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PubMed2002

Sodium transporter abundance profiling in kidney: effect of spironolactone.

Renal tubule profiling studies were carried out to investigate the long-term effects of administration of spironolactone, a mineralocorticoid receptor antagonist, on abundances of the major Na transporter and Na channel proteins along the rat renal tubule. Oral administration of spironolactone for 7 days to NaCl-restricted rats did not significantly alter abundances of Na transporters expressed proximal to the macula densa, while substantially decreasing the abundances of the thiazide-sensitive Na-Cl cotransporter (NCC), the alpha-subunit of the amiloride-sensitive epithelial Na channel (ENaC), and the 70-kDa form of the gamma-subunit of ENaC. A dependency of NCC expression on aldosterone was confirmed by showing increased NCC expression in response to aldosterone infusion in adrenalectomized rats. Immunoperoxidase labeling of ENaC in renal cortex confirmed that dietary NaCl restriction causes a redistribution of ENaC to the apical domain of connecting tubule cells and showed that high-dose spironolactone administration does not block this apical redistribution. In contrast, spironolactone completely blocked the increase in alpha-ENaC abundance in response to dietary NaCl restriction. We conclude that the protein abundances of NCC, alpha-ENaC, and the 70-kDa form of gamma-ENaC are regulated via the classical mineralocorticoid receptor, but the subcellular redistribution of ENaC in response to dietary NaCl restriction is not prevented by blockade of the mineralocorticoid receptor.

Adrenalectomy↗
PubMed1977

Natriuresis after adrenal enucleation: effect of spironolactone and dexamethasone.

After adrenal enucleation, rats have an impaired ability to excrete a salt load because of enhanced collecting duct reabsorption. This antinatriuretic effect, thought to be secondary to a mineralocorticoid-like substance secreted by the enucleate gland, can be reversed by treatment with spironolactone or dexamethasone. To define the renal mechanisms involved in this drug-induced natriuresis we have utilized clearance and micropuncture techniques in enucleate saline-expanded rats that were treated with either spironolactone (S) or dexamethasone (D), or were untreated (U). Sodium excretion was clearly increased after S, 13.9, and D, 19.3 mueq/min vs. u, 5.9 mueq/min. The mechanisms of this natriuresis, however, were dissimilar. Spironolactone-treated rats were not different from untreated rats except with regard to function beyond the superficial late distal tubule, where U rats reabsorbed over 50% of the delivered sodium. In the S group 38% of the excreted sodium was added along this tubular locus, 5.2% of the filtered sodium reaching the late distal tubule and 7.3% appearing in the urine. These data demonstrate that the natriuresis after S is secondary to the net addition of sodium beyond the superficial late distal tubule. Spironolactone may work by inhibiting a mineralocorticoid-like product of the enucleate gland and, thereby, eliminate the sodium-retaining effect of this product. The natriuresis after D, however, can be explained solely on the basis of a markedly increased filtered load of sodium traversing the nephron.

Adrenalectomy↗
PubMed1979

Modification of D-galactosamine-induced liver injury in the rat by spironolactone.

Spironolactone, a competitive inhibitor of mineralocorticoid effects on the distal tubule of the kidney, has recently been found to have other metabolic effects. In these studies, spironolactone (200mg/kg intraperitoneally) for 3 days was found to have a marked protective effect against the hepatotoxic effect of D-galactosamine (275 mg/kg) in rats. Further progress in defining the mechanism of protection from D-galactosamine hepatic necrosis by spironolactone will require assessment of effects of spironolactone on uridine nucleotide metabolism.

Animals↗
PubMed1984

Intrarenal sodium handling during chronic spironolactone treatment.

Intrarenal sodium handling was studied in 8 patients with essential hypertension before spironolactone treatment (200 mg/day), on the 4th day of treatment, and after 3 months of treatment. The results were compared with similar studies with chlorthalidone (50 mg/day). Renal sodium handling was assessed by simultaneous determination of the glomerular filtration rate, sodium, and potassium excretion, and maximal free-water clearance (CH2O). We took CH2O as an index of 'distal' sodium chloride reabsorption from which the proximal sodium reabsorption was calculated. During the first days of spironolactone treatment a natriuresis and increase in urinary flow rate was found. It resulted in a decrease of the extracellular fluid volume amounting to 0.9 liters and a 2.5-fold increase in the plasma renin activity. Potassium excretion showed a small but significant rise. After 3 months, virtually the same degree of volume depletion was found, which was comparable to that obtained after 3 months of chlorthalidone treatment. CH2O, as a fraction of glomerular filtration rate, decreased by 24% both after 3 days and 3 months, whereas proximal sodium reabsorption increased from 87.8 to 90.4% of the filtered load. CH2O, corrected for the 'distal' delivery of sodium, decreased from 85.3 to 80.7%. These changes were nearly the same as those found after 3 months of chlorthalidone treatment. It is concluded from these calculated values that spironolactone inhibits sodium chloride reabsorption in the diluting segment of the nephron and that the resulting increase in sodium delivery or urinary flow to the potassium excretory site partly counteracts the blocking effect of spironolactone on this part of the nephron, thus increasing potassium excretion during the acute administration of this drug.

Adult↗
PubMed1989

Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy.

Plasma levels of canrenone and androgen receptor-active materials (ARM) were determined during long-term oral K-canrenoate or spironolactone therapy in cirrhotics with chronic recurrent ascites. Mean plasma canrenone level was approximately 3 times higher under K-canrenoate than under spironolactone treatment; moreover, the levels were not dose related. Either type of treatment did not affect plasma aldosterone and testosterone concentrations. Plasma ARM during K-canrenoate treatment did not change, whereas in the spironolactone group a 3-fold increase of ARM occurred (p less than 0.05). No dose-related effect was evident with the latter treatment. The lower incidence of gynecomastia in the K-canrenoate group was not correlated with values of plasma canrenone or ARM (p greater than 0.05). Our study questions the traditional view that the mode of action of spironolactone is via its metabolite canrenone. The two antialdosterone drugs, although equally effective in clearing ascites from cirrhotics, appear to act through partially different metabolites. The lower incidence of antiandrogenic or estrogen-like side effects during K-canrenoate seems to be related to metabolites other than canrenone itself.

Adult↗
PubMed1994

Androgens affect the activity of human sebocytes in culture in a manner dependent on the localization of the sebaceous glands and their effect is antagonized by spironolactone.

To investigate the varying response of the pilosebaceous unit to androgens functional studies were performed on the effects of testosterone and 5 alpha-dihydrotestosterone on cultured human sebocytes derived from different skin regions. In addition, the effect of spironolactone on the proliferation of androgen-stimulated human sebocytes derived from facial skin was evaluated. Testosterone (10(-11) to 10(-5) M), 5 alpha-dihydrotestosterone (10(-11) to 10(-5) M) and spironolactone (10(-12) to 10(-7) M) were added for 10 days as single substances or in combinations to human sebocytes in secondary culture maintained in a serum-free medium. Cell proliferation was assessed using a fluorometric assay. Intracellular lipids were extracted from sebocytes treated with androgens (10(-7) M) for 10 days after confluency. Testosterone inhibited the proliferation of sebocytes derived from the legs with a 50%-inhibitory concentration at 10(-5) M and induced a 50% decrease of intracellular lipids. In contrast, 5 alpha-dihydrotestosterone stimulated the activity of leg sebocytes with a 50% increase of proliferation at 10(-5) M, and a 175% increase of intracellular lipids. On the other hand, the proliferation of facial sebocytes was significantly stimulated by testosterone with a 50%-stimulatory concentration at 10(-6) to 10(-5) M and mostly by 5 alpha-dihydrotestosterone with a 50% enhancement at 10(-8) to 10(-7) M. Spironolactone inhibited the proliferation of facial sebocytes in a dose-dependent manner with a 25%-inhibitory concentration at 10(-9) M. Simultaneous treatment of facial sebocytes with spironolactone and testosterone or 5 alpha-dihydrotestosterone resulted in decreased proliferation when compared to the growth obtained under androgens alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1978

Spironolactone. An aldosterone agonist in the stimulation of H+ secretion by turtle urinary bladder.

In the isolated turtle bladder, spironolactone inhibits sodium transport in the presence of aldosterone or endogenous mineralocorticoid hormone. In contrast to this antagonism for the stimulation of sodium transport by aldosterone, the stimulation of hydrogen ion secretion by aldosterone is not inhibited by spironolactone. In hormone-depleted bladders, spironolactone stimulates hydrogen ion secretion. The extent of stimulation is similar to that of aldosterone. Spironolactone functions as an agonist for aldosterone for the stimulation of urinary acidification.

Aldosterone↗
PubMedDate not supplied

Lymphocyte function tests in cirrhotic patients under treatment with spironolactone and potassium canrenoate.

This controlled study in cirrhotic patients investigated whether two antialdosteronic steroids, spironolactone (100-200 mg/day; n = 12 patient pairs) and potassium canrenoate (50-100 mg/day, n = 32 patient pairs) which are reported to bind to intracellular membranes and modify cytochrome P-450, could also produce nuclear changes. The model used was the response of peripheral lymphocytes to blastogenic agents by studying lymphocyte sub-populations. No changes occurred in the B- and T-lymphocyte sub-populations or in the helper and suppressor sub-types. The response to the blastogenic agents, phytohaemagglutinin and purified protein derived from mycobacteria, did not change significantly from before entry into the study to the follow-up (18.1 +/- 2.9 months). All control patients (n = 44 patient pairs) had slightly greater mitogenic activity compared with patients treated with spironolactone; no difference was found when control patients were compared with patients given potassium canrenoate. The difference between spironolactone and potassium canrenoate might be due to toxicity caused by the thio group of spironolactone. Overall, however, both drugs may be regarded as safe, in terms of effects on lymphatic tissue, occurring during the course of cirrhosis.

B-Lymphocytes↗
PubMed1987

A double-blind, placebo-controlled evaluation of spironolactone in the premenstrual syndrome.

The effect of spironolactone in the alleviation of the symptoms of the premenstrual syndrome was compared with placebo in a double-blind, parallel group controlled study. One tablet daily of 100 mg spironolactone or placebo was given to 63 women from Day 12 of the menstrual cycle until the first day of the next menstrual bleed. This regimen was repeated for two consecutive cycles. Spironolactone was statistically significantly superior in providing relief from bloatedness (p less than 0.001). No statistically significant changes were observed in blood biochemistry of plasma hormone levels of oestradiol, progesterone or prolactin, though an increase in serum aldosterone levels was seen in the spironolactone-treated group. No differences were detected in weight, blood pressure or the incidence and severity of complaints following treatment.

Adult↗
PubMed2006

Spironolactone preserves cardiac norepinephrine reuptake in salt-sensitive Dahl rats.

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [(3)H]NE in isolated perfused rat hearts and [(3)H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The alpha(1)-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.

Aldosterone↗
PubMed1975

Interaction of spironolactone and digitalis with the 5 alpha-dihydrotestosterone (DHT) receptor of rat ventral prostate.

The aldosterone antagonist, spironolactone, has been shown to block the effects of exogenously administered androgen in rat. This suggests that interaction of the drug with androgen at the target tissues may occur. In this paper we have studied the possible interaction of spironolactone with the 5alpha-dihydrotestosterone (DHT)1 receptor of rat ventral prostate. The competitive receptor assay used involves precipitation of the 105,000 X g supernatant of the homogenized tissue with protamine sulfate, removal of the unprecipitated cytosol, and incubation of the precipitate in the presence of the appropriate [3H]DHT steroid solution at 0 C for 18 hours. Using this method the Kd (dissociation constant) for DHT in the rat prostate was in the range of 1.9-4.0 X 10(-9)M and the binding capacity was 0.21 pmol/mg protein. Spironolactone was found to interfere with the binding of DHT to the precipitated cytosol and displayed an estimated Kd of 1.3-4.6 X 10(-8)M. Several digitalis preparations were similarly studied. Digitoxin and digitoxigenin also interfered with the binding of [3H]DHT and had an estimated Kd of 0.8-3.6 X 10(-8)M. Digoxin interacted less strongly and its estimated Kd was 10(-6)M. We believe these results suggest an interaction of spironolactone and digitalis with the DHT receptor and may help explain some of their antiandrogenic actions in the rat and in man.

Animals↗
PubMed1999

Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset.

Short term treatment with spironolactone, testolactone, and, after the onset of central puberty, deslorelin can normalize the rate of growth and bone maturation in boys with familial male-limited precocious puberty. To test the hypothesis that this treatment can achieve long term normalization of the growth and development of these children, we examined the growth rate, bone maturation rate (change in bone age/change in chronological age), and predicted adult height of 10 boys who were treated with spironolactone (5.7 mg/kg x day) and testolactone (40 mg/kg x day) for at least 6 yr. Deslorelin (4 microg/kg x day) treatment was initiated 2.6 +/- 1.3 yr after beginning spironolactone and testolactone treatment. The growth rate normalized within 1 yr of starting treatment and remained normal during the next 5 yr of treatment (P < 0.001). The rate of bone maturation normalized during the second year of treatment and remained normal thereafter (P < 0.001). Predicted height increased from 160.7 +/- 14.7 centimeters at baseline to 173.6 +/- 10.1 centimeters after 6 yr of treatment (P < 0.05 during the fourth through the sixth year of treatment compared to baseline). We conclude that long term treatment with spironolactone, testolactone, and, after central puberty, deslorelin normalizes the growth rate and bone maturation and improves the predicted height in boys with familial male-limited precocious puberty. The ultimate effect of this approach on adult height will require further study.

Adolescent↗
PubMed2006

Anti-inflammatory effect of spironolactone on human peripheral blood mononuclear cells.

We evaluated the effect of alacepril, CV-11974, and spironolactone on the production of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in cultured human peripheral blood mononuclear cells stimulated with angiotensin (Ang) II. Alacepril, CV-11974, and spironolactone significantly reduced the enhanced production of MCP-1 and TNF-alpha induced by exogenous Ang II. Specifically, 10 muM of spironolactone significantly reduced cytokine production, compared to the same dose of alacepril or CV-11974. These findings indicate that spironolactone may contribute to ameliorate the prognosis of patients with cardiovascular diseases by reducing Ang II-induced inflammation, although further exploration including determining the mechanisms would be required.

Adult↗
PubMed2001

High serum level of procollagen type III amino-terminal peptide contributes to the efficacy of spironolactone and angiotensin-converting enzyme inhibitor therapy on left ventricular hypertrophy in essential hypertensive patients.

We recently demonstrated that spironolactone may have beneficial effects on left ventricular hypertrophy in selected patients with essential hypertension undergoing treatment with an angiotensin-converting enzyme (ACE) inhibitor. To clarify the possible mechanisms by which spironolactone improves cardiac hypertrophy, we investigated the change in serum procollagen type III amino-terminal peptide (PIIINP) in 11 patients with essential hypertension treated with spironolactone and an ACE inhibitor for 24 weeks. Both blood pressure and serum PIIINP levels were significantly decreased by treatment. There was a statistical significant correlation between the changes in LVMI and those in PIIINP. The reduction in PIIINP was significant in patients whose initial serum PIIINP levels were above the normal range. Before treatment, there were no statistically significant correlations between serum PIIINP levels and either LVMI, blood pressure, or plasma aldosterone concentration. Essential hypertensive patients matched in terms of duration of therapy, blood pressure and LVMI and treated with an ACE inhibitor alone showed no change in serum PIIINP levels. In conclusion, the results of the present study demonstrate that patients with essential hypertension and high serum levels of PIIINP are particularly responsive to MR blockade in terms of left ventricular hypertrophy. Moreover, these results suggest that spironolactone limits cardiac collagen turnover in such patients. Larger studies may provide definitive evidence for the involvement of aldosterone in left ventricular hypertrophy in patients with abnormally high PIIINP levels.

Adult↗
PubMed2005

Spironolactone for hirsutism in polycystic ovary syndrome.

OBJECTIVE: To evaluate the level of evidence for treatment of hirsutism associated with polycystic ovary syndrome (PCOS) with spironolactone. DATA SOURCES: Studies and reports were located in MEDLINE (1966-January 2005), EMBASE, and International Pharmaceutical Abstracts through the second week of January 2005. DATA SYNTHESIS: Hirsutism is a common clinical problem and is often associated with PCOS. Research has been performed to assess the efficacy of spironolactone therapy in patients with hirsute characteristics. Five studies that evaluated the effectiveness of spironolactone for hirsutism in PCOS were identified and reviewed. CONCLUSIONS: The effects of multiple treatment options on the subjective and objective measures of hirsutism have displayed varying results. The outcomes reported to date have shown a positive trend toward using spironolactone in women with PCOS and hirsutism.

Female↗
PubMed1992

Twenty-four year spironolactone therapy in an aged patient with aldosterone-producing adenoma.

A case of primary aldosteronism treated with spironolactone therapy has been followed up for 24 years. This is probably the longest case of spironolactone therapy for primary aldosteronism that has ever been reported. Long-term treatment with spironolactone controlled the hypertension and prevented hypokalemic alkalosis in this patient, without any deleterious effects on steroid biosynthesis. Based on data obtained during dose reduction and subsequent withdrawal of spironolactone, it is suggested that the suppressed plasma renin activity associated with adenoma-induced aldosteronism develops prior to hypokalemia and hypertension.

Adenoma↗
PubMed2003

Effects of spironolactone and metoprolol on QT dispersion in heart failure.

The effects of spironolactone or metoprolol added to a conventional treatment protocol on QT dispersion, which is accepted as a sudden cardiac death predictor, were evaluated in heart failure patients.? A total of 105 New York Heart Association class III patients were included in this study. The conventional treatment protocol was standardized by giving ramipril, furosemide, and digoxin to all patients for 3 weeks at the same doses. At the end of this period, the patients were divided into three groups. Conventional treatment was continued in group 1, 25 mg spironolactone was added in group 2, and 12.5 mg metoprolol was added in group 3. Patients were followed for 12 weeks and clinical and laboratory tests were conducted at 3 week intervals. No significant change in corrected QT dispersion was observed in group 1 at the end of 12 weeks (corrected QT dispersion: 80 +/- 2 msc to 79 +/- 2 msc, P: 0.22). However, corrected QT dispersion in group 2 was reduced by 32.5% (83 +/- 2 msc to 56 +/- 1 msc; P: 0.01). A 32.9% reduction in corrected QT dispersion (79 +/- 2 msc to 53 +/- 2 msc; P: 0.01) was observed in group 3. In conclusion, the addition of spironolactone or metoprolol to a conventional treatment in heart failure patients resulted in improved clinical conditions and the significant decrease in sudden death predictors corrected QT dispersion. The effects of spironolactone and metoprolol on corrected QT dispersion were similar.

Aged↗
PubMed1984

Angiotensin II analogue infusion test in renovascular hypertension under low sodium intake and under spironolactone administration: is angiotensin II analogue infusion test useful in determining the mode of treatment?

An angiotensin II antagonist (1-Sar, 8-Ileu-angiotensin II) was infused into 5 hypertensive patients with unilateral renal artery stenosis under 5-day low sodium diet (2 g NaCl/day) and under 7-day spironolactone administration (300 mg/day). In the sodium depleted state, 1 case showed depressor response, 2 cases pressor response and the other 2 no response. During the spironolactone administration, 3 cases showed depressor, 1 case pressor, and another case no response. Angiotensin II analogue (A II A) infusion test under spironolactone administration was more effective than under sodium depletion. However, there were cases which showed pressor response, i.e. false negative, under low sodium diet and under spironolactone administration. The hypertension of these patients was cured by converting enzyme inhibitor, percutaneous transluminal renal angioplasty (PTRA) or bypass surgery. A II A infusion test has been used for screening, diagnosis and determination of the surgical repair of renovascular hypertension. However, the proportion of depressor response was low in our cases, yet pressor responders and non-responders were also cured by PTRA. PTRA is a painless and low risk procedure of the treatment of renovascular hypertension, so PTRA will become the preferential mode of therapy for the treatment of renovascular hypertension of the cases with no depressor response by AIIA infusion.

Adolescent↗