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PubMed2006

The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy.

Angiotensin II can influence adipocytokine levels in adipose tissue, but the association between aldosterone, which mediates the effect of angiotensin II, and adipocytokines has yet to be fully elucidated. This study was designed to investigate the effect of spironolactone, a representative aldosterone blocker, on adipocytokines such as adiponectin, visfatin, plasminogen activator inhibitor (PAI)-1 and tumor necrosis factor alpha in patients with type 2 diabetic nephropathy: the study included 33 patients, 22 of whom were randomly assigned to the spironolactone (50 mg/d) group and 11 to the amlodipine (2.5 mg/d) group. Data were collected at baseline and after 3 months of treatment and compared with baseline data for 25 age-matched healthy subjects. A significant decrease in plasminogen activator inhibitor 1 in the spironolactone group was observed (22.6 +/- 13.4 to 19.2 +/- 11.3 ng/mL, P =.0323), but this did not occur in the amlodipine group. Adiponectin and visfatin levels did not change in the spironolactone and amlodipine groups, but significant increases in these adipocytokines were found in a subgroup of patients in the spironolactone group with glycated hemoglobin A(1c) (HbA(1c)) 8.0% or greater (11.8 +/- 6.4 to 13.3 +/- 7.4 microg/mL, P = .0344; and 1.39 +/- 0.92 to 2.26 +/- 0.76 ng/mL, P =.0397, respectively). The tumor necrosis factor alpha level at baseline exceeded the lower detection limit of the assay in only 6 patients in the spironolactone group, and no change occurred in these patients. Moreover, neither spironolactone nor amlodipine therapy caused a change in high-sensitivity C-reactive protein or soluble CD40 ligand, but a significant decrease in the level of brain natriuretic peptide was found in the spironolactone group only. Furthermore, significant increases of HbA(1c), creatinine, potassium, and aldosterone levels and plasma renin activity, and a decrease in urinary albumin excretion were also observed only in the spironolactone group. The number of patients with HbA(1c) 8.0% or greater increased after spironolactone treatment. A significant decrease in systolic but not in diastolic blood pressure was observed in both treatment groups. In conclusion, our data suggest that in patients with type 2 diabetes mellitus complicated by diabetic nephropathy, spironolactone can decrease plasminogen activator inhibitor 1 and brain natriuretic peptide levels in addition to urinary albumin excretion, and systolic blood pressure, and that in patients with poor glycemic control, spironolactone can increase the levels of adiponectin and visfatin. However, the significant elevation of HbA(1c) levels by spironolactone should be emphasized.

Adiponectin↗
PubMed1984

Effect of spironolactone on fluid volumes and adrenal steroids in primary aldosteronism.

Plasma volume (PV) and extracellular fluid volume (ECF) were determined in 7 patients with essential hypertension (controls) and in 10 patients with primary aldosteronism, while on a high Na diet (342 mEq/day) and on a low Na diet (12 mEq/day). The volume studies were repeated in 6 of the primary aldosteronism patients during treatment with spironolactone for over 3 months. Plasma renin activity (PRA), plasma aldosterone concentration (PAC), cortisol concentration, and serum Na and K concentrations were measured in all patients while on a Na-restricted diet (85 mEq/day) as well as on high-Na and low-Na diets. There were no significant changes in arterial pressure during different Na diets in any groups of patients with essential hypertension, or primary aldosteronism with and without spironolactone therapy. Spironolactone treatment normalized the arterial pressure in patients with primary aldosteronism at all Na intakes. These patients had greater values for PV and ECF than did those with essential hypertension. Spironolactone treatment reduced PV during the low-Na diet, but did not alter it during the high-Na diet. Spironolactone did not produce significant changes in ECF during either the high-Na or low-Na diets. Although there were no changes in PV and ECF in patients with primary aldosteronism due to changes in Na intake, both PV and ECF were significantly less in these patients during spironolactone treatment and in patients with essential hypertension during low-Na intake than during high-Na intake. With primary aldosteronism, PRA was depressed and PAC was elevated when compared to essential hypertension, these were not altered by different Na diets in the patients with primary aldosteronism as they were in those with essential hypertension. During treatment with spironolactone the PRA was restored to normal and showed normal changes with variations in dietary Na, but PAC remained elevated during spironolactone. Plasma cortisol was the same among those with essential hypertension and patients with untreated and spironolactone-treated primary aldosteronism. Serum K was less in untreated primary aldosteronism during all Na diets than in essential hypertension, but during spironolactone it was restored to normal. These results suggest that in primary aldosteronism the reduction in arterial pressure by spironolactone treatment does not occur simply by reductions in body fluid volumes. The long-term treatment of patients with primary aldosteronism with spironolactone does not inhibit the production of aldosterone, possibly because of enhanced activity of the renin-angiotensin system and an increase in serum K.

Adrenal Cortex Hormones↗
PubMed1987

The metabolism and biopharmaceutics of spironolactone in man.

Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

Aged↗
PubMedDate not supplied

Myocardial changes after spironolactone in spontaneous hypertensive rats. A laser scanning confocal microscopy study.

The present study aims to objectivate by laser scanning confocal microscopy, the cardiac structure of the spontaneously hypertensive rats (SHR) treated with different doses of spironolactone, either alone or in combination with an angiotensin converting enzyme inhibitor or with a calcium channel blocker. Thirty SHRs were divided into six groups and treated during 13 weeks as follows: control, spironolactone (5, 10 and 30 mg/kg/day), spironolactone + enalapril and spironolactone + verapamil. Spironolactone action on the SHR blood pressure (BP) was dose-dependent. The cardiac hypertrophy was affected by the treatment with spironolactone (high dose) or a combination of spironolactone and Enalapril. The myocardial structure was less affected by the spironolactone monotherapy (at all doses) showing hypertrophied cardiac myocytes, focal areas of the reactive fibrosis, inflammatory infiltrate. The treatment with spironolactone in combination with enalapril or verapamil prevented these alterations. In conclusion, the monotherapy with spironolactone had only a limited effect in the preservation of the myocardial structure and in the attenuation of the interstitial fibrosis in SHRs, even after high dose. This action on the myocardium is more efficient when the spironolactone (even in medium dose) was associated with enalapril or verapamil.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

The spironolactone renaissance.

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.

Aldosterone↗
PubMed2002

Cardiomyocyte volume-weighted nuclear volume and spironolactone therapy in spontaneously hypertensive rats.

OBJECTIVE: To evaluate the blood pressure (BP) and cardiomyocyte nuclei hypertrophy of spontaneously hypertensive rats (SHR) treated with spironolactone and with spironolactone and an angiotensin-converting enzyme inhibitor and calcium channel blocker. STUDY DESIGN: Six groups with 5 SHR each were treated for 13 weeks: control group, spironolactone groups (5, 10 and 30 mg/kg/d, or low, moderate and high doses, respectively), and spironolactone and enlapril or/and verapamil. Blood pressure (BP) and cardiomyocyte volume-weighted nuclear volume (VWNV) were studied. RESULTS: The usual evolution of BP in young adult SHR was greatly altered by spironolactone treatment, with either attenuation or reversion of the BP tendency to increase. The treatments efficiently reduced the cardiomyocyte VWNV > 45%, confirming efficient action of both spironolactone monotherapy at moderate and high dose and spironolactone combined with enalapril or verapamil. However, the high dose of spironolactone, and spironolactone plus enalapril or verapamil showed no significant differences in cardiomyocyte VWNV. Correlation between VWNV and BP (13th week) suggested that BP degree influences cardiomyocyte VWNV. CONCLUSION: The effect of spironolactone monotherapy seems to be dose dependent, and the combination with enalapril or verapamil improves spironolactone efficiency in BP reduction but not in prevention/attenuation of cardiac myocyte nuclear hypertrophy.

Animals↗
PubMedDate not supplied

Volume-weighted mean glomerular volume in spontaneously hypertensive rats treated with different doses of spironolactone.

OBJECTIVES: Ascertain alterations in volume-weighted glomerular volume in monotherapy of spontaneously hypertensive rats with different doses of spironolactone. MATERIAL AND METHODS: We have studied young adult male spontaneously hypertensive rats (SHR) 20 weeks old, divided in 4 groups of 5 animals each: Controls, spironolactone lower dose (5mg/kg/day), spironolactone average dose (10mg/kg/day), and spironolactone higher dose (30mg/kg/day) dissolved in drinking water (for 12 weeks). Serum albumin, blood urea nitrogen (BUN), and creatinine, and the volume-weighted mean glomerular volume (VWGV) were measured. RESULTS: Common progress of blood pressure (BP) in young adult SHR was greatly altered by spironolactone treatment, by either attenuation or reversion of BP increasing tendency. Biochemical evaluation of kidney function indicated normal levels for albumin and creatinine, and high levels for BUN in SHR in all groups. Thickened intrarenal arteries and venous stasis were observed in all groups. Treated SHR spironolactone average and higher doses glomeruli presented smaller and more regular profiles; glomerular hypertrophy with glomerular tuft gross disarray in controls and treated SHR spironolactone lower dose was observed. VWGV was significantly greater in control and treated SHR spironolactone lower dose than in treated SHR spironolactone average and higher doses. CONCLUSIONS: Monotherapy with spironolactone may affect glomerular size and shape in a dose-dependent way; spironolactone showed a significant effect in preserving VWGV, and may be used associated with other drugs in antihypertensive therapy to prevent secondary effects of hypertension in the kidney.

Journal Article↗
PubMedDate not supplied

The effects of spironolactone monotherapy on blood pressure and myocardial remodeling in spontaneously hypertensive rats: a stereological study.

The aim of this study was to evaluate the cardiac structure of spontaneously hypertensive rats (SHRs) treated with different doses of spironolactone. Twenty SHRs were separated into four groups and treated for 13 weeks, as follows: one control group and three spironolactone treatment groups receiving doses of 5, 10 or 30 mg/kg/day. The spironolactone treatment either attenuated or prevented the tendency for increased blood pressure. However, the myocardial structure was not significantly affected by the spironolactone monotherapy treatment (all doses); it showed hypertrophied cardiac myocytes, focal areas of reactive fibrosis, inflammatory infiltrate and a decrease in the density of intramyocardial microvessels. None of the cardiac myocyte stereological parameters in the left ventricular myocardium showed significant differences among the SHR groups. The cardiac myocyte volume density was around 80%, the cardiac myocyte surface density varied from 3.6 to 4.1 x 10(4) mm2/mm3 and the cardiac myocyte mean cross-sectional area varied from 351 to 415 micro m2. The connective tissue volume density of the SHRs treated with the highest dose of spironolactone was 75% lower than in the control SHRs, and this was the only significant difference found for this parameter among SHR groups. The intramyocardial vessels showed some differences when the control SHRs and the other SHRs were compared. The lowest intramyocardial vessel volume density was found in the control group (more than 20% lower than that in the treated SHRs), but no significant difference was detected among the treated SHRs (all doses). The intramyocardial vessel length density (Lv[v]) and surface density (Sv[v]) showed a similar tendency, being significantly greater in the treated SHRs than in the control rats. The Lv[v] was 45% greater in the high-dose spironolactone group than in the control group, and it was 28% greater in the high-dose spironolactone SHRs than in the other treated SHRs. The Sv[v] was 50% greater in the high-dose spironolactone SHRs than in both control and low-dose spironolactone SHRs. Long-term spironolactone monotherapy showed a partial effect in the preservation of intramyocardial vessels and also in the attenuation of interstitial fibrosis.

Animals↗
PubMed2006

Treatment of polycystic ovary syndrome with spironolactone plus licorice.

OBJECTIVE: The aim of the study was to compare the effect of spironolactone (antagonist of mineralocorticoid and androgen receptors) versus spironolactone plus licorice (agonist of mineralocorticoid receptors and mild inhibitor of androgen synthesis) on plasma renin activity, aldosterone and androgen levels in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Thirty-two women with PCOS were divided into two groups: 16 received 100 mg spironolactone and 16 spironolactone plus 3.5 g of licorice a day. Blood pressure, body mass index, serum electrolytes, plasma renin activity, plasma aldosterone and cortisol, serum testosterone, and urinary tetrahydrocortisol/tetrahydrocortisone ratio were measured before and during treatment. RESULTS: Mean blood pressure was significantly reduced during spironolactone treatment, while it was unchanged in women receiving spironolactone plus licorice. Twenty percent of women treated with spironolactone and none treated with the addition of licorice complained of symptoms related to volume depletion. Consistently, the activation of the renin-aldosterone system was significantly lower during spironolactone plus licorice than with spironolactone alone. The prevalence of metrorrhagia was lower in the combined therapy. CONCLUSIONS: In patients with PCOS the mineralocorticoid properties of licorice can reduce the prevalence of side effects related to the diuretic activity of spironolactone.

Adult↗
PubMed1998

Effects of spironolactone on exercise capacity and neurohormonal factors in patients with heart failure treated with loop diuretics and angiotensin-converting enzyme inhibitor.

1. Treatment with spironolactone is reported to be useful when combined with loop diuretics and an angiotensin-converting enzyme (ACE) inhibitor in severe congestive heart failure (CHF). However, the effects of the addition of spironolactone on exercise capacity and neurohormonal variables have not been demonstrated. This study determined the effects of additive spironolactone on exercise capacity and neurohormonal factors in patients with mild CHF. 2. Oxygen uptake (VO2), plasma norepinephrine (NE), renin activity (PRA), angiotensin II (AII), aldosterone (ALD), and atrial natriuretic peptide (ANP) were measured at rest and after peak exercise in nine patients with CHF (six idiopathic and three ischemic cardiomyopathy; New York Heart Association (NYHA) classes II and III) who were already taking furosemide (mean 29 +/- 5 mg/day) and enalapril (mean 4.7 +/- 0.8 mg/day). Studies were repeated after 16 weeks of treatment with additive single daily dose of 25 mg of spironolactone. In four of nine patients, the exercise test was repeated after a 4-weeks washout of spironolactone. 3. Treatment with spironolactone caused natriuresis, decreased cardiothoracic ratio in chest X-ray (before vs. after treatment: 53.7 +/- 1.2 vs. 50.7 +/- 1.4%, P < 0.01), and improved NYHA functional class. Peak VO2 (17.1 +/- 1.6 vs. 17.5 +/- 2.2 ml/min/kg, NS) and heart rate and blood pressure responses to exercise were not altered. Resting NE (215 +/- 41 vs. 492 +/- 85 pg/ml, P < 0.01) and resting PRA (8.2 +/- 2.3 vs. 16.2 +/- 4.1 ng/ml/hr, P < 0.01) as well as peak NE (1618 +/- 313 vs. 2712 +/- 374 pg/ml, P < 0.01) and peak PRA (12.8 +/- 3.2 vs. 28.1 +/- 11.8 ng/ml/hr, P = 0.17) were augmented after additive spironolactone. ALD and AII were insignificantly increased, and ANP was insignificantly decreased at peak exercise after spironolactone treatment. Spironolactone washout was associated with a trend of the neurohormones to return toward pretreatment values. 4. In conclusion, chronic additive treatment with spironolactone was associated with neurohormonal activation both at rest and during exercise without changing the exercise capacity of patients with mild CHF who were already on loop diuretics and ACE inhibitor therapy.

Adult↗
PubMed1999

Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study.

AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio. METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years. RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP</=90 mmHg and 78% achieved a systolic BP</=160 mmHg. In total 48% had BP</=140/90 mmHg and 13/27 (48%) were treated with spironolactone monotherapy. Assessing only patients on drug treatment at baseline (n=24), spironolactone significantly reduced the need for antihypertensive drugs by -0.5 (CI 0.1-1.0), P=0.02, as well as reducing blood pressure [systolic BP -15 mmHg (CI 5-25), P=0.007 and diastolic BP (mmHg) by -8 mmHg (CI 4-13), P=0.001]. CONCLUSIONS: Spironolactone was a highly effective antihypertensive agent in hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio was highly predictive of nonsuppression of plasma aldosterone suggesting primary aldosteronism, it might be worthwhile using spironolactone in this subgroup of hypertensive patients with raised aldosterone/renin ratios, provided that adrenal adenomas are excluded with imaging techniques.

Aldosterone↗
PubMed2000

Spironolactone as a single agent for long-term therapy of hirsute patients.

OBJECTIVE: To assess the androgen-suppressing effect of spironolactone, and the use of this drug as a single agent in the long-term therapy of hirsute patients with either polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). Standard cyproterone acetate (CPA) treatment was used to evaluate the results obtained with spironolactone. DESIGN: Prospective randomized study. PATIENTS: Forty-six hirsute women were separated randomly into two groups, stratified for polycystic ovary syndrome. For 12 months, Group 1 (21 patients, 10 PCOS) received spironolactone only (200 mg/day). Group 2 (23 patients, nine PCOS) received CPA (50 mg/day) with ethinyl oestradiol (35 microgram/day). MEASUREMENTS: Ferriman-Gallwey clinical score for hirsutism and serum testosterone, androstenedione, and LH levels. RESULTS: In IH patients, hirsutism regressed equally with spironolactone (21 +/- 2-14.5 +/- 2) and CPA (23 +/- 2-13 +/- 2). In PCOS patients, the mean score for hirsutism after 12 months was significantly lower with CPA (12 +/- 1) than with spironolactone (16 +/- 1). Testosterone levels did not change with spironolactone; with CPA there was a decrease from baseline in PCOS (47% and 51%, 6 and 12 months) and IH patients (31% and 30%). Androstenedione levels also declined from baseline in CPA-treated PCOS patients (38% and 39%, 6 and 12 months). Androgen levels were significantly different between the groups after 6 and 12 months. LH levels decreased with CPA (72%) but not with spironolactone. CONCLUSION: Our results suggest that spironolactone used as a single agent is as effective as cyproterone acetate combined with oestradiol for long-term treatment of patients with idiopathic hirsutism. In PCOS patients, spironolactone is still effective for reducing hirsutism; however, for treatment of the hormonal or metabolic manifestations associated with PCOS, it may be necessary to combine spironolactone with either an antigonadotrophic agent or a drug that improves peripheral insulin sensitivity.

Adolescent↗
PubMed2003

Safety of low-dose spironolactone administration in chronic haemodialysis patients.

BACKGROUND: Prevention of cardiovascular diseases is essential in chronic haemodialysis patients. Recently, low-dose spironolactone has been shown to decrease cardiovascular mortality in patients with severe heart failure. However, since haemodialysis patients are prone to hyperkalaemia, a known side effect of spironolactone, this treatment is not used in this population. We performed a study to assess whether low-dose spironolactone (3 x 25 mg/week) could be administered without inducing hyperkalaemia in haemodialysis patients. METHODS: The study design included a 2-week baseline period, followed by a 4-week treatment period in which doses of spironolactone were started at 12.5 mg three times/week for 2 weeks, then increased to 25 mg three times/week, and followed by a 2-week wash-out period. Fourteen patients receiving low-dose spironolactone after each dialysis were compared with 21 haemodialysis patients (control group). RESULTS: Low-dose spironolactone did not change mean serum potassium (4.9 +/- 0.7 vs 4.9 +/- 0.3 mmol/l: control). The mean plasma canrenone level induced by administration of spironolactone 25 mg three times/week in the 14 treated patients was 13 +/- 5.3 ng/ml. Serum aldosterone was not significantly modified by the administration of spironolactone in these patients [before, median 0.35; interquartile range (IQR) 0.11-2.83 nmol/l vs after, median 0.22; IQR 0.12-0.60 nmol/l, NS]. Dietary potassium intake and the use of ion-exchange resin, angiotensin-converting enzyme inhibitors and beta-blockers were similar for the two groups throughout the study. CONCLUSION: This non-randomized and non-blinded study shows that administration of 25 mg spironolactone thrice weekly is not associated with an increased frequency of hyperkalaemia in haemodialysis patients when they are carefully monitored. More studies are required, however, before concluding that spironolactone administration is safe in the chronic haemodialysis population.

Adult↗
PubMed2005

Serum concentration of potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate, losartan potassium or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate elevation of serum potassium when spironolactone (25 or 50 mg/day) and furosemide were administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) to patients with chronic heart failure for 12 months and occurrence of hyperkalemia and hypokalemia because of concomitant administration of spironolactone plus an ACE-I or ARB and furosemide. METHODS: Patients with chronic heart failure, who visited departments of cardiovascular internal medicine and cardiovascular surgery at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine, uric acid, and serum sodium were determined in every patient at the time of start of treatment and at 3 and 12 months of treatment. Data from patients in Groups A (25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) and B (50 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) were analysed for differences with respect to the ACE-I and ARB used. RESULTS: When 50 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril) or 50 mg/day losartan potassium (losartan) or 8 mg/day candesartan cilexetil (candesartan) plus 40 mg/day furosemide were concomitantly used, the mean value of serum potassium was significantly elevated only in the group treated with 50 mg/day spironolactone regardless of the concomitant drug. The number of patients with hyperkalemia (>5.5 mEq/L) at 12 months of treatment was 12 (8.8%), while the number of patients with hypokalemia (<or=3.5 mEq/L) was 7 (5.1%). However, the occurrence of hyperkalemia was almost the same regardless of the dose of spironolactone or the ACE-I or ARB concomitantly administered. Therefore, if enalapril, losartan, or candesartan is concomitantly used, it is necessary to monitor the serum concentration of potassium, even if spironolactone is administered at a dose of 25 mg/day. CONCLUSION: The occurrence of hyperkalemia in patients administered spironolactone is influenced by the dose, but when it is used concomitantly with enalapril, losartan or candesartan, the occurrence of hyperkalemia exceeding 5.5 mEq/L may increase even if the dose of spironolactone is as low as 25 mg. Thus it is essential to always monitor serum potassium.

Adult↗
PubMed1987

Spironolactone inhibition of contraction and calcium channels in rat portal vein.

1. The effects of spironolactone have been studied on the mechanical activity of rat portal vein strips and the calcium channel currents of isolated cells using the patch clamp technique (whole-cell configuration). 2. Spironolactone (50 nM to 0.1 mM) depressed both K+-induced and twitch contractions within 5-6 min. This inhibitory effect was overcome by elevating the calcium concentration in the perfusing solution. 3. Spironolactone (60 microM) depressed the transient contractions induced in a Ca2+-free, EGTA-containing solution by either acetylcholine (0.1 mM) or noradrenaline (10 microM). The effect of spironolactone was dependent on a reduction in the filling of the internal calcium store. 4. Rapidly inactivating calcium channel current was maintained in the presence of spironolactone (60 microM), while slowly inactivating calcium channel current was blocked in a concentration-dependent manner. Half-inhibition of slow calcium channel current was obtained at concentrations between 5-7 microM. 5. Administration of spironolactone (10 microM) at rest reduced calcium channel current by about 70% (tonic inhibition). Repetitive depolarizations (300 ms long pulses to zero mV, applied between 0.05 and 0.5 Hz) had no further inhibitory effect on the inward current (absence of use-dependence). 6. When cells were held at depolarized membrane potentials at which slow calcium current was inactivated by about 80%, the inhibitory effect of spironolactone (10 microM) was similar to that obtained with cells normally polarized. Spironolactone (10 microM) had no effect on the voltage-dependence of inactivation of the calcium channel current. 7. Our results suggest that spironolactone acts primarily on the plasma membrane by depressing inward current through slow calcium channels. This effect may be explained by a preferential binding of the drug to the resting state of the slow calcium channel. In addition, spironolactone may depress contractions dependent on the release of calcium from the sarcoplasmic reticulum.

Animals↗
PubMed2000

Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators.

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 microgram/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 was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively. CONCLUSIONS: In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.

Aged↗
PubMed2002

Rapid effects of aldosterone and spironolactone in the isolated working rat heart.

Chronic administration of aldosterone promotes myocardial fibrosis in rats. The Randomized Aldactone Evaluation Study reported that the aldosterone antagonist spironolactone improved outcome in patients with congestive heart failure, suggesting a deleterious effect of aldosterone in the heart. Aldosterone has been shown to have rapid nongenomic effects in different tissues including the heart. However, the hemodynamic actions of aldosterone and spironolactone are not well characterized. In this study, we examined the hemodynamic effects of aldosterone and its receptor antagonist, spironolactone, in the isolated rat heart by use of the Langendorff-Neely technique. Perfusion with 10 nmol/L aldosterone increased contractility by 45% within 2 to 4 minutes (P<0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (P<0.01). Furthermore, 100-fold molar excess of spironolactone did not block the aldosterone effect. Perfusion of aldosterone plus spironolactone resulted in the highest increase in contractility 106% (P<0.01). The threshold response for aldosterone occurred within physiological concentrations (0.5 to 1 nmol/L), and maximal contractility was achieved with 10 nmol/L aldosterone. For spironolactone, the threshold and maximal contractile responses occurred at concentrations readily achieved with clinical dosing, 0.1 to 0.5 nmol/L and 1.0 nmol/L, respectively. These data demonstrate that aldosterone and spironolactone have rapid, positive inotropic actions on the myocardium. Moreover, addition of spironolactone to aldosterone increased contractility beyond the maximal responses elicited by each agent when perfused alone, thus suggesting different pathways of action. Furthermore, the intrinsic inotropic effects of spironolactone might be relevant to the apparent beneficial effect this compound has in patients with congestive heart failure.

Aldosterone↗
PubMed2002

Spironolactone improves angiotensin-induced vascular changes and oxidative stress.

Angiotensin II plays an important role in vascular remodeling. We investigated the role of aldosterone, which is stimulated by angiotensin II, as a mediator of angiotensin II-induced vascular structural and functional alterations. Sprague-Dawley rats (n=8 to 12/group) received angiotensin II (120 ng/kg per minute, subcutaneously) for 14 days +/- spironolactone or hydralazine (25 mg/kg per day). An additional group received aldosterone (750 ng/h, subcutaneously) +/- spironolactone. Systolic blood pressure was increased by angiotensin II (P<0.001) and reduced by spironolactone and hydralazine (P<0.001). Aldosterone-induced increase of blood pressure was reduced by spironolactone (P<0.05). In mesenteric small arteries studied on a pressurized myograph, media/lumen ratio was increased (P<0.001) and acetylcholine-mediated relaxation was impaired in angiotensin II-infused rats (P<0.001); both were partially improved by spironolactone (P<0.05) but not by hydralazine. Aldosterone-induced increase of media/lumen ratio (P<0.001) and impaired response to acetylcholine (P<0.001) were normalized by spironolactone. Response to sodium nitroprusside was similar in all groups. Aortic NADPH oxidase activity was increased (P<0.01) by angiotensin II and reduced by spironolactone and hydralazine. Aldosterone also increased (P<0.05) activation of NADPH oxidase, an effect abolished by spironolactone. Plasma thiobarbituric acid-reactive substances (a marker of oxidative stress), higher in angiotensin II and aldosterone rats (P<0.001), were normalized by spironolactone. In conclusion, spironolactone, which inhibited aldosterone actions, partially corrected structural and functional angiotensin II-induced abnormalities. These effects were associated with reduced vascular NADPH oxidase activity and decreased plasma markers of oxidative stress. Our findings suggest that aldosterone may mediate some of angiotensin II-induced vascular effects in hypertension, in part via increased oxidative stress.

Aldosterone↗