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PubMed1997

Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism.

OBJECTIVE: To compare the efficacy of finasteride and spironolactone in the treatment of idiopathic hirsutism. DESIGN: Prospective, randomized, single-blind study. SETTING: A tertiary hirsutism clinic. PATIENT(S): Forty women with idiopathic hirsutism were selected. INTERVENTION(S): Patients were assigned randomly to receive either 5 mg of finasteride or 100 mg of spironolactone for 9 months. MAIN OUTCOME MEASURE(S): Hirsutism scores were measured according to the Ferriman-Gallwey scoring system, and side effects were monitored for 9 months of treatment. Blood samples were taken at each visit for assessment of endocrine, biochemical, and hematologic parameters. RESULT(S): Hirsutism scores were decreased significantly in both groups at the end of 9 months. The mean percent change (+/- SD) in hirsutism scores in the finasteride and spironolactone groups was as follows: 5.91% +/- 7.18% and 20.60% +/- 12.59% at 3 months, 10.61% +/- 12.18% and 32.57% +/- 15.68% at 6 months, and 15.15% +/- 15.38% and 42.36% +/- 12.31% at 9 months, respectively. There was a significantly better response with spironolactone treatment at the end of 9 months. Eleven (55%) of 20 patients in the spironolactone group experienced side effects. However, none of them stopped treatment because of side effects. CONCLUSION(S): The present data suggest that both finasteride and spironolactone are effective in the treatment of idiopathic hirsutism. However, it appears that the spironolactone group responded significantly better.

Adult↗
PubMed1997

Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo.

BACKGROUND/AIMS: Diuretic requirements after mobilization of ascites by paracentesis have never been assessed in cirrhosis. It is also unknown whether diuretics increase the incidence of postparacentesis circulatory dysfunction. The aim of this study was to investigate these features and to assess whether measurement of plasma renin activity and aldosterone prior to paracentesis predicts diuretic response after this procedure. METHODS: Thirty-six patients with non-azotemic cirrhosis and ascites treated by total paracentesis plus i.v. albumin were randomly assigned to receive placebo (n=17) or spironolactone 225 mg/day (n=19) immediately after paracentesis and followed-up for 4 weeks. RESULTS: Five patients (three in the placebo and two in the spironolactone group) abandoned the treatment prior to ascites recurrence or the end of the study due to complications or lack of compliance. The analysis was performed in the remaining 31 patients. Ascites recurrence was more common in the placebo group (13 cases, 93%) than in the spironolactone group (3 cases, 18%) (p<0.0001) and occurred within the first 2 weeks of follow-up in more than 50% of patients. Patients developing ascites in the spironolactone group had higher levels of renin (14.1, 20.6, 32.4 ng/ml per h) and aldosterone (120, 149, 288 ng/dl) than those who did not develop ascites (renin: 2.0+/-2.1 ng/ml per h; range 0.1-6.8; aldosterone: 43+/-38 ng/dl; range 4-116). Three patients in the placebo group and two in the spironolactone group developed postparacentesis circulatory dysfunction (defined as an increase in renin at the third day after paracentesis greater than 50% over baseline levels up to a value higher than 4 ng/ml per h). CONCLUSIONS: Patients with cirrhosis treated by paracentesis should receive diuretics immediately after this procedure to prevent early recurrence of ascites. The administration of 225 mg/day of spironolactone is a good empiric treatment for non-azotemic patients with cirrhosis, because it is effective in most cases and does not increase the incidence of postparacentesis circulatory dysfunction. The determination of plasma levels of renin or aldosterone prior to paracentesis predicts the efficacy of spironolactone in the prevention of ascites recurrence.

Aldosterone↗
PubMed2002

Spironolactone increases integrin beta3 gene expression in kidney and heart muscle cells.

In clinical trials of heart failure, spironolactone, an antagonist of the mineralocorticoid receptor (MR), reduced mortality rates by unknown mechanisms. We hypothesized that spironolactone functions by upregulating expression of certain cardiovascular genes. An RNA differential display technique was used to identify genes whose expression was increased by spironolactone in an Xenopus kidney epithelial cell line (A6), a known target of aldosterone. We found that integrin beta3 gene expression was increased by spironolactone, and reversed by aldosterone or dexamethasone in a dose dependent manner. Competition binding studies and RT-PCR indicate the presence of MR in A6 cells, suggesting that regulation of expression occurred primarily through MR. Spironolactone also increased integrin beta3 expression in rat neonatal cardiomyocytes. In summary, spironolactone increases integrin beta3 gene expression in kidney epithelial cells and cardiomyocytes. The findings suggest new mechanisms for spironolactone actions with possible relevance to treatment of heart disease.

Aldosterone↗
PubMed2001

Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure.

OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohumoral factors and left ventricular remodeling in patients with congestive heart failure (CHF). BACKGROUND: Aldosterone (ALD) promotes collagen synthesis and structural remodeling of the heart. Spironolactone, an ALD receptor antagonist, is reported to reduce mortality in patients with CHF, but its influence on left ventricular remodeling has not been clarified. METHODS: Thirty-seven patients with mild-to-moderate nonischemic CHF were randomly divided into two groups that received treatment with spironolactone (n = 20) or placebo (n = 17). We measured left ventricular volume and mass before treatment and after four months of treatment. We also measured the plasma levels of neurohumoral factors, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), as well as plasma procollagen type III aminoterminal peptide (PIIINP), a marker of myocardial fibrosis. RESULTS: Left ventricular volume and mass were significantly decreased and ejection fraction was significantly increased in the spironolactone group, while there were no changes in the placebo group. Plasma levels of ANP, BNP and PIIINP were significantly decreased after spironolactone treatment, but were unchanged in the placebo group. There was a significant positive correlation between the changes of PIIINP and changes of the left ventricular volume index (r = 0.45, p = 0.045) as well as the left ventricular mass index (r = 0.65, p = 0.0019) with spironolactone treatment. CONCLUSIONS: These findings indicate that four months of treatment with spironolactone improved the left ventricular volume and mass, as well as decreased plasma level of BNP, a biochemical marker of prognosis and/or ventricular hypertrophy, suggesting that endogenous aldosterone has an important role in the process of left ventricular remodeling in nonischemic patients with CHF.

Aged↗
PubMed2003

Effect of spironolactone on cardiac sympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy.

OBJECTIVES: We sought to evaluate the effects of spironolactone on cardiac sympathetic nerve activity and left ventricular (LV) remodeling in patients with dilated cardiomyopathy (DCM). BACKGROUND: Aldosterone prevents the uptake of norepinephrine and promotes structural remodeling of the heart. Spironolactone, an aldosterone receptor blocker, improves LV remodeling in patients with DCM, but its influence on cardiac sympathetic nerve activity has not been determined. METHODS: We selected 30 patients with DCM who were treated with an angiotensin-converting enzyme inhibitor and a loop diuretic. Fifteen patients were assigned to receive spironolactone additionally, whereas the remaining 15 patients continued their current regimen. The delayed heart/mediastinum (H/M) count ratio, delayed total defect score (TDS), and washout rate (WR) were determined from iodine-123 ((123)I)-meta-iodobenzylguanidine (MIBG) images before and six months after treatment. The left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) were determined by echocardiography, and New York Heart Association (NYHA) functional class was estimated. RESULTS: In the spironolactone group, the TDS decreased from 36 +/- 9 to 24 +/- 13 (p < 0.0001), the H/M ratio increased from 1.64 +/- 0.20 to 1.86 +/- 0.27 (p < 0.0001), and WR decreased from 55 +/- 12% to 41 +/- 15% (p < 0.0005). In addition, the LVEDV decreased from 187 +/- 26 to 154 +/- 41 ml (p < 0.005), and LVEF increased from 33 +/- 6% to 39 +/- 6% (p < 0.005). However, there were no significant changes in these parameters in the control group. There was a significant correlation between changes in the (123)I-MIBG findings and changes in LVEDV with spironolactone treatment (TDS: r = 0.684, p = 0.0038; H/M ratio: r = -0.878, p < 0.0001; and WR: r = 0.737, p = 0.0011). The NYHA functional class improved in both groups but showed a greater improvement in the spironolactone group than in the control group (p < 0.01). CONCLUSIONS: Spironolactone improves cardiac sympathetic nerve activity and LV remodeling in patients with DCM.

Adult↗
PubMed1998

Inhibition of tissue repair by spironolactone: role of mineralocorticoids in fibrous tissue formation.

Mineralocorticoids have been implicated in promoting fibrous tissue formation in various organs. In the present study, we sought to address the potential contribution of mineralocorticoids to fibrous tissue formation using a skin pouch model which has proved valuable for the analysis of inflammatory and wound healing responses. Skin pouches were induced in rats by administration of a phorbol ester, croton oil (0.5 ml of a 1% solution). After 2 weeks, rats were killed and intact pouch tissue collected. Pouch weights of control and aldosterone-treated (0.75 microg/h via osmotic minipump) rats were similar (3.33 +/- 0.44 g vs. 3.70 +/- 0.28 g respectively). However, pouch weights were reduced by more than 50% in spironolactone-treated (25 mg/day powdered in food) animals (1.62 +/- 0.22 g and 1.27 +/- 0.23 g respectively in aldosterone and spironolactone alone groups). To ascertain the effects of different treatments on collagen accumulation, hydroxyproline concentration was measured. Compared with controls, hydroxyproline concentration was significantly reduced following spironolactone treatment (17.1 +/- 0.08 vs. 7.5 +/- 2.0 microg/mg dry wt, respectively, p < 0.01). This response to spironolactone was negated by coadministration of aldosterone (hydroxyproline concentration was 18.6 +/- 2.1 microg/mg dry wt). Following bilateral adrenalectomy, spironolactone reduced pouch weight and hydroxyproline concentration, which was not the case for adrenalectomy alone. Two week aldosterone administration in uninephrectomized rats on high salt diet was deemed ineffective in modulating pouch development (pouch wet wts were 3.48 +/- 0.4 g vs. 3.00 +/- 0.19 g in controls and aldosterone-treated rats, respectively). Mineralocorticoid receptor expression in pouch tissue was demonstrated by RT/PCR. Furthermore, NADP+-dependent 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) activity was detected in pouch tissue, together with lower levels of NAD+-dependent 11beta-HSD2. Spironolactone (p < 0.05) significantly reduced 11beta-HSD1 activity compared with controls. Thus, fibrous tissue possesses requisite components of MC action, and antagonism of mineralocorticoid receptors by spironolactone attenuates its formation. Pouch formation is under the influence of circulating MC and, we would like to propose, is also mediated through corticosteroids generated de novo at the site of tissue repair.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1980

Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients.

Dose-response curves for amiloride and spironolactone were defined in 15 hypertensive patients treated with bendroflumethiazide (bendrofluazide). The relative potency amiloride:spironolactone in correcting hypokalemia was 2.8:1, an estimate significantly lower than the 5:1 potency currently accepted. The relative potency for reduction of plasma sodium was 3.9:1 (amiloride:spironolactone). Amiloride was disproportionately potent in lowering serum bicarbonate, and the data do not suggest that these drugs elevate plasma potassium simply by correcting metabolic alkalosis. Changes in blood pressure were confounded by the presence of carryover effect between treatment phases. Both drugs increased plasma angiotension II and aldosterone, but the rise in aldosterone with spironolactone was smaller than expected from concurrent plasma angiotension II and potassium concentrations. This was consistent with a partial block of aldosterone biosynthesis by spironolactone. The activity of spironolactone did not require the presence of hyperaldosteronism. In a smaller study potassium chloride induced a significant log dose-response on plasma potassium, but the effect was small in absolute terms. At least 64 mmole potassium chloride was needed to match the effect of 20 mg amiloride or 56 mg spironolactone.

Adult↗
PubMed1984

Digoxin-quinidine-spironolactone interaction.

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0-mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t 1/2. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.

Adult↗
PubMed1985

New insights into the pharmacokinetics of spironolactone.

Four healthy men took a single oral dose of 200 mg spironolactone after a standardized breakfast. Blood samples were drawn until 24 hours after dosing. A specific HPLC method was used to determine the serum concentrations of spironolactone and its metabolites 7 alpha-thiomethylspirolactone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and canrenone. Pharmacokinetic parameters were derived from the serum concentration-time course of each compound. Spironolactone, 7 alpha-thiomethylspirolactone, and canrenone are known to have antimineralocorticoid activity in man. Our study demonstrated that: (1) 7 alpha-Thiomethylspirolactone is the main metabolite of spironolactone after a single oral dose as judged by the AUC(0-24) and the maximum concentration; and (2) unchanged spironolactone was detected in serum, with a maximum concentration at 1 hour and detectable levels up to 8 hours after dosing. Our findings are contrary to the widely accepted belief that spironolactone is metabolized too rapidly to be detected in serum after oral dosing and that canrenone is the principal metabolite of spironolactone.

Absorption↗
PubMed2003

Spironolactone prevents cardiac collagen proliferation after myocardial infarction in rats.

1. Aldosterone has been considered a key hormone in the regulation of water, sodium and potassium metabolism, thus influencing blood pressure regulation. More recently, several studies have demonstrated that aldosterone is also produced in extra-adrenal tissues (e.g. the heart), suggesting a paracrine effect for aldosterone, such as to increase collagen synthesis in the heart. 2. Because aldosterone production in the heart increases after myocardial infarction (MI), we investigated the effect of chronic administration of spironolactone, an aldosterone receptor antagonist, in rats after MI compared with the effects produced by losartan and hydralazine. 3. Myocardial infarction was produced in male Wistar rats by surgical ligature of the left coronary artery. Sham-operated animals were used as controls. 4. Spironolactone (20 mg/kg per day), losartan (15 mg/kg per day) or hydralazine (20 microg/kg per day) were administered after MI and used for 1 month. 5. At the end of the treatment period, animals underwent haemodynamic recording (arterial and intraventricular pressures). The collagen content of the heart was evaluated by measuring the hydroxyproline (OH-Pro) concentration in right (RV) and left ventricle (LV) muscle fragments. 6. Infarct size was unaffected by drug treatments. The increased LV end-diastolic pressure observed in MI rats was prevented by losartan and remained unchanged following administration of spironolactone or hydralazine. 7. Losartan prevented RV and LV hypertrophy, as well as collagen proliferation in both ventricles, after MI. The postinfarction hypertrophy observed in RV and LV after MI remained unchanged in infarcted groups treated with spironolactone or hydralazine. 8. The OH-Pro concentration was significantly reduced in LV muscle in the MI group treated with spironolactone (682 +/- 40 vs 557 +/- 21 microg/g for MI vs MI + spironolactone, respectively; P < 0.05), an effect not observed in the hydralazine-treated group. 9. These data suggest that spironolactone prevents collagen proliferation in the surviving myocardium by mechanisms independent of the loading conditions of the heart chambers. Control of postinfarction hypertrophy and collagen accumulation produced by losartan seems to depend on the reduction in loading conditions of the heart chambers.

Animals↗
PubMedDate not supplied

[Effect of dexamethasone and spironolactone therapy on diuresis and creatine clearance in premature infants with a birth weight below 1,500 g].

BACKGROUND: The aim of the study was to examine the influence of dexamethasone and spironolactone on diuresis and creatinine clearance in 8-40 day old premature infants with a birth weight less than 1500 g. PATIENTS: 85 preterm infants were included in this study. Median birth weight was 1195 g (range 560-1495), mean gestational age was 28 (range 25-34) weeks. 31 infants were given dexamethasone if bronchopulmonary dysplasia was diagnosed and 32 infants received spironolactone. Indication for spironolactone was persistent ductus arteriosus or bronchopulmonary dysplasia. METHOD: The multivariate variance analysis (MANOVA) was performed to investigate the influence of spironolactone and dexamethasone on diuresis and creatinine clearance. Additional influence of gestational age, postnatal age and fluid intake wa eliminated by the multivariate variance analysis. RESULTS: Spironolactone therapy resulted in no differences for diuresis and creatinine clearance. Dexamethasone therapy increased creatinine clearance (p < 0.05) and diuresis (p < 0.005). CONCLUSIONS: Spironolactone is not very effective in the therapy of persistent ductus arteriosus and bronchopulmonary dysplasia. Diuresis and creatinine clearance are not increased. In conclusion spironolactone is more effective in clinical conditions associated with high circulating levels of aldosterone. Dexamethasone, on the other hand, has a high effect on diuresis and creatinine clearance. The pathomechanism for the increase of parameters studied is not completely understood.

Birth Weight↗
PubMed1981

Spironolactone bodies. An immunoperoxidase study with biochemical correlation.

The present immunoperoxidase study attempted to localize aldosterone and cortisol in formalin-fixed paraffin-embedded adrenal glands or tumors. Apparently, steroid substances are solubilized during routine tissue processing, and the cytoplasm of adrenal cortical cells is not stained by either antialdosterone or anticortisol antibodies. However, spironolactone bodies react positively with antialdosterone antibody. The presence of aldosterone in the concentric laminations of spironolactone bodies supports the concept that spironolactone bodies are not artifacts. Furthermore, the fact that aldosterone does survive in spironolactone bodies suggests that it is bound in some unusual form. The spironolactone bodies are probably derived from endoplasmic reticulum, and the membranes of endoplasmic reticulum are considered capable of storing steroids. It is likely that during the formation of spironolactone bodies are probably derived from endoplasmic reticulum, and the membranes of endoplasmic reticulum are considered capable of storing steroids. It is likely that during the formation of spironolactone bodies, aldosterone or a few cortisol-like substances are trapped in these laminated concentric bodies.

Adrenal Glands↗
PubMed2002

Combined effects of metoprolol and spironolactone in dilated cardiomyopathic hamsters.

The use of beta-blockers reduces angiotensin II levels, but could not adequately suppress aldosterone production. Thus, the combination of a beta-blocker with an aldosterone receptor antagonist could exert additive effects. The effects of metoprolol and spironolactone and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters (CMH) were investigated. The Bio TO-2 dilated strain of CMH was treated orally with metoprolol (10 mg/kg/day), spironolactone (20 mg/kg/day), or both according to a 2 x 2 factorial design (24 animals per group) from 120 days of age and during 120 days. As compared to corresponding untreated groups, metoprolol significantly decreased mean blood pressure (-7%), and metoprolol and spironolactone significantly increased cardiac output (18% and 19%, respectively), mesenteric blood flow (11% and 14%), and femoral blood flow (13% and 17%), and significantly decreased systemic (-24% and -15%), mesenteric (-14% and -13%) and femoral (-19% and -10%) vascular resistances. Metoprolol significantly increased renal blood flow (22%) and significantly decreased renal vascular resistance (-23%). Metoprolol and spironolactone significantly decreased the cavity area of the left ventricle (-21% and -32%, respectively) and the collagen density of the left (-36% and -39%) and right (-38% and -43%) ventricles. Although the combination did not induce stronger effects than each drug alone on the systemic and most regional hemodynamic variables, it did have a stronger effect on the cardiac remodeling (compared to control group: -24%, -34%, and -46% for the left ventricle cavity area, -33%, -35%, and -62% for collagen density in the left ventricle, and -52%, -57%, and -59% for collagen density in the right ventricle, respectively, in the metoprolol, spironolactone, and metoprolol + spironolactone groups). In CMH, metoprolol and spironolactone combined did not improve hemodynamics more than each drug alone, but did exert additive effects on cardiac remodeling.

Animals↗
PubMed1981

Spironolactone in thiazide-induced hypokalaemia: variable response between patients.

1 The influence of spironolactone 25, 50, 100 and 200 mg daily, and placebo, on plasma potassium and other variables was examined in a random crossover study of 15 hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone produced significant dose-related increases in plasma potassium and aldosterone, and reductions in plasma sodium and bicarbonate. 3 In 14 compliant patients plasma concentrations of the major metabolite canrenone were related linearly to the dose of spironolactone, and there was less than twofold variation between patients. The plasma canrenone concentration correlated negatively with body weight (r = -0.77, P less than 0.001). 4 The plasma potassium response to spironolactone varied sevenfold between compliant patients. The response correlated negatively with placebo plasma potassium (r = -0.62, P less than 0.02), positively with plasma canrenone (r = +0.55, P less than 0.05), but was unrelated to plasma aldosterone (r = -0.22). In one patient relative resistance to spironolactone was attributed to exaggerated secondary hyperaldosteronism induced by the drug. 5 The variability in response to spironolactone between patients is such that fixed dose thiazide-spironolactone combination tablets are unlikely to prevent hypokalaemia reliably.

Adult↗
PubMed2004

The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study.

OBJECTIVE: The effect of spironolactone, cilazapril and their combination on albuminuria was examined in a randomized prospective study in female patients with diabetes and hypertension. PATIENTS AND METHODS: Sixty female diabetic patients aged 45-70 years with blood pressure (BP) 140-180/90-110 mmHg, serum creatinine (sCr) < or = 160 micro mol/l, HbA(1c) < or = 10%, and albuminuria were treated by atenolol 12.5-75 mg/d and hydrochlorothiazide 6.25-25 mg/d. Titration-to-target helped to reach BP values < or = 135/85 mmHg in 46 patients after 12 weeks. These patients were randomized to spironolactone 100 mg/d or cilazapril 5 mg/d for 24 weeks. Then both groups received spironolactone 50 mg/d and cilazapril 2.5 mg/d for 24 weeks. BP was stabilized by tapering the dose of the initial agents. Urinary albumin/creatinine ratio (ACR), BP, K(+). sCr and HbA(1c) were assessed at baseline and at weeks 12, 16, 36 and 60. RESULTS: The average BP at week 12 was 128 +/- 4/81 +/- 3 mmHg and remained constant, in both groups, throughout the study. ACR declined on spironolactone from a median value (range) of 452 (124-1571) to 216 (64-875) mg/g (P = 0.001), and on cilazapril to 302 (90-975) mg/g (P = 0.001). The difference between spironolactone and cilazapril was significant (P = 0.002). Combined treatment resulted in a further modest decline in ACR. Serum creatinine was unaltered by spironolactone and rose slightly (121 to 126 micro mol/l, P = 0.02) on cilazapril. CONCLUSION: At the doses tested, spironolactone was superior to cilazapril in reducing albuminuria. Combined administration was more effective than either drug alone. These effects were independent of BP values. Hyperkalaemia was the main side-effect.

Aged↗
PubMed1997

Cell-specific, promoter-dependent mineralocorticoid agonist activity of spironolactone.

The agonist activity of the antimineralocorticoid spironolactone was evaluated in various cell lines through the use of transfection experiments. The target promoters were derived from the deltaMTV promoter in which one or several glucocorticoid-responsive elements (GRE) were inserted in tandem. Spironolactone at 100 nM activated by 6-fold the GRE/deltaMTV promoter in the human hepatoma HepG2 cell line and only partially prevented the 10-fold activation of this promoter by 0.1 nM aldosterone. Both effects were completely dependent on the cotransfection of an expression vector for the mineralocorticoid receptor. The half-maximal agonist effect of spironolactone was similar to its half-maximal antagonist effect (approximately 10 nM). For the GRE-2/deltaMTV, GRE-4/deltaMTV, and wild-type MMTV promoters, the activation by aldosterone was much more potent (70-, 100-, and 110-fold, respectively), whereas spironolactone elicited a 10-, 24-, and 25-fold activation, respectively. Thus, the effect of both compounds and the relative efficiency of spironolactone, compared with that of aldosterone, were dependent on the number of GREs present in the regulatory region of the promoter. The agonist effect of spironolactone was cell specific. Indeed, although spironolactone agonist activity was observed in H5 kidney tubule cells, none could be detected at concentrations of < or = 1 microM in the CV1 monkey fibroblast cells. In contrast, the antagonist effect was observed in all cells. Furthermore, other antimineralocorticoids, such as RU 26752 and progesterone, also displayed mineralocorticoid receptor-dependent agonist activity in the HepG2 cells. The antiprogesterone RU 486 and the antiandrogen cyproterone acetate were ineffective at < or = 1 microM. In conclusion, we show that under certain experimental conditions, several antimineralocorticoids display significant agonist activity in a cell-specific and promoter-dependent manner.

Aldosterone↗
PubMed1999

Influence of spironolactone on neonatal screening for congenital adrenal hyperplasia.

AIM: To determine if the diuretic spironolactone cross reacts with 17alpha-hydroxyprogesterone (17OHP) in an enzyme linked immunosorbent assay (ELISA) kit used for the mass screening of congenital adrenal hyperplasia. METHODS: Concentrations of 17OHP on a blood filter paper disc were measured using an ELISA kit (kit C-7: ENZAPLATE N-17alpha -OHP-7; Chiron, Tokyo, Japan). The cross reactivity of spironolactone and its metabolites with 17OHP was determined. The concentrations of spironolactone and its metabolites in blood were measured using HPLC (high performance liquid chromatography). RESULTS: Spironolactone cross reacted with 17OHP using kit C-7 (0.01%), by increasing 17OHP concentration in a dose dependent manner. The blood concentration of spironolactone and its metabolites was nearly 900 ng/ml, high enough to show an additive effect on the 17OHP concentration. About 12% of the false positive cases screened using the kit were due to the administration of spironolactone. CONCLUSIONS: Spironolactone interferes with 17OHP concentrations, leading to false positive test results for CAH.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats.

Remodeling of the cerebral vasculature contributes to the pathogenesis of cerebral ischemia. Remodeling is caused by increased smooth muscle proliferation and may be due to an increase in the responsiveness of vascular cells to epidermal growth factor (EGF). Aldosterone is a risk factor for stroke, and the literature suggests it may play a role in increasing the expression of the receptor for EGF (EGFR). We hypothesized that mRNA for the EGF-stimulated pathway would be elevated in the vasculature of stroke-prone spontaneously hypertensive rats (SHRSP) and that this and experimental ischemic cerebral infract size would be reduced by aldosterone inhibition with spironolactone. We found that spironolactone treatment reduced the size of cerebral infarcts after middle cerebral artery occlusion in SHRSP (51.69 +/- 3.60 vs. 22.00 +/- 6.69% of hemisphere-infarcted SHRSP vs. SHRSP + spironolactone P < 0.05). Expression of EGF and EGFR mRNA was higher in cerebral vessels and aorta from adult SHRSP compared with Wistar-Kyoto rats. Only the expression of EGFR mRNA was elevated in the young SHRSP. Spironolactone reduced the EGFR mRNA expression in the aorta (1.09 +/- 0.25 vs. 0.56 +/- 0.11 phosphorimage units SHRSP vs. SHRSP + spironolactone P < 0.05) but had no effect on EGF mRNA. In vitro incubation of aorta with aldosterone +/- spironolactone produced similar results, suggesting a direct effect of aldosterone. Thus spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.

Aldosterone↗