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PubMed2002

Spironolactone: is it a novel drug for the prevention of amphotericin B-related hypokalemia in cancer patients?

OBJECTIVE: Nephrotoxicity is the major adverse effect of amphotericin B (AmB), often limiting administration of full dosage. Selective distal tubular epithelial toxicity seems to be responsible for the profound potassium wasting that is a major clinical side effect of treatment with AmB. Potassium depletion also potentiates the tubular toxicity of AmB. This study was designed to assess the ability of spironolactone to reduce potassium requirements and to prevent hypokalemia in neutropenic patients on AmB treatment. METHODS: In this study 26 patients with various hematological disorders were randomized to receive either intravenous AmB alone or AmB and oral spironolactone 100 mg twice daily when developing a proven or suspected fungal infection. RESULTS: Patients receiving concomitant AmB and spironolactone had significantly higher plasma potassium levels than those receiving AmB alone (P = 0.0027). Those patients receiving AmB and spironolactone required significantly less potassium supplementation to maintain their plasma potassium within the normal range (P = 0.022). Moreover, urinary potassium losses were significantly less in patients receiving AmB and spironolactone than those receiving AmB alone (P = 0.040). CONCLUSION: This study showed that spironolactone can reduce potassium requirements and prevent hypokalemia by reducing urinary potassium loss in neutropenic patients on AmB treatment.

Amphotericin B↗
PubMed1993

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Activation of the renin-angiotensin-aldosterone system in arterial hypertension can lead to remodeling of the myocardial collagen network, with progressive collagen accumulation in the cardiac interstitium. This reactive myocardial fibrosis, which is not secondary to myocyte necrosis, appears to be an important determinant of diastolic dysfunction and thus of pathologic hypertrophy. To examine the effects of the aldosterone antagonist spironolactone on myocardial fibrosis, we analyzed interstitial fibrosis in 7 different models of arterial hypertension in rats: 2 kidney, 1 clip model of renovascular hypertension (RHT); continuous subcutaneous aldosterone (0.75 micrograms/hr) infusion; RHT and aldosterone models treated with 20 mg/kg per day of subcutaneous spironolactone; uninephrectomized rats on a high sodium diet; and age- and sex-matched controls with or without spironolactone treatment. Systolic arterial pressure was comparably elevated in RHT and aldosterone models; it was modestly lowered but not normalized by 8 weeks of spironolactone treatment at the low doses used. Such treatment also failed to prevent left ventricular hypertrophy (LVH) in all experimental groups with hypertension. Spironolactone, however, was able to prevent myocardial fibrosis in RHT and aldosterone models of acquired arterial hypertension irrespective of the development of LVH and the presence of hypertension. These findings provide further evidence that elevated aldosterone levels play an important role in the adverse remodeling of the myocardium in arterial hypertension. The antifibrotic effects of spironolactone, if confirmed in human studies, may be a valuable strategy in treating hypertensive heart disease.

Aldosterone↗
PubMed1989

The effects of chronic ingestion of spironolactone on serum thyrotropin and thyroid hormones in the male rat.

Male rats were fed spironolactone admixed with feed at doses of 6, 50, and 200 mg/kg/day for up to 13 weeks. After 13 weeks of treatment, there were dose-related increases in thyroid weight and follicular hypertrophy. Serum thyrotropin (TSH) concentrations were significantly increased throughout the treatment period. Serum thyroxine (T4) and triiodothyronine (T3) were significantly decreased at Weeks 2 and 4, but returned to control concentrations by Week 13. The TSH increase and transient T4 decrease suggested that the thyroid hypertrophy was a compensatory reaction to lowered thyroid hormone levels. To determine the effect of spironolactone ingestion on T4 synthesis and metabolism, male rats were fed spironolactone admixed with feed at 200 mg/kg for 2 weeks. The decrease in T4 was not due to decreased synthesis, since iodide uptake and organification were significantly increased by spironolactone treatment. Since uridine diphosphate glucuronosyl transferase activity was significantly increased by spironolactone treatment, it appears that, by increasing hepatic clearance of T4, spironolactone causes a decrease in the serum concentration of this hormone. The lower T4 level causes a release of feedback inhibition and an increase in TSH resulting in the increase in thyroid gland size and activity.

Animals↗
PubMed2004

Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure.

BACKGROUND: A previous randomized controlled trial evaluating the use of spironolactone in heart failure patients reported a low risk of hyperkalemia (2%) and renal insufficiency (0%). Because treatments for heart failure have changed since the benefits of spironolactone were reported, the prevalence of these complications may differ in current clinical practice. We therefore sought to determine the prevalence and clinical associations of hyperkalemia and renal insufficiency in heart failure patients treated with spironolactone. METHODS: We performed a case control study of heart failure patients treated with spironolactone in our clinical practice. Cases were patients who developed hyperkalemia (K(+) >5.0 mEq/L) or renal insufficiency (Cr >or=2.5 mg/dL), and they were compared to 2 randomly selected controls per case. Clinical characteristics, medications, and serum chemistries at baseline and follow-up time periods were compared. RESULTS: Sixty-seven of 926 patients (7.2%) required discontinuation of spironolactone due to hyperkalemia (n = 33) or renal failure (n = 34). Patients who developed hyperkalemia were older and more likely to have diabetes, had higher baseline serum potassium levels and lower baseline potassium supplement doses, and were more likely to be treated with beta-blockers than controls (n = 134). Patients who developed renal insufficiency had lower baseline body weight and higher baseline serum creatinine, required higher doses of loop diuretics, and were more likely to be treated with thiazide diuretics than controls. CONCLUSIONS: Spironolactone-induced hyperkalemia and renal insufficiency are more common in our clinical experience than reported previously. This difference is explained by patient comorbidities and more frequent use of beta-blockers.

Adrenergic beta-Antagonists↗
PubMed2006

Appropriateness of spironolactone prescribing in heart failure patients: a population-based study.

BACKGROUND: The Randomized Aldactone Evaluation Study (RALES) established the safety and benefit of spironolactone for heart failure (HF) patients with systolic dysfunction. However, recent data have raised concerns regarding hyperkalemia secondary to spironolactone use and suggest it occurs more commonly in routine practice. METHODS AND RESULTS: We explored factors potentially associated with hyperkalemia from spironolactone therapy in a population-based cohort of 9165 HF patients hospitalized in Ontario, Canada, between 1999 and 2001. Compared with patients enrolled in RALES, community-based patients were older (mean age 75 years versus 65 years, P < .001) and were more likely to be female (50% versus 27%, P < .001). Of the 1502 patients that were prescribed spironolactone at discharge, 18% had elevated serum potassium levels (>5 mmol/L) during hospitalization and 23% were discharged on concurrent potassium supplements. Although only 8% of patients had serum creatinine >2.5 mg/dL, many patients had stage III (53.1%), stage IV (12.8%), or stage V (3.9%) chronic renal insufficiency according to glomerular filtration rate. CONCLUSION: Spironolactone was often prescribed to inappropriate HF candidates because of the presence of relative or absolute contraindications. These findings highlight the need for more careful patient selection when prescribing spironolactone to minimize potential life-threatening hyperkalemia.

Aged↗
PubMed2006

Preparation and characterization of spironolactone-loaded nanocapsules for paediatric use.

Spironolactone is a steroidal diuretic showing incomplete oral behaviour because of its low solubility and slow dissolution rate. In this study, we applied the nanoprecipitation method to prepare spironolactone-loaded nanocapsules, at laboratory-scale and pilot-scale. The effect of several formulation variables on the spironolactone-loaded nanocapsules properties (average size, drug release rate and drug entrapment) was investigated. The optimized formulations at laboratory-scale and pilot-scale lead to the preparation of spironolactone-loaded nanocapsules with a mean size of 320 and 400 nm, respectively, a high encapsulation efficiency (96.21% and 90.56% respectively), both stable for 6 months. The release of spironolactone from nanocapsules was rapid and complete in a simulated gastric fluid, therefore recourse to spironolactone nanoencapsulation should enhance its oral bioavailability and probably its efficiency. The optimized formulations lead to a high drug-concentration in the liquid preparation (1.5 mg/ml) allowing minimizing the preparation volume administered for children medication.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease.

In chronic heart failure, a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor only partially suppresses aldosterone despite the fact that aldosterone has many harmful effects independent of angiotensin II. These possible harmful effects of aldosterone are magnesium loss, increased cardiac sympathetic activity, and increased ventricular arrhythmias. We have therefore assessed whether adding the aldosterone antagonist, spironolactone, to a loop diuretic and ACE inhibitor reverses any of these potentially harmful effects of residual aldosterone. In a preliminary animal study, we found that exogenous aldosterone reduced myocardial norepinephrine uptake by 24% in anesthetized rats in vivo. In our main study, 42 patients with New York Heart Association II to III congestive heart failure were randomized to spironolactone (50 to 100 mg/day, titrated to blood pressure and plasma potassium) or placebo in a double-blind fashion. Our principal finding is that cardiac norepinephrine uptake as assessed by 123I-metaiodobenzylguanidine scintigraphy increased with spironolactone (p < 0.01). Spironolactone also elevated plasma magnesium (p < 0.05), reduced urinary magnesium excretion (p < 0.05), and caused a reduction in ventricular arrhythmias on 24-hour ambulatory electrocardiography (p < 0.05). Spironolactone increased plasma renin activity, plasma aldosterone (p < 0.01), 24-hour urinary sodium excretion (p < 0.05), and urinary sodium/potassium ratio (p < 0.01). Echocardiographic-determined measurements of left ventricular systolic and diastolic function were unaltered by spironolactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2003

Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism.

OBJECTIVE: To compare the effectiveness of cyproterone acetate, finasteride, and spironolactone in the treatment of idiopathic hirsutism. DESIGN: Prospective randomized clinical study. SETTING: University hospital. PATIENT(S): Forty-one women (median age, 21 years [range, 18-34 years]) with idiopathic hirsutism who had requested to use an oral contraceptive. INTERVENTION(S): Patients were randomly assigned to receive cyproterone acetate (12.5 mg/d for the first 10 days of the cycle), finasteride (5 mg/d), or spironolactone (100 mg/d) for 12 months. Follow-up was done at the end of therapy. MAIN OUTCOME MEASURE(S): Ferriman-Gallwey score before treatment, at 6 and 12 months of treatment, and 1 year after the end of treatment, and androgenic profile before and after treatment. RESULT(S): At the end of therapy, the Ferriman-Gallwey score decreased by 38.9%, 38.6%, and 38.5% in patients who used cyproterone acetate, finasteride, and spironolactone, respectively. One year after therapy, the Ferriman-Gallwey score of patients who used spironolactone was significantly lower (6.74 +/- 1.41) than that of patients who used either cyproterone acetate (7.92 +/- 1.08), or finasteride (9.08 +/- 0.99). The androgenic profile did not change significantly during treatment. CONCLUSION(S): In patients with idiopathic hirsutism, the short-term results of treatment with cyproterone acetate, finasteride, and spironolactone are similar, but spironolactone is effective for a longer time.

17-alpha-Hydroxyprogesterone↗
PubMed1985

The effects of spironolactone on adrenal steroidogenesis in hirsute women.

The effect of spironolactone on adrenal androgen and cortisol production was studied in six hirsute women. Hirsute women were evaluated before and 1 month after receiving 200 mg of spironolactone daily. Basal levels of serum androgens, 17-hydroxyprogesterone (17-OHP), cortisol (F), corticosteroid-binding globulin, and plasma adrenocorticotropic hormone (ACTH) were normal and did not change with therapy. The delta maximum (delta max) responses after dexamethasone suppression and ACTH administration of dehydroepiandrosterone (DHEA), androstenedione (delta 4A), 17-hydroxypregnenolone, and 17-OHP were similar in hirsute women and ovulatory control subjects. After spironolactone administration, the delta max DHEA response was unchanged, whereas the delta max delta 4A response was decreased (P less than 0.05). The delta max ratios of DHEA/delta 4A and 17-OHP/delta 4A were significantly increased after spironolactone in hirsute women, which suggested inhibitions of 3 beta-ol-dehydrogenase-isomerase and delta 4 17,20 desmolase activities. A significant reduction in delta max F occurred after spironolactone administration (P less than 0.05). Although baseline 11-desoxycortisol (S) and the plasma S/ACTH ratio were unaltered, the delta max S/F ratio increased after treatment (P less than 0.01), suggesting an inhibition of 11 beta-hydroxylase activity. Inhibition of adrenal androgen production occurs with spironolactone, but only serum levels of delta 4A are decreased, whereas DHEA and its sulfate (DHEA-S) levels remain unchanged.

17-alpha-Hydroxyprogesterone↗
PubMed1986

The effect of spironolactone on aromatase activity.

Spironolactone, an aldosterone antagonist, causes decreased plasma testosterone (T) levels and gynecomastia in men and is clinically useful in the treatment of hirsutism in women. Many mechanisms of action for spironolactone have been proposed. It has been suggested that one cause for low plasma T levels may result from an increased metabolic clearance rate of T due to increased extraglandular aromatization to 17 beta-estradiol. The purpose of this investigation was to determine the effect of spironolactone on the rate of activity of aromatase in human fetal liver (hFL) cells. The activity of aromatase was assayed by determining the rate of incorporation of [1-3H]androstenedione into [3H]water in hFL cells exposed to spironolactone (10(-10) to 10(-4) M) for 24 or 72 hours. The aromatase activity in control hFL cells remained constant during the study. Dibutyryl cyclic adenosine monophosphate significantly stimulated aromatase activity from 63 to 257 pmol X mg-1 protein X 2 hours-1 after 24 hours and 72 hours exposure, respectively. In contrast, when hFL cells were exposed to spironolactone (10(-10) to 10(-5) M) for up to 72 hours, the activity of aromatase did not differ significantly from that in control hFL cells. It is concluded that spironolactone in therapeutic concentrations does not stimulate aromatase activity in hFL cells maintained in vitro.

Aromatase↗
PubMed1994

Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial.

OBJECTIVE: To compare the clinical efficacy and safety of the pure antiandrogen flutamide and the steroidal derivative spironolactone in the treatment of hirsutism in women. DESIGN: Fifty-three premenopausal women suffering from moderate to severe hirsutism were randomized into two groups and received either flutamide or spironolactone in association with a triphasic oral contraceptive (OC) pill. Hirsutism, acne, seborrhea, alopecia, and side effects were monitored monthly for a treatment period of 9 months and a follow-up after treatment period of 6 months. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULTS: After only 6 months of therapy, flutamide caused a maximal reduction in the hirsutism score to a value within almost normal range; during the same period, spironolactone caused only a 30% reduction of the hirsutism score. Whereas flutamide caused a dramatic (80%) decrease in total acne, seborrhea, and hair loss score after only 3 months of therapy, spironolactone caused only a 50% reduction in acne and seborrhea, with no significant effect on the hair loss score. Four patients in the spironolactone group but only one in the flutamide group stopped the medication because of adverse side effects. CONCLUSION: The present data obtained in a randomized prospective study clearly demonstrate that the pure antiandrogen flutamide is superior to spironolactone in the treatment of female hirsutism and its related androgen-dependent symptoms and signs in women.

Adult↗
PubMed1987

The endocrine effects of spironolactone used as an antiandrogen.

Eight castrate, estrogen-replaced women were given 200 mg spironolactone daily for 4 weeks. The response of plasma dehydroepiandrosterone sulfate (DHEAS), testosterone (T), and androstenedione (delta 4A), all indicators of adrenal C19-steroid production, varied greatly among individuals. Sixteen women with idiopathic hirsutism were given night-time dexamethasone (DEX) and then superimposed spironolactone for 4 weeks, followed by DEX without spironolactone for an additional 4 weeks. As expected, DHEAS, T, and delta 4A declined on DEX treatment. On addition of spironolactone, there was little further change in DHEAS, while plasma T declined in 7 of 16 women, including all those whose T level had remained elevated despite DEX treatment; most values rebounded when spironolactone was discontinued. The authors conclude from intact DEX-suppressed women that ovarian T, especially when increased, is frequently lowered by spironolactone. Thus, both adrenal and ovarian androgen production (as measured by prevailing plasma levels) may be diminished by this agent. These highly variable effects on androgen production are unlikely to account for the consistent antiandrogenic effects reported clinically.

Adult↗
PubMed1986

Effect of spironolactone on renal prostaglandin excretion in patients with liver cirrhosis and ascites.

The effect of spironolactone on the urinary excretion of prostaglandins was studied in patients with liver cirrhosis and ascites. Patients were kept in bed and given a sodium-restricted diet for at least 4 days before spironolactone treatment was considered. Starting from the 5th day of protocol, patients were treated with this diuretic if their spontaneous weight loss had been less than 600 g during the 2 previous days. Patients were distributed in groups according to weight loss during the first 4 days on diuretic therapy: Group I (high responders), II (medium responders) and III (low responders). Group I patients showed higher basal values (4th day of protocol) of urinary sodium (P less than 0.02) and urinary 6-keto-PGF1 alpha (P less than 0.02) than the other patients, but there were no significant differences in the basal excretion rates of PGE2 nor TXB2 among the groups. The therapeutic requirement for spironolactone treatment in patients from Group I was delayed as compared with the other two groups (P less than 0.001) due to the fact that their spontaneous weight loss took place over a long period. For all patients, spironolactone administration produced a significant increase in 6-keto-PGF1 alpha excretion (P less than 0.01) without affecting significantly urinary elimination of PGE2 nor TXB2. A close relationship was found between the spironolactone-induced increments in urinary sodium and urinary 6-keto-PGF1 alpha excretion (r = 0.74, P less than 0.001). It is suggested that the ability of the kidney to synthetize prostacyclin can influence the natriuretic response to spironolactone therapy in patients with liver cirrhosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Simultaneous determination of spironolactone and its metabolites in human plasma.

This study describes a specific, precise, sensitive and accurate method for determination of unchanged spironolactone and its major active metabolites in human plasma. After one-step liquid-liquid extraction, analysis of the parent drug and its metabolites was performed in one chromatographic run, using a high performance liquid chromatography (HPLC) method with a programmed switchover of the UV wavelength. Spironolactone and 7 alpha-thiomethyl-spironolactone were detected at 245 nm, while canrenone and internal standard were detected at 280 nm. The column used was an S5 ODS2 (500 mm x 4.6 mm i.d.). The mobile phase was a mixture of acetonitrile-aqueous orthophosphoric acid (pH 3.4). Chromatographic separations were performed at 5 degrees C. The standard curves were linear over the range 10-400 ng ml-1 for spironolactone and 10-600 ng ml-1 for 7 alpha-thiomethyl-spironolactone and canrenone. The precision and accuracy of the method were confirmed by relative standard deviations below 10% for different concentrations, except for the concentration equal to the quantitation limit, where these parameters ranged from 12-15%. The recovery was above 80% for all investigated compounds and for the internal standard. The assay proved to be suitable for pharmacokinetic studies of spironolactone.

Canrenone↗
PubMed2003

Efficacy of low-dose spironolactone in subjects with resistant hypertension.

BACKGROUND: Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and, to a lesser degree, subjects with resistant hypertension. METHODS: In current analysis, we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in subjects with resistant hypertension with and without primary aldosteronism. Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity, 24-h urinary aldosterone and sodium during a high dietary salt ingestion. The diagnosis of primary aldosteronism was confirmed with a renin activity <1.0 ng/mL/h, urinary aldosterone >12 mug/24 h and urinary sodium >200 mEq/24 h. After biochemical evaluation, spironolactone (12.5 to 25 mg/d) was added to each subject's antihypertensive regimen. If blood pressure (BP) remained uncontrolled, the dose of spironolactone was titrated up to 50 mg/d. Follow-up BP was determined at 6 weeks, 3 months, and 6 months. RESULTS: A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 +/- 21/10 +/- 14 mm Hg at 6 weeks and 25 +/- 20/12 +/- 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics. CONCLUSIONS: We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism.

Adult↗
PubMedDate not supplied

Canrenone formation via general-base-catalyzed elimination of 7 alpha-(methylthio)spironolactone S-oxide.

The preparation of the two diastereomeric S-oxides of 7 alpha-(methylthio)spironolactone, the major metabolite of spironolactone in humans, is described. When placed in aqueous solution, these diastereomers undergo elimination reactions to give canrenone. The rate of canrenone formation from 7 alpha-(methylthio)spironolactone S-oxide was carefully investigated spectrophotometrically. In weakly acidic media, canrenone formation was found to proceed at significant rates, and the reaction was catalyzed by basic buffer species. At strongly acidic or basic pH only, specific-acid or specific-base catalysis of sulfoxide elimination, respectively, was observed. The observation that formation of canrenone could occur from nonenzymatic elimination of 7 alpha-(methylthio)spironolactone S-oxide may have toxicological significance since it has been determined that canrenone can be metabolized to mutagenic epoxides in vitro. Our studies demonstrate a novel chemical pathway leading from a major metabolite of spironolactone, 7 alpha-(methylthio)spironolactone S-oxide, to canrenone.

Buffers↗
PubMed2001

Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats.

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.

Animals↗
PubMed2005

Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective?

1. Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2. Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11+/-4 and 9+/-2%, and decreased coronary flow (CF) by maximally 36+/-7 and 20+/-4%, respectively. Spironolactone did not significantly affect LVP or CF. 3. In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68+/-2 to 45+/-3%, similar to the reduction (34+/-2%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71+/-5%). 4. In cardiomyocytes, aldosterone decreased [(3)H]thymidine incorporation maximally by 73+/-3%, whereas in cardiac fibroblasts it decreased [(3)H]proline incorporation by 33+/-7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5. In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.

Aldosterone↗