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PubMed2004

Mechanisms for aldosterone and spironolactone-induced positive inotropic actions in the rat heart.

Previously, we reported that aldosterone and spironolactone have inotropic effects in the isolated perfused heart. To address the mechanisms underlying these inotropic effects, we examined the effects of aldosterone and spironolactone on isolated cardiac myocyte shortening, intracellular calcium ([Ca+2]i), pHi, and calcium-dependent actinomyosin ATPase activity. Aldosterone significantly increased shortening in cardiac myocytes (8.0+/-1.0 versus 16.0+/-1.3%, P<0.01) but neither diastolic [Ca+2]i (61.0+/-1.1 versus 66.0+/-4.4 nmol/L) nor peak systolic [Ca+2]i (302+/-11 versus 304+/-17 nmol/L) was affected. Spironolactone-increased shortening was also not coupled with changes in peak systolic calcium; however, diastolic calcium was significantly increased by spironolactone. Aldosterone, but not spironolactone, increased pHi from 7.23+/-0.03 to 7.59+/-0.02 (P<0.01); this was completely blocked by coadministration of 100 micromol/L of ethyl-isopropyl amiloride (EIPA), an inhibitor of the Na+/H+ exchanger (P<0.01). Consistent with this finding, aldosterone increased cytosolic sodium concentration ([Na+]i) from 9.2+/-0.15 to 11.4+/-0.2 mmol/L and produced a leftward shift in the pCa ATPase curve (pCa=5.82+/-0.02 versus 6.35+/-0.02, P<0.01) without affecting maximal myosin ATPase activity. Conversely, spironolactone, but not aldosterone, significantly increases maximal actomyosin ATPase activity (837+/-59 versus 355+/-52 nmol inorganic phosphate (P(i)) x min(-1) x g tissue(-1)). Collectively, these data strongly suggest that the inotropic actions of aldosterone and spironolactone are caused by different mechanisms of action. Aldosterone appeared to increase inotropy primarily through increased cytosolic pH, whereas spironolactone increased myosin ATPase calcium sensitivity and diastolic calcium concentration.

Adenosine Triphosphatases↗
PubMed2001

Effect of spironolactone on cisplatin-induced nephrotoxicity in rabbits.

The effects of a single interaperitoneal dose of cisplatin (6.5 mg kg day(-1)), oral doses of spironolactone (20.0 mg kg day(-1)) for 5 days or the combined treatment (spironolactone+cisplatin) on the kidney function and liver function parameters, as well as the serum, liver and kidney cortical lipid contents were studied. The serum urea and creatinine concentrations (measured as kidney function parameters) were not altered by spironolactone treatment, but were significantly (P<0.001) elevated by cisplatin administration. However, animals exposed to both spironolactone+cisplatin revealed drastic increases in the serum creatinine and urea concentrations amounting to about four- and twofold those of cisplatin-alone treated animals, respectively. The histological examination of slides of kidneys from animals exposed to the combined drugs exhibited more extensive necrosis in the tubules compared to those from animals treated with cisplatin alone. Non of the drug treatments had any effects on the serum alanine transaminase (ALT) and aspartate transaminase (AST) levels (measured as liver function parameters) or liver protein content or hepatic alkaline phosphatase (ALP) activity. The histological examination also revealed apparently normal livers in all experimental groups. The cisplatin-induced nephrotoxicity was accompanied by hypercholesterolaemia and hyperphospholipidaemia, whereas spironolactone showed a hypocholesterolaemic effect. The concomitant treatment with both cisplatin and spironolactone significantly (P<0.05) raised the serum triacylglycerol (TAG) concentration compared to the cisplatin-alone-treated group. Both spironolactone and cisplatin administered separately or jointly caused accumulation of cholesterol and TAG in the kidney cortex with significant depletion of the liver cholesterol content. The present results indicated that spironolactone aggravates the cisplatin-induced nephrotoxicity in the rabbit.

Animals↗
PubMed2002

Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans.

Recent studies have defined a link between the renin-angiotensin-aldosterone system and fibrinolysis. The present study tests the hypothesis that endogenous aldosterone regulates plasminogen activator inhibitor-1 (PAI-1) production in humans. Hemodynamic parameters, PAI-1 and tissue-type plasminogen activator (t-PA) antigen, potassium, PRA, angiotensin II, and aldosterone were measured in nine male hypertensive subjects after a 3-wk washout, after 2 wk of hydrochlorothiazide (HCTZ; 25 mg plus 20 mmol KCl/d), and after 2 wk of spironolactone (100 mg/d plus KCl placebo). Spironolactone (P = 0.04), but not HCTZ (P = 0.57 vs. baseline; P = 0.1 vs. spironolactone), significantly lowered systolic blood pressure. Angiotensin II increased from baseline during both HCTZ (P = 0.02) and spironolactone (P = 0.02 vs. baseline; P = 0.19 vs. HCTZ) treatments. Although both HCTZ (P = 0.004) and spironolactone (P < 0.001 vs. baseline) increased aldosterone, the effect was greater with spironolactone (P < 0.001 vs. HCTZ). HCTZ increased PAI-1 antigen (P = 0.02), but did not alter t-PA antigen. In contrast, there was no effect of spironolactone on PAI-1 antigen (P = 0.28), whereas t-PA antigen was increased (P = 0.01). There was a significant correlation between PAI-1 antigen and serum aldosterone during both baseline and HCTZ study days (r(2) = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r(2) = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.

Adult↗
PubMed1995

Treatment of premenstrual syndrome by spironolactone: a double-blind, placebo-controlled study.

BACKGROUND: To reevaluate whether spironolactone, a steroid receptor antagonist, is effective in improving premenstrual syndrome (PMS) in a double-blind, placebo-controlled cross over study. METHODS: Thirty-five women with PMS were given one tablet of 100 mg spironolactone or placebo daily from day 14 of the menstrual cycle until the first day of the following menstruation. Two pretreatment cycles were observed for diagnosis in each woman, followed by 6 treatment cycles with spironolactone and placebo applied in either the first or second 3 months. The assessment of symptoms and diagnosis of PMS were based on prospective daily self-ratings made by the women using a validated visual analogue scale. RESULTS: The treatment with spironolactone was associated with an improvement in PMS symptoms compared to placebo as judged by significant decrease in negative mood symptom scores (p < 0.001) and somatic symptom scores (p < 0.001). Of the individual symptoms, spironolactone significantly improved irritability, depression, feeling of swelling, breast tenderness and food craving in comparison to placebo. A lasting effect of spironolactone was observed in women started with spironolactone after cross over to placebo. CONCLUSIONS: Spironolactone appears to be an effective therapy for the negative mood changes and somatic symptoms in PMS.

Adult↗
PubMed2004

Spironolactone does not prevent restenosis after coronary stenting in humans.

INTRODUCTION: In animal studies, aldosterone enhanced neointimal proliferation by increasing extracellular accumulation of collagen and potentiating the effects of angiotensin II. Spironolactone, an aldosterone antagonist, is a potent inhibitor of neointimal proliferation. We conducted a placebo-controlled, double-blind, randomised study to assess the effect of spironolactone on angiographic 6-month in-stent restenosis. MATERIALS AND METHODS: Of the 310 randomised patients with significant coronary artery disease, 258 patients were available for analysis: 128 constituted the placebo group and 130 were assigned to receive spironolactone. Eligible patients were randomly assigned to receive a dose of 50 mg spironolactone or placebo orally twice a day for 6 months. The primary endpoint was the angiographic restenosis (>50% stenosis) rate at follow-up angiography. RESULTS: At 6-month follow-up angiography after stenting, there was no difference between the 2 groups in minimal lumen diameter, percent diameter stenosis, late loss, and net gain. Angiographic restenosis occurred in 46 (35.4%) of 130 patients receiving spironolactone and 50 (39.0%) of 128 in the placebo group with an odds ratio (OR) of 0.85 with a 95% confidence interval (CI) of 0.49 to 1.46 (P = 0.62). Restenosis rate was found in 60 (32.9%) of 182 lesions in the spironolactone group, and 61 (35.5%) of 172 lesions in the placebo group with an OR of 0.89 with a 95% CI of 0.56 to 1.42 (P = 0.89). CONCLUSIONS: Spironolactone did not reduce the incidence of in-stent restenosis as compared with placebo in human, contrary to the fact that reduction of neointimal formation in animal models has been observed upon administration of spironolactone.

Adult↗
PubMed2005

[Effect of spironolactone on left ventricular remodeling in patients with acute myocardial infarction].

OBJECTIVE: To investigate the effect of spironolactone on left ventricular remodeling (LVRM) in patients with acute myocardial infarction. METHODS: In this multicentric, randomized, controlled study, spironolactone 40 mg/d was randomly administered in addition to the routine treatment for patients with AMI. During the 6 months the serum PIIINP, BNP and echocardiography were examined in all patients to assess myocardial fibrosis, LV function and volume. RESULTS: A total of 88 AMI patients entered the study came from 4 hospitals in Shijiazhuang. There were 43 patients with anterior MI and 45 with inferior MI. In anterior MI group 23 patients received spironolactone and 20 accepted the routine treatment. In inferior MI group 23 received spironolactone and 22 accepted the routine treatment. In anterior MI group: (1) At 3rd, 6th month PIIINP and BNP serum levels were significantly lower in the spironolactone group compared with those in control group [PIIINP (260.2 +/- 59.9) vs (328.0 +/- 70.3) ng/L, P = 0.001, (197.1 +/- 46.3) vs (266.7 +/- 52.4) ng/L, P < 0.001], [BNP (347.4 +/- 84.0) vs (430.1 +/- 62.9) ng/L, P < 0.001, (243.7 +/- 79.7) vs (334.6 +/- 62.8) ng/L, P < 0.001]; (2) There were smaller LVEDD and LVESD in spironolactone group compared with those in control group after 6 months intervention [(51.0 +/- 5.5) vs (55.6 +/- 4.5) mm, P = 0.005, (35.7 +/- 4.6) vs (39.1 +/- 5.6) mm, P = 0.046]. However, in inferior MI group: (1) There were no significant differences in PIIINP and BNP values between the two groups after 6 months intervention; (2) There were no significant differences in the LVEDD, LVESD, LVEF after 6 months treatment. CONCLUSION: (1) In patients with anterior MI, spironolactone combined with the routine treatment could inhibit myocardial fibrosis and left ventricular dilation and prevent LVRM. (2) In patients with inferior MI, no significant difference in prevention of LVRM was found between the spironolactone combined with the routine treatment and the routine treatment alone.

Female↗
PubMed1984

In vitro responses of aldosterone-producing adenomas to angiotensin II and ACTH after treatment with spironolactone before adrenalectomy.

Aldosterone-producing adenomas in patients who have not been given spironolactone are more responsive to ACTH than to angiotensin II. In vitro, adenomas respond to ACTH, but their response to angiotensin II has not been clearly defined. Treatment with spironolactone has been given before the removal of some of the adenomas studied in vitro, and it can blunt increases in plasma aldosterone concentrations that occur in response to increases in renin activity. To assess the effect of preoperative spironolactone therapy on the responsiveness of aldosterone-producing adenomas in vitro, tissue from five patients with adenomas was incubated for 4 hours with and without angiotensin II and ACTH, 10(-7) to 10(-5) mol/L. The responsiveness of the adenomas was then related to the duration of preoperative spironolactone therapy. The serum potassium concentration was normal in the patients before the operations. Adenoma tissue from a patient given spironolactone for 4 days was responsive to angiotensin II and to ACTH. Treatment of longer duration with spironolactone appeared to be associated with a pattern of decreasing responsiveness to ACTH and an absence of response to angiotensin II in vitro. Aldosterone production by nonadenomatous adrenal tissue did not respond to angiotensin II or to ACTH. Our results suggest that preoperative spironolactone therapy might decrease the responsiveness of aldosterone-producing adenomas to angiotensin II and ACTH in vitro. Therefore, studies of aldosterone-producing adenomas in vitro should consider the possible effects of preoperative treatment with spironolactone on the responsiveness of the adenomas to angiotensin II and ACTH.

Adenoma↗
PubMed1980

Spironolactone and enzyme induction in patients with alcoholic cirrhosis.

The present study was undertaken to determine whether or not spironolactone could induce drug-metabolizing enzymes in patients with ascites due to alcoholic cirrhosis of the liver. The disposition of antipyrine was therefore studied in 15 patients with cirrhosis before and after 13 days of spironolactone treatment (200 mg/day) and in 15 comparable patients not treated by spironolactone. In spironolactone-treated patients, a 40% increase in elimination rate constant of antipyrine (P less than 0.01) was due both to a decrease in apparent volume of distribution by 11% (P less than 0.01) and to a 20% rise in metabolic clearance rate (P less than 0.01). In control patients treated with furosemide or by paracentesis no significant change in metabolic clearance rate of antipyrine was found. As with spironolactone, furosemide decreased the apparent volume of distribution (9%, P less than 0.05) in proportion to the loss in body weight. Since spironolactone treatment was not associated with improvement in the fractional clearance of bromosulfophthalein, nor in serum albumin, prothrombin time, and factor V, the data are compatible with the idea that even in cirrhosis the hepatic drug-oxidizing enzymes were induced by spironolactone. Thus, the consequences of enzyme induction should be considered when spironolactone is associated with other drugs for the treatment of cirrhotic patients.

Adult↗
PubMed1976

Mechanism of action of spironolactone on adrenocortical function in guinea pigs.

Spironolactone administration (50 mg/kg/day for 3 days) to make guinea pigs decreased cortisol production by adrenal slices in vitro. Adrenal microsomal and mitochondrial cytochrome P-450 levels were also decreased after treatment with spironolactone. The decline in adrenal cytochrome P-450 content was accompanied by decreases in microsomal 21-hydroxylase and mitochondrial cholesterol side-chain cleavage and 11beta-hydroxylase activities. Activities of other adrenal enzymes, such as delta4-hydrogenase and NADPH-cytochrome c reductase, were unaffected by spironolactone treatment. Cortisone administration to guinea pigs failed to mimic the effects of spironolactone on adrenal function, which indicates specificity of spironolactone action and excludes inhibition of adrenocorticotropin secretion as a mode of action. Addition of spironolactone to isolated adrenal mitochondria or microsomes produced type I spectral changes with spectral dissociation constants similar to those for endogenous steroid substrates. Spironolactone, in vitro, inhibited 11beta- but not 21-hydroxylase activity. The results indicate that spironolactone administration diminishes the activity of adrenal mitochondrial as well as microsomal cytochrome P-450-containing enzymes, resulting in a fall in corticosteroid output.

Adrenal Cortex↗
PubMed2005

Spironolactone improves diastolic function in the elderly.

BACKGROUND: Diastolic dysfunction is common in the elderly. Increased myocardial fibrosis, a major determinant of diastolic function, has been observed with advancing age. Spironolactone prevents age-related increases in myocardial fibrosis in old normotensive rats. HYPOTHESIS: Spironolactone, via its antifibrotic activity, can improve diastolic function in the elderly with isolated diastolic dysfunction. METHODS: The study was a prospective, double-blind, randomized, placebo-controlled trial. Thirty elderly subjects between 60 and 85 years of age with isolated diastolic dysfunction and no contraindications for spironolactone were randomized to 25 mg/day of spironolactone or placebo for 4 months. Mitral E/A and deceleration time, plasma levels of carboxy-terminal of procollagen type I (PICP), and brain natriuretic peptide (BNP) were measured at baseline and at the end of 4 months. Plasma level of potassium was also monitored to prevent clinically significant hyperkalemia. RESULTS: There was no serious adverse event or clinically significant hyperkalemia in the spironolactone group. Compared with baseline values, spironolactone significantly improved mitral E/A ratio (0.71 +/- 0.08 vs. 0.84 +/- 0.19, p = 0.025) and deceleration time (285.5 +/- 73.1 vs. 230.0 +/- 54.7, p = 0.035). There were no significant differences in the magnitude of change in the levels of PICP and BNP between the two treatment groups. CONCLUSION: Spironolactone may improve diastolic function in the elderly.

Aged↗
PubMed1976

In vitro and in vivo availability of spironolactone from oral dosage forms.

Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.

Animals↗
PubMed1987

Endocrine and clinical effects of spironolactone in female hyperandrogenism.

In a double-blind cross-over study, 24 hyperandrogenic women were treated for three months at a time with either spironolactone 100 mg or placebo daily from the 5th to the 21st days of the menstrual cycle. Spironolactone had a slight but statistically insignificant effect on hirsutism when compared with placebo. Slightly more regular menstruation and better follicular growth was noted during spironolactone treatment. Ovulation (defined as a day 21 serum progesterone level of more than 10 nmol/l) occurred in only 12% of spironolactone cycles, as against 28% of placebo cycles. Spotting occurred in one-third of the spironolactone cycles. No significant differences were found between spironolactone and placebo cycles in serum levels of LH, FSH, prolactin, estradiol, progesterone, androstenedione, total testosterone, sex-hormone binding globulin (SHBG), unbound testosterone, dehydroepiandrosterone sulphate (DHEAS), cortisol, potassium and sodium. The average ovarian volume was 13.0 (5.7-21.8) cm3, and no significant differences were found between treatment and placebo cycles. No significant effect of spironolactone could be demonstrated on androgen secretion and the incidence of ovulation.

Adult↗
PubMed2006

Addition of spironolactone to an angiotensin-converting enzyme inhibitor decreases lung congestion and edema in Dahl hypertensive rats.

We investigated the effect of adding spironolactone to treatment with an angiotensin-converting enzyme (ACE) inhibitor, imidapril, in Dahl salt-sensitive (DS) hypertensive heart failure rats with preserved systolic function. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Rats were divided into four groups and treated for 9 weeks with vehicle alone (water; n = 23), the ACE inhibitor imidapril (1 mg kg(-1) day(-1); n = 16), spironolactone (2 mg kg(-1) day(-1); n = 15), or a combination of imidapril and spironolactone at the doses above (n = 16). The left ventricular weight to body weight (BW) ratio was significantly lower in the imidapril group (3.28 +/- 0.30 mg g(-1)) and the combination group (3.34 +/- 0.38 mg g(-1)) than in the vehicle group (3.71 +/- 0.46 mg g(-1)). Adding spironolactone to imidapril inhibited an increase in the ratio of lung weight to BW (4.38 +/- 0.50 mg g(-1)) related to high salt intake, while monotherapy (imidapril group, 4.61 +/- 0.90 mg g(-1); spironolactone group, 5.40 +/- 2.50) did not significantly change the ratio from that seen with vehicle treatment (6.32 +/- 3.62 mg g(-1)). All active treatments (imidapril, 0.66% +/- 0.67%; spironolactone, 0.51% +/- 0.55%; both together, 0.31% +/- 0.26%) inhibited a salt-intake related increase in the percentage area representing fibrous tissue compared with vehicle treatment alone (1.81% +/- 1.51%). These findings suggest that adding spironolactone to an ACE inhibitor is more effective in improving pulmonary congestion and edema in hypertensive heart failure with preserved systolic function than an ACE inhibitor alone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Relation of rates of excretion of urinary prostaglandin E metabolites to administration of angiotensin, aldosterone, and spironolactone in vivo.

Using a new radioimmunoassay for measurement of the mixed urinary metabolites of prostaglandin E (U-PGE-M) as an indirect measure of the endogenous formation of prostaglandin E, the effect of aldosterone, angiotensin-II, and spironolactone on excretion rates of U-PGE-M in normal and adrenalectomized rat urines was studied. In normal rats, pharmacologically inactive doses of aldosterone and angiotensin-II stimulated, while pharmacologically inactive doses of spironolactone inhibited U-PGE-M excretion in a linear, log-dose manner. Pharmacologically inactive doses of spironolactone inhibited aldosterone and angiotensin-II-stimulated U-PGE-M excretion, in a linear, log-dose relation. Adrenalectomy resulted in elevation of normal rat basal U-PGE-M excretion rate. Angiotensin-II further stimulated, and spironolactone depressed the elevated U-PGE-M levels of adrenalectomized rats. Spironolactone inhibited angiotensin-II-stimulated increase of U-PGE-M in adrenalectomized rats, the first unequivocal demonstration of inhibition of an effect of angiotensin-II by spironolactone. The results demonstrate a strong mechanistic relationship of aldosterone, angiotensin-II, spironolactone, to prostaglandin E (PGE), and demonstrate possible new pathways for regulating blood pressure via changes in phospholipase/prostaglandin synthetase activity.

Adrenal Glands↗
PubMed2004

Usefulness of spironolactone in a specialized heart failure clinic.

Several case series published after the Randomized Aldactone Evaluation Study (RALES) have focused on the adverse effects of spironolactone when prescribed to participants not in a trial and the appropriateness of these prescribing practices; however, there is a paucity of data on potential benefits in patients not in a trial. Therefore, we examined data from a prospective cohort study of 1,037 patients with heart failure seen at the University of Alberta Heart Function Clinic. Median age was 69 years, 66% were men, 75% had systolic dysfunction, and mean ejection fraction was 33%. Only 40% of the 136 patients prescribed spironolactone had New York Heart Association class III or IV symptoms, and <25% fulfilled all of the RALES eligibility criteria. Mean daily dose of spironolactone was 23.9 mg; 25% of patients had spironolactone withdrawn after initiation, mostly due to increases in potassium and/or creatinine (9%), gynecomastia (5%), or dehydration/hyponatremia (6%). Only 1 of our spironolactone-treated patients developed serum potassium >6 mmol/L. Cox's proportional hazards analysis confirmed the association between use of spironolactone and increased survival rate (relative risk 0.09, 95% confidence interval 0.02 to 0.39), even though 78% of our patients did not fulfill the RALES eligibility criteria. Thus, although the complication rate was higher, the benefits of spironolactone seen in RALES extended to participants not in a trial who were treated with similar doses and followed closely in a clinic specializing in heart failure.

Aged↗
PubMed2005

Does aldosterone-to-renin ratio predict the antihypertensive effect of the aldosterone antagonist spironolactone?

BACKGROUND: The recognition that some 10% to 15% of the hypertensive population may have aldosterone excess has increased the frequency of measurement of the aldosterone-to-renin ratio (ARR) and the use of aldosterone antagonists. Whether this ratio will predict the blood pressure (BP) response to spironolactone is not clear. METHODS: We correlated the BP response to spironolactone 50 mg/day to baseline ARR in 69 hypertensive patients (mean [+/-SD] age 57 +/- 2 years, 65% male), consisting of 39 subjects with long-standing hypertension (4.0 +/- 0.2 years) whose hypertension was uncontrolled on at least three antihypertensive medications and 30 previously untreated patients who were randomized in a cross-over design to receive either spironolactone 50 mg/day or bendroflumethiazide 2.5 mg/day for 4 weeks. RESULTS: After 4 weeks of spironolactone, BP in patients with never-treated hypertension was reduced by 18 +/- 3 / 11 +/- 1 mm Hg. There was a highly significant correlation between log ARR and the fall in systolic BP (r = 0.69, P < .001) and diastolic BP (r = 0.45, P < .05). Nine of ten patients with low renin activity (< or =0.5 ng/mL/h) showed a >20-mm Hg fall in systolic BP. No such correlations were seen when BP was reduced by bendroflumethazide 2.5 mg. For patients with resistant hypertension, despite a BP reduction of 28 +/- 3 / 13 +/- 2 mm Hg after 14 weeks of spironolactone, there was no relationship between the reduction in BP and the ARR; however, subjects with pretreatment potassium <4.0 mmol/L had a greater response than those with levels > or =4.0 mmol/L (34 +/- 3 / 16 +/- 2 v 20 +/- 6 / 8 +/- 3 mm Hg, P < .05) CONCLUSIONS: Based on the study results, ARR and low renin activity may predict the response to spironolactone in never-treated hypertensive patients but not in patients taking antihypertensive drugs, possibly because of the effect of these agents on ARR. In such patients a trial of spironolactone is required to assess the BP response.

Aldosterone↗
PubMed2006

Spironolactone treatment and clinical outcomes in patients with systolic dysfunction and mild heart failure symptoms: a retrospective analysis.

BACKGROUND: The effect of spironolactone on clinical outcomes in patients with mild heart failure is unclear. METHODS AND RESULTS: We performed a retrospective analysis of 482 consecutive patients with left ventricular ejection fraction < or =40% and New York Heart Association I-II symptoms. Major cardiac event (MCE) was defined as death, left ventricular assist device implantation, or United Network of Organ Sharing 1 cardiac transplantation. Proportional hazards analysis was used to determine predictors of MCE and to derive an adjusted hazard for spironolactone therapy. Spironolactone was prescribed to 279 (58%) patients and mean follow-up was 1029 days. After controlling for predictors of clinical events, spironolactone treatment was associated with a trend for lower risk of MCE or heart failure rehospitalization (HR, 0.68; 95% CI, 0.43-1.07; P = .095). Exploration of interaction terms between medications revealed that treatment with the combination of spironolactone and thiazide diuretics was associated with lower risk of clinical events (HR, 0.32; 95% CI, 0.12-0.89; P = .029). CONCLUSION: In subjects with mild heart failure treated with a thiazide diuretic, the use of spironolactone is associated with reduced risk of MCE or heart failure rehospitalization. A randomized controlled trial is necessary to accurately define the clinical effects of spironolactone in patients with mild heart failure.

Adult↗
PubMed2005

The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure.

OBJECTIVES: This study was designed to determine the adequacy of monitoring patients receiving spironolactone as well as spironolactone's relationship to hyperkalemia. BACKGROUND: After the Randomized Aldactone Evaluation Study (RALES) demonstrated a 30% mortality benefit for treating severe heart failure patients with spironolactone, acceptance of this drug was overwhelming. Hyperkalemia and worsening renal function were rare in RALES, but laboratory monitoring was frequent. In clinical practice, the incidence of hyperkalemia and worsening renal function and adequacy of follow-up is unknown. METHODS: We reviewed the monitoring of congestive heart failure (CHF) patients with spironolactone initiation after publication of RALES. All potassium and creatinine determinations at baseline and within three months following therapy initiation were assessed. Increased potassium was defined as any [K] > or = 5.5 mEq/l and severe hyperkalemia as any [K] > or = 6.0. RESULTS: A total of 840 patients had new prescriptions for spironolactone. Of these, 91% had baseline laboratory values, and 34% did not have any serum potassium or creatinine determined within three months. Patients seen in the cardiology clinic were more likely to have appropriate follow-up (p < or = 0.001). Of 551 patients with follow-up laboratory values determined, 15% developed hyperkalemia and 6% developed severe hyperkalemia. Fifty-one patients (9%) developed renal dysfunction, of whom 25 developed hyperkalemia within three months. Hyperkalemia developed in 48 of 138 (35%) patients with baseline creatinine > or = 1.5 mg/dl and 12 of 19 (63%) with baseline creatinine > or = 2.5 mg/dl. CONCLUSIONS: Many patients treated with spironolactone for CHF do not receive needed follow-up of potassium or creatinine concentrations, although hyperkalemia and renal dysfunction are common. Elevated baseline creatinine predicts patients at high risk. Physician education of the risks of spironolactone and the need for follow-up is essential.

Aged↗