotective action. However, the doses (25 to 50 mg/day) at which they are being used in cardiac patients as reported in the Randomized Aldactone Evaluation Study are not natriuretic. It is likely, therefore, that the mortality benefit relates primarily from their effect on cardiac and vascular fibrosis. Resistance to commonly used loop diuretics is frequently present in patients with advanced HF. In patients with decompensated HF with volume overload who are loop diuretic resistant, ultrafiltration may be the only available option. This is, however, an invasive procedure. For these patients, natriuretic doses of aldosterone antagonists (spironolactone >50 mg/day) may be a potential option. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-angiotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis. This article will discuss the potential use of natriuretic doses of aldosterone antagonists in patients with HF, including the potential side effect of hyperkalemia.

Hypertension of Kcnmb1−/− is linked to deficient K secretion and aldosteronism

Abstract: Mice lacking the β1-subunit (gene, Kcnmb1; protein, BK-β1) of the large Ca-activated K channel (BK) are hypertensive. This phenotype is thought to result from diminished BK currents in vascular smooth muscle where BK-β1 is an ancillary subunit. However, the β1-subunit is also expressed in the renal connecting tubule (CNT), a segment of the aldosterone-sensitive distal nephron, where it associates with BK and facilitates K secretion. Because of the correlation between certain forms of hypertension and renal defects, particularly in the distal nephron, it was determined whether the hypertension of Kcnmb1−/− has a renal origin. We found that Kcnmb1−/− are hypertensive, volume expanded, and have reduced urinary K and Na clearances. These conditions are exacerbated when the animals are fed a high K diet (5% K; HK). Supplementing HK-fed Kcnmb1−/− with eplerenone (mineralocorticoid receptor antagonist) corrected the fluid imbalance and more than 70% of the hypertension. Finally, plasma [aldo] was elevated in Kcnmb1−/− under basal conditions (control diet, 0.6% K) and increased significantly more than wild type when fed the HK diet. We conclude that the majority of the hypertension of Kcnmb1−/− is due to aldosteronism, resulting from renal potassium retention and hyperkalemia.

Advances in Heart Failure Sodium Retention in Heart Failure and Cirrhosis Potential Role of Natriuretic Doses of Mineralocorticoid Antagonist

Abstract: Patients with cirrhosis and heart failure (HF) share the pathophysiology of decreased effective arterial blood volume because of splanchnic vasodilatation in cirrhosis and decreased cardiac output in HF, with resultant stimulation of the renin-angiotensin-aldosterone system. Hyperaldosteronism plays a major role in the pathogenesis of ascites and contributes to resistance to loop diuretics. Therefore, the use of high doses of aldosterone antagonist (spironolactone up to 400 mg/day) is the main therapy to produce a negative sodium balance in cirrhotic patients with ascites. Hyperaldosteronism also has increasingly been recognized as a risk factor for myocardial and vascular fibrosis. Therefore, low-dose aldosterone antagonists are being used in patients with HF for cardioprotective action. However, the doses (25 to 50 mg/day) at which they are being used in cardiac patients as reported in the Randomized Aldactone Evaluation Study are not natriuretic. It is likely, therefore, that the mortality benefit relates primarily from their effect on cardiac and vascular fibrosis. Resistance to commonly used loop diuretics is frequently present in patients with advanced HF. In patients with decompensated HF with volume overload who are loop diuretic resistant, ultrafiltration may be the only available option. This is, however, an invasive procedure. For these patients, natriuretic doses of aldosterone antagonists (spironolactone 50 mg/day) may be a potential option. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-an- giotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis. This article will discuss the potential use of natriuretic doses of aldosterone antagonists in patients with HF, including the potential side effect of hyperkalemia. (Circ Heart Fail. 2009;2:370-376.)

Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial.

Abstract: Aims To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes Methods and results The 6632 patients of the EPHESUS study were randomized from day 3 to 14 after the index AMI (median = 7 days), of these 3319 were assigned to eplerenone We analysed the differential effects of time-to-eplerenone initiation vs placebo, based on the median time to initiation of treatment (<7 days—‘earlier’, ≥7days—‘later’) Effects on outcomes were evaluated over a mean 16-month follow-up, using Cox proportional hazards regression analysis The earlier eplerenone initiation (<7 days) reduced the risk of all-cause mortality by 31% (P = 0001) when compared with the ‘earlier’ placebo’ and also reduced the risks of cardiovascular (CV) hospitalization/CV mortality by 24% (P < 00001) and sudden cardiac death (SCD) by 34% (P < 00001) In contrast, later eplerenone initiation (≥7 days) had no significant effect on outcomes Interactions between time-to-randomization and treatment were significant These associations remained substantially unchanged after risk adjustment in multivariable models Conclusion An earlier eplerenone administration (3–7days) post-AMI improved outcomes in patients with LVSD and HF This benefit was not observed when eplerenone was initiated later (≥7days)

Spironolactone Attenuates Experimental Uremic Cardiomyopathy by Antagonizing Marinobufagenin

Abstract: Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its major metabolite, canrenone (both 100 nM), on marinobufagenin stimulation of rat cardiac fibroblasts. Both spironolactone and canrenone prevented the stimulation of collagen production by 1 nM marinobufagenin but not 100 nM marinobufagenin, as assessed by proline incorporation and procollagen 1 expression, as well as signaling through the sodium-potassium-ATPase, as evidenced by protein kinase C isoform δ translocation and extracellular signal regulated kinase 1/2 activation. Both spironolactone and canrenone also altered ouabain binding to cultured porcine cells in a manner consistent with competitive inhibition. Our data suggest that some of the antifibrotic effects of spironolactone may be attributed to antagonism of marinobufagenin signaling through the sodium-potassium-ATPase.

Hair loss in women.

Abstract: Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a progestogen. Antiandrogens such as cyproterone acetate, always accompanied by tricyclic contraceptives, are the best choice of antiandrogens to use in patients with FPHL. Gonadotropin-releasing hormone agonists such as leuprolide acetate suppress pituitary and gonadal function through a reduction in luteinizing hormone and follicle-stimulating hormone levels. Subsequently, ovarian steroid levels also will be reduced, especially in patients with polycystic ovary syndrome. When polycystic ovary syndrome is associated with insulin resistance, metformin must be considered as treatment. Hyperprolactinemic SAHA and alopecia of pituitary hyperandrogenism should be treated with bromocriptine or cabergoline. Postmenopausal alopecia, with previous high levels of androgens or with prostatic-specific antigen greater than 0.04 ng/mL, improves with finasteride or dutasteride. Although we do not know the reason, postmenopausal alopecia in normoandrogenic women also improves with finasteride or dutasteride at a dose of 2.5 mg per day. Dermatocosmetic concealment with a hairpiece, hair prosthesis as extensions, or partial hairpieces can be useful. Lastly, weight loss undoubtedly improves hair loss in hyperandrogenic women.

Bumetanide, a new potent diuretic. A clinical evaluation in congestive heart failure

Abstract: Bumetanide, a new compound with diuretic action, has been evaluated in 106 patients with congestive heart failure. Bumetanide was found to be a very potent natriuretic and diuretic agent with a rapid onset and a short duration of action. Bumetanide natriuresis was associated with an increased urinary output of potassium and chloride and a trend to development of hypokalemia, hypochloraemia and metabolic alkalosis. Bumetanide was able to decrease renal-diluting and renal-concentrating abilities and has apparently a site of action in the ascending limb of the loop of Henle. In comparative short-term and long-term studies bumetanide proved to be equipotent with furosemide at one-fortieth of its molar dosage. On continued daily administration for several months and with supplements of potassium chloride or spironolactone, bumetanide produced effective diuresis with minimal changes in blood chemistry, haematological status or liver function. Like other saluretics it caused a tendency to hyperuricaemia, but it did not provoke gouty arthritis or diabetes mellitus. Bumetanide is very well tolerated and is one of the most potent diuretics available to-day.

Drug treatments for polycystic ovary syndrome.

Abstract: Polycystic ovary syndrome is a condition present in approximately 5 to 10 percent of women of childbearing age. Diagnosis can be difficult because the signs and symptoms can be subtle and varied. These may include hirsutism, infertility, menstrual irregularities, and biochemical abnormalities, most notably insulin resistance. Treatment should target specific manifestations and individualized patient goals. When choosing a treatment regimen, physicians must take into account comorbidities and the patient's desire for pregnancy. Lifestyle modifications should be used in addition to medical treatments for optimal results. Few agents have been approved by the U.S. Food and Drug Administration specifically for use in polycystic ovary syndrome, and several agents are contraindicated in pregnancy. Insulin-sensitizing agents are indicated for most women with polycystic ovary syndrome because they have positive effects on insulin resistance, menstrual irregularities, anovulation, hirsutism, and obesity. Metformin has the most data supporting its effectiveness. Rosiglitazone and pioglitazone are also effective for ameliorating hirsutism and insulin resistance. Metformin and clomiphene, alone or in combination, are first-line agents for ovulation induction. Insulin-sensitizing agents, oral contraceptives, spironolactone, and topical eflornithine can be used in patients with hirsutism.

Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients.

Abstract: Context: Previous studies in rats indicated that thiazide-type diuretics reduced blood pressure (BP) and triggered baroreflex-mediated increase in sympathetic nerve activity (SNA), whereas spironolactone exerted central sympathoinhibitory action in addition to diuretic effects. Objectives: The objectives were to determine effects of spironolactone and chlorthalidone on SNA and the role of SNA on diuretic-induced insulin resistance in human hypertension. Methods: We conducted a randomized crossover study in 23 untreated hypertensive patients in which we measured muscle SNA at baseline, after 1 and 3 months of chlorthalidone (12.5–25 mg/d), and after 1 and 3 months of spironolactone (50–75 mg/d). Ambulatory BP, baroreflex sensitivity, and indices of insulin resistance were also assessed at baseline and after 3 months of each drug treatment. Results: Chlorthalidone caused a similar reduction in ambulatory BP from baseline when compared with spironolactone (11 ± 2/4 ± 2 and 10 ± 2/4 ± 2 mm Hg, respectively). However, chlorthalidone increased SNA by 23% (P < 0.01) within 1 month of treatment, whereas spironolactone had no effect in the same subjects. SNA continued to be elevated after 3 months of chlorthalidone when compared with baseline and spironolactone. Baroreflex control of SNA was unaffected by either drug. Chlorthalidone increased indices of insulin resistance, which were significantly correlated with increases in SNA from baseline, whereas spironolactone had no effect in the same subjects. Conclusions: Our data suggest that chlorthalidone, the first-line drug therapy for hypertension, causes persistent activation of sympathetic nervous system and insulin resistance in hypertensive patients. These side effects, however, are avoided by spironolactone despite similar reduction in BP.

Spironolactone in chronic hemodialysis patients improves cardiac function

Abstract: We performed this study to assess whether low dose spironolactone could be administered in hemodialysis (HD) patients with moderate to severe heart failure to improve cardiovascular function and reduce hospitalization without inducing hyperkalemia. We enrolled 16 chronic HD patients with moderate to severe heart failure and left ventricle ejection fraction :5 45%. In a double blinded randomized placebo controlled study, one group of 8 patients received 25 mg of spironolactone after each dialysis session within six months, and the rest received a placebo. Echocardiography was performed on all the patients to assess ejection fraction and left ventricular mass during 12 hours after completion of hemodialysis at the beginning and the end of study. Serum potassium was measured predialysis every 4 weeks. The mean ejection fraction increased significantly more in spironolactone group during the study period than in the placebo group (6.2 +/- 1.64 vs. 0.83 +/- 4.9, P= 0.046). The mean left ventricular mass decreased in the spironolactone group, but increased significantly in the placebo group during the period (-8.4 +/- 4.72 vs. 3 +/- 7.97. 95%, P= 0.021). The incidence of hyperkalemia was not significantly increased in the study or controlled groups. In conclusion, we found in this study that administration of spironolactone in chronic HD patients with moderate to severe heart failure substantially improved their cardiac function and decreases left ventricular mass without development of significant hyperkalemia.

Sex-specific impact of aldosterone receptor antagonism on ventricular remodeling and gene expression after myocardial infarction

Abstract: Aldosterone receptor antagonism reduces mortality and improves post-myocardial infarction (MI) remodeling. Because aldosterone and estrogen signaling pathways interact, we hypothesized that aldosterone blockade is sex-specific. Therefore, we investigated the impact of eplerenone on left ventricular (LV) remodeling and gene expression of male infarcted rats versus female infarcted rats. MI and Sham animals were randomized to receive eplerenone (100 mg/kg/day) or placebo 3 days post-surgery for 4 weeks and assessed by echocardiography. In the MI placebo group, left ventricular end-diastolic dimension (LVEDD) increased from 7.3 +/- 0.4 mm to 10.2 +/- 1.0 mm (p < 0.05) and ejection fraction (EF) decreased from 82.3 +/- 4% to 45.5 +/- 11% (p < 0.05) in both sexes (p = NS between groups). Eplerenone attenuated LVEDD enlargement more effectively in females (8.8 +/- 0.2 mm, p < 0.05 vs. placebo) than in males (9.7 +/- 0.2 mm, p = NS vs. placebo) and improved EF in females (56.7 +/- 3%, p < 0.05 vs. placebo) but not in males (50.6 +/- 3%, p = NS vs. placebo). Transcriptomic analysis using Rat_230-2.0 microarrays (Affymetrix) revealed that in females 19% of downregulated genes and 44% of upregulated genes post-MI were restored to normal by eplerenone. In contrast, eplerenone only restored 4% of overexpressed genes in males. Together, these data suggest that aldosterone blockade reduces MI-induced cardiac remodeling and phenotypic alterations of gene expression preferentially in females than in males. The use of transcriptomic signatures to detect greater benefit of eplerenone in females has potential implications for personalized medicine.

Left ventricular remodeling after acute myocardial infarction: Does eplerenone have an effect?

Abstract: Aims Aldosterone antagonism reduces cardiovascular morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and heart failure or diabetes after acute myocardial infarction (AMI). The mechanism of this effect is unclear. We performed a contrast-enhanced cardiac magnetic resonance study to assess the effects of eplerenone on LV remodeling after AMI. Methods One hundred patients (mean age, 58.9 ± 12 years; 77% male) with LV systolic dysfunction but without heart failure or diabetes were randomized to 24 weeks' double-blind treatment with eplerenone or placebo started 1 to 14 days after AMI. Contrast-enhanced cardiac magnetic resonance was performed, and plasma concentrations of matrix metalloproteinase-2 (MMP-2) and MMP-9 were measured before randomization and at 12 and 24 weeks. Results Baseline LV ejection fraction was, by chance, significantly higher in eplerenone than in placebo-treated patients. Eplerenone had no effect on the primary end point (change in LV end-systolic volume index); after covariate adjustment, the primary end point fell by 6.1 ± 2.7 mL/m 2 with eplerenone compared to placebo ( P = .027), and LV end-diastolic volume index fell by 7.5 ± 3.4 mL/m 2 ( P = .031); eplerenone did not significantly influence LV ejection fraction. Eplerenone, after covariate adjustment, significantly decreased MMP-2 and increased MMP-9 over 24 weeks relative to placebo. Conclusions In a population of patients with AMI with high uptake of contemporary antiremodeling therapy, eplerenone provides modest incremental protection against LV remodeling, only after covariate adjustment.

Adrenalectomy prevents renal ischemia-reperfusion injury

Abstract: Spironolactone treatment prevents renal damage induced by ischemia-reperfusion (I/R), suggesting that renoprotection conferred by spironolactone is mediated by mineralocorticoid receptor (MR) block...

Hyperkalemia in patients with heart failure: Incidence, prevalence, and management

Abstract: Multilevel inhibition of neurohormonal activation using angiotensin-converting enzyme inhibitors, β-blockers, angiotensin receptor blockers, and aldosterone antagonists is the cornerstone of modern heart failure treatment. Use of these agents in optimal doses is associated with significant improvements in heart failure-associated morbidity and mortality but also may increase serum potassium. Because potassium excretion already is impaired in many heart failure patients because of advanced age, diabetes, or chronic kidney disease, the risk of life-threatening hyperkalemia during treatment is significant. This review discusses the mechanisms, incidence, predictors, and management of hyperkalemia in heart failure, emphasizing the importance of careful patient selection for medical treatment and regular surveillance of potassium and creatinine.

Long-Term Low-Dose Spironolactone Therapy Is Safe in Oligoanuric Hemodialysis Patients

Abstract: The Randomized Aldactone Evaluation Study showed that low-dose spironolactone treatment dramatically reduced mortality in patients with heart failure. However, the clinical use of this drug may be limited due to its tendency to cause life-threatening hyperkalemia in hemodialysis (HD) patients. We assessed whether low-dose spironolactone could be safely administered to HD patients for a long period. The study design comprised 2-month baseline and 6-month treatment periods. Sixty-one oligoanuric HD patients were administered a spironolactone dose of 25 mg/day. Serum potassium levels at baseline were compared with those during the treatment. Eleven patients discontinued the treatment because of adverse events other than hyperkalemia or for other reasons. The remaining 50 patients completed the trial, and none of them showed a potassium level of >6.8 mEq/l or required additional ion exchange resin therapy throughout the study period. The mean potassium levels during the treatment were higher than those at baseline; the differences were statistically significant, but only marginally. The safety of spironolactone should be examined in larger trials. However, from this study, we conclude that long-term low-dose spironolactone treatment is clinically safe for many HD patients. A more extensive treatment may help in determining whether spironolactone can reduce cardiovascular mortality in HD patients.

Antifibrotic effects of aldosterone receptor blocker (spironolactone) in patients with chronic kidney disease.

Abstract: Aims. Proteinuria and transforming growth factor β (TGF-β) are parameters that can lead to glomerulosclerosis and tubulointerstitial fibrosis. All components of the renin-angiotensin-aldosterone system (RAAS) activate the TGF-β. Aldosterone may not be inhibited with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) due to aldosterone escape. We aimed to evaluate the effect of spironolactone on parameters leading to fibrosis. Methods. This prospective study included 30 non-diabetic chronic kidney disease (CKD) patients treated with ACEIs and/or ARBs. The patients were divided into two groups that are similar in terms of demographic parameters. 25 mg of spironolactone was added to group 1 (n = 15) for six months, though it was not administered to group 2 (n = 15). Creatinine (U-Cr), protein (U-Prot), and TGF-β1 (U- TGF-β1) were measured in spot urine sample in the beginning of study and six months later. Results. Twenty-four patients completed the study. There were...

Mineralocorticoid Receptor Antagonism Attenuates Vascular Apoptosis and Injury via Rescuing Protein Kinase B Activation

Abstract: Emerging evidence indicates that mineralocorticoid receptor (MR) blockade reduces the risk of cardiovascular events beyond those predicted by its blood pressure-lowering actions; however, the underlying mechanisms remain unclear. To investigate whether protection elicited by MR blockade is through attenuation of vascular apoptosis and injury, independently of blood pressure lowering, we administered a low dose of the MR antagonist spironolactone or vehicle for 21 days to hypertensive transgenic Ren2 rats with elevated plasma aldosterone levels. Although Ren2 rats developed higher systolic blood pressures compared with Sprague-Dawley littermates, low-dose spironolactone treatment did not reduce systolic blood pressure compared with untreated Ren2 rats. Ren2 rats exhibited vascular injury as evidenced by increased apoptosis, hemidesmosome-like structure loss, mitochondrial abnormalities, and lipid accumulation compared with Sprague-Dawley rats, and these abnormalities were attenuated by MR antagonism. Protein kinase B activation is critical to vascular homeostasis via regulation of cell survival and expression of apoptotic genes. Protein kinase B serine(473) phosphorylation was impaired in Ren2 aortas and restored with MR antagonism. In vivo MR antagonist treatment promoted antiapoptotic effects by increasing phosphorylation of BAD serine(136) and expression of Bcl-2 and Bcl-xL, decreasing cytochrome c release and BAD expression, and suppressing caspase-3 activation. Furthermore, MR antagonism substantially reduced the elevated NADPH oxidase activity and lipid peroxidation, expression of angiotensin II, angiotensin type 1 receptor, and MR in Ren2 vasculature. These results demonstrate that MR antagonism protects the vasculature from aldosterone-induced vascular apoptosis and structural injury via rescuing protein kinase B activation, independent of blood pressure effects.

Investigation into the cardiac effects of spironolactone in the experimental model of type 1 diabetes.

Abstract: We have studied the effect of 8-week treatment with spironolactone (20 mg*kg(-1)*day(-1)) on cardiovascular complications associated with streptozotocin (STZ)-diabetic rats. Wistar rats were made diabetic with STZ (45 mg/kg, intravenously). Various biochemical and cardiac parameters were measured at the end of 8 weeks. STZ produced hyperglycemia; hypoinsulinemia; hyperlipidemia; increased blood pressure; increased creatinine, cardiac enzyme, and C-reactive protein levels; reduction in heart rate; and cardiac hypertrophy. Chronic treatment with spironolactone significantly prevented STZ-induced bradycardia, hypertension, and elevated fasting glucose level with simultaneous increase in serum insulin levels. It significantly reduced the elevated cholesterol, very-low-density lipoprotein, and triglyceride levels and increased the lower high-density lipoprotein-cholesterol levels in diabetic rats. Furthermore, spironolactone also produced a significant reduction in the elevated creatinine levels, C-reactive protein, and levels of lactate dehydrogenase and creatinine kinase. It also produced beneficial effect in diabetic rats by preventing cardiac hypertrophy as evident from decrease in left ventricular collagen levels, cardiac hypertrophy index, and left ventricular hypertrophy index. Our data suggest that spironolactone prevents not only the STZ-induced metabolic abnormalities but also cardiovascular complications.

Aldosterone excess or escape: Treating resistant hypertension

Abstract: Aldosterone excess or "escape" can occur after treatment with medications that block the renin-angiotensin-aldosterone system or in undiagnosed primary aldosteronism. Spironolactone is thought to be an important addition to resistant hypertension (RH) treatment. In this study, resistant (RH) and controlled (CH) hypertensives and normotensive patients were submitted to echocardiography, flow-mediated vasodilation, carotid intima-media wall thickness studies, renin plasma activity, and aldosterone plasma levels and plasma and urinary sodium and potassium concentrations at baseline (pre-spironolactone phase). Subsequently, for only RH and CH groups, 25 mg/d spironolactone was added to preexisting treatments over 6 months. Afterwards, these parameters were reassessed (post-spironolactone phase). The RH and CH groups achieved reductions in blood pressure (P<.001), decreases in left ventricular hypertrophy (P<.001), improved diastolic function (Kappa index RH: 0.219 and Kappa index CH: 0.392) and increases in aldosterone concentrations (P<.05). The RH group attained improved endothelium-dependent (P<.001) and independent (P=.007) function. Optimized RH treatment with spironolactone reduces blood pressure and improves endothelial and diastolic function and left ventricular hypertrophy despite the presence of aldosterone excess or escape.

Effect of aldosterone antagonism on exercise tolerance, Doppler diastolic function, and quality of life in older women with diastolic heart failure.

Abstract: Optimal therapy for diastolic heart failure (DHF), the most common form of heart failure in older persons, is unclear. To determine the effect of aldosterone antagonism in DHF, the authors conducted an open-label preliminary trial of spironolactone 25 mg/d in 11 women with DHF. Cardiopulmonary exercise testing, Doppler echocardiography, and a quality-of-life survey were administered at baseline and after 4 months. Peak exercise VO(2) increased by 8.3% (P=.001), the ratio of Doppler diastolic early filling velocity to mitral annulus velocity decreased by 25% (P=.02), quality-of-life score improved by 21% (P=.16 for trend), and median New York Heart Association class improved from class III to class II (P=.004). Findings from this preliminary study confirm the role of aldosterone in the pathophysiology of DHF and suggest that aldosterone antagonism may benefit such patients. These hypotheses are currently being tested in two separated National Institutes of Health-funded, randomized trials, the Spironolactone for Failure in the Elderly (SPIFFIE) and the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trials.

Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis

Abstract: Objective: Chronic inflammation in rheumatoid arthritis (RA) is associated with vascular endothelial dysfunction. The aim of this study was to determine the effect of spironolactone on endothelial function in anti‐tumour necrosis factor (TNF)‐naive RA patients.Methods: Twenty‐four anti‐TNF‐naive RA patients (mean age 49±1.8 years; disease duration 8.5±5.8 years) with high disease activity [Disease Activity Score including a 28‐joint count (DAS28>5.1)] despite treatment with stable doses of conventional disease‐modifying anti‐rheumatic drugs (DMARDs) were investigated. Inflammatory disease activity [DAS28 and Health Assessment Questionnaire‐Disability Index (HAQ‐DI) scores, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP)], serum markers of endothelial dysfunction, serum nitrite concentration, and endothelium‐dependent and ‐independent vasodilation of the brachial artery were measured before and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day.Results: After treatment with s...