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PubMed1985

In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay.

We have established a sensitive and specific radioreceptor assay for androgen receptor active materials in plasma, using tritiated methyltrienolone ([3H]R1881) as tracer, and spayed mouse kidney cytosol receptor as the binding species. On radioreceptor assay, plasma from mice chronically administered spironolactone contained approximately 10 times higher levels of androgen receptor active material than from mice administered potassium canrenoate. In parallel bioassays (antagonism of the effect of testosterone on seminal vesicle weight), spironolactone was greater than 4 times as potent an antiandrogen as potassium canrenoate. Administered potassium canrenoate circulates as canrenoic acid, in equilibrium with its lactonized congener canrenone. Since over 80% of administered spironolactone is irreversibly converted to canrenone/canrenoic acid, its much higher anti-androgen activity on radioreceptor assay and bioassay may point to the generation of unidentified, minor metabolites with very high affinity for androgen receptors and/or a very long plasma half-life.

Animals↗
PubMed1976

The effect of spironolactone on transport of Na+, K+ and H+. A microperfusion study in rat main submaxillary duct.

The epithelium of the main excretory duct of the rat submaxillary gland was used as a target tissue for studies on the effect of a spironolactone on electrolyte transport. The spironolactone decreased net Na+ reabsorption by 27% and net K+ secretion by 23%. HCO-3 was found to be about 2-fold accumulated in the duct lumen, which was considered to result from decreased H+ion secretion. The results can be reconciled with an action of spironolactone on 1) the peritubular Na+-K+-exchange mechanism and 2) the functional coupling of Na+ entry from lumen to cell with K+ and H+ transfer from cell to lumen.

Animals↗
PubMed1992

Development of a stable oral liquid dosage form of spironolactone.

A clear, stable, oral liquid dosage form of spironolactone has been developed. Solubility profiles of spironolactone were obtained in several co-solvent blends. Using this data, a co-solvent blend containing polyethylene glycol 400 (30% v/v), propylene glycol (10% v/v), glycerin (10% v/v) and ethyl alcohol (10% v/v) was used to solubilize spironolactone at a concentration of 2 mg/ml. The final formulation contained sweetening agents (sucrose, saccharin sodium), flavours (cherry, sweet), a desensitizing agent (menthol), a dye (FD&C Red #40) and a preservative (benzoic acid) to incorporate the desired organoleptic and preservative properties. A phosphate buffer was used to maintain a pH value of 4.5 (pH of maximum stability as reported earlier) to minimize hydrolysis. The final dosage form was stable for at least 93 days at 40 degrees C (loss of potency less than 4%). According to FDA guidelines, a tentative expiration date of 2 years at 25 degrees C is justifiable.

Administration, Oral↗
PubMed1982

The effect of ethacrynic acid, bumetanide, frusemide, spironolactone and ADH on electrolyte excretion in ponies.

The effect of ethacrynic acid, bumetanide, frusemide, spironolactone and anti-diuretic hormone (ADH) on the urinary and faecal excretion of water and electrolytes by ponies was studied. Ethacrynic acid, bumetanide, and frusemide given intravenously, increased urinary sodium excretion, and, excepting frusemide, decreased faecal sodium excretion. Given by stomach tube ethacrynic acid reduced urinary and faecal sodium. Bumetanide, given intravenously, spironolactone, frusemide and ADH increased urinary sodium and all except frusemide intravenously decreased faecal sodium regardless of route of administration. Ethacrynic acid and bumetanide, given by stomach tube or intravenously decreased urinary and faecal potassium excretion, as did spironolactone and frusemide given orally. Ethacrynic acid and bumetanide given orally or intravenously, frusemide given orally and ADH intranasally reduced urinary chloride excretion; these same drugs by the same routes also reduced faecal chloride excretion. Excepting frusemide given intravenously, and ethacrynic acid orally, the effect of the drugs studied was not the same on urinary sodium excretion as on faecal sodium excretion. This suggested that different mechanisms were involved in the control of sodium excretion by the kidney and in the gut. There were similarities in the treatment of potassium and chloride by these organs.

Animals↗
PubMedDate not supplied

Androgens in the feedback regulation of gonadotropin secretion in men: effects of administration of dihydrotestosterone to eugonadal and agonadal subjects and of spironolactone to eugonadal subjects.

To study the role of androgens in the feedback regulation of gonadotropin secretion, we measured the effects of administration of dihydrotestosterone undecanoate (DHTU) and of spironolactone. Basal and LRH stimulated LH/FSH levels were determined in: Six eugonadal men, before and after six weeks' DHTU 120 mg/day. Six agonadal subjects after 12 weeks' DHTU 120 mg/day. The results of B were compared to those of Six agonadal subjects without sex steroid treatment. Six eugonadal subjects were studied before and after six weeks' administration of spironolactone. In the two groups of eugonadal subjects, administration of either dihydrotestosterone or spironolactone had no effect on basal and LRH-stimulated gonadotropin levels. A clear but modest suppression was observed in agonadal subjects. Possibly DHT exerts some suppressive effect on gonadotropin secretion in the absence of other testicular products (estradiol, testosterone, inhibin), known to play a role in the negative feedback regulation. From these data it seems unlikely that in the eugonadal male circulating DHT has an important role in the feedback regulation of gonadotropin secretion.

Adult↗
PubMed1994

A girl having congenital chloride diarrhea treated with spironolactone for seven years.

We report on a girl having congenital chloride diarrhea (CCD) who has been followed for 7 years and 6 months sequentially. Dilated intestinal loops, marked enlargement of the abdominal circumference of the fetus and hydramnios were noted by ultrasound examination at 31 weeks of gestation. After delivery by cesarean section for hydramnios, she excreted profuse watery yellow green stools with marked abdominal distension. At 4 months of age, hypochloremia, hyponatremia and a high concentration of chloride in the stool were identified. She was diagnosed as having CCD. Because it was difficult to administer a large volume of potassium chloride (KCl), and sodium chloride (NaCl), we decided to administer spironolactone. After administration of spironolactone, we could generate correct serum electrolytes using less amounts of KCl. At 7 years and 6 months of age, her body size was within normal limits and her intellectual, mental and physical development had been normal. In spite of normal serum electrolytes, blood pH and the presence of chloriduria, secondary hyperaldosteronism was noted. We consider that spironolactone may be useful to decrease the amount of KCl administration in the neonatal period, but frequent measurements of renin, angiotensin and aldosterone would be necessary for adequate control in CCD cases.

Child↗
PubMed1981

Spironolactone therapy in infants with congestive heart failure secondary to congenital heart disease.

The efficacy of treatment with spironolactone for congestive heart failure secondary to congenital heart disease was studied in 21 infants under 1 year of age. All received digoxin and chlorothiazide. In addition, group A (n = 10) was given supplements of potassium and group B (n = 11) received spironolactone. Daily clinical observations of vital signs, weight, hepatomegaly, and vomiting were recorded. Paired t test analysis showed significant reduction in liver size and weight (P less than 0.01) and respiratory rate (P less than 0.05) in group B, and less significant decreases in group A. The incidence of vomiting was slightly lower in group B. We conclude that the addition of spironolactone hastens and enhances the response to standard treatment with digoxin and chlorothiazide in infants with congestive heart failure.

Chlorothiazide↗
PubMed1972

Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin.

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery.Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment.In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied.Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped.In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.

Adenoma↗
PubMed2006

Spironolactone and risk of upper gastrointestinal events: population based case-control study.

OBJECTIVE: To confirm and quantify any association between spironolactone and upper gastrointestinal bleeding and ulcers. DESIGN: Population based case-control study. SETTING: A primary care information database in the Netherlands. PARTICIPANTS: All people on the database who were aged 18 or more between 1 January 1996 and 30 September 2003. Patients with a history of alcoholism or gastrointestinal cancer were excluded. Ten controls were matched to each case of gastroduodenal ulcer or upper gastrointestinal bleeding by age (year of birth), sex, and index date. MAIN OUTCOME MEASURES: The occurrence of an upper gastrointestinal event (bleeding or ulcers), adjusted for potential confounders with conditional logistic regression analysis. RESULTS: Within the source population of 306 645 patients, 523 cases of gastric or duodenal ulcer or upper gastrointestinal bleeding were identified and matched to 5230 controls. Current use of spironolactone was associated with a 2.7-fold (95% confidence interval 1.2 to 6.0) increased risk of a gastrointestinal event. CONCLUSION: The risk of gastroduodenal ulcers or upper gastrointestinal bleeding is significantly increased in patients using spironolactone.

Adolescent↗
PubMed1970

Spironolactone diuresis in patients with cirrhosis and ascites.

Increased aldosterone levels with consequent or diuretic-potentiated electrolyte abnormalities are an important consideration when patients with cirrhosis and ascites undergo diuresis. A simple clinical method using the urinary Na/K ratio as a guide to spironolactone dosage is outlined. Patients with a ratio greater than 1 responded well to 100 mg. of spironolactone a day; those when it was one or less responded well to 200 to 1,000 mg. a day.Administration of spironolactone alone (11 patients) or as the main diuretic (three patients) was a safe and effective means of inducing sustained uncomplicated diuresis in all these patients.

Alcoholism↗
PubMed1979

Interaction of spironolactone with rat skin androgen receptor.

Some characteristics of the dorsal skin cytoplasmic androgen receptor (AR) have been studied in male rats. The affinity constant, the binding specificity, and the sedimentation profile of the receptor have been found to be similar to the rat prostate AR. The measurement of the number of binding sites in various hormonal conditions (deprivation) led to the conclusion that this receptor was largely occupied by endogeneous hormones from gonadal and (or) adrenal sources. Administration of spironolactone or canrenone to 7-day-castrated rats was accompanied by a rapid and drastic decrease of available binding sites. This diminution was ascribed to the competitive inhibition of canrenone, the active in vivo metabolite of spironolactone. It is postulated that the antiandrogenic action of spironolactone, at the skin level, is mediated by canrenone which inhibits the formation of specific testosterone and (or) 5 alpha-dihydrotestosterone receptor complex in cytoplasm and consequently in nuclei.

Adrenalectomy↗
PubMed1990

Sex differences in spironolactone induction of rat intestinal and hepatic p-nitrophenol UDP-glucuronyltransferase.

In the present study we analyzed the effect of spironolactone administration on hepatic and intestinal p-nitrophenol-UDP-glucuronyltransferase activity. We used microsomal preparations from male and female Wistar rats to establish whether or not this effect was sex dependent. Enzyme activity was measured in the presence of UDP-N-acetylglucosamine, a presumed physiological activator of the enzyme. Female but not male microsomes showed an increase in enzyme activity of both hepatic and intestinal tissue preparations in response to the inducer pretreatment. In addition, the inducer effect observed in female rats showed a tissue-related difference, since percent increase in the intestinal enzyme activity was greater than that in the liver (127 and 52%, respectively). These results suggest that factors regulating enzyme activity or mechanisms involved in the inducer effect of spironolactone could be different in the intestinal mucosa in comparison to the liver. A possible explanation of sex-related response to spironolactone administration was discussed.

Animals↗
PubMed1981

Effects of spironolactone and amiloride on corticosteroid-induced changes in colonic function.

Mineralocorticoid and glucocorticoid effects on colonic electrolyte absorption were compared by examining the alterations caused by spironolactone and amiloride in corticosteroid-treated rats. Animals were treated for 3 days with deoxycorticosterone acetate (DOCA; 0.5 mg . 100 g-1 . day-1), methylprednisolone (MP; 3 or 0.5 mg . 100 g-1 . day), and spironolactone (14 mg . 100 g-1 . day-1 im) singly or in combination. On day 4, rats were anesthetized with pentobarbital sodium and perfused in vivo with Ringer-HCO3 solution. Both doses of MP and DOCA increased net colonic sodium and water absorption and mucosal Na-K-ATPase activity. Concurrent spironolactone treatment completely prevented these effects in DOCA-treated rats but had no effect in MP-treated rats. Untreated, MP-treated, and DOCA-treated animals were perfused with a Ringer-HCO3 solution containing 1 mM amiloride. Amiloride reduced net colonic sodium and water absorption, transmural potential difference, and potassium secretion in all rats by approximately 55%. These effects were almost immediate and completely reversible. These findings in the rat suggest that 1) different receptors mediate the colonic effects of mineralocorticoids and glucocorticoids and 2) these corticosteroids do not differ in their relative effects on amiloride-sensitive and amiloride-resistant colonic sodium transport processes.

Adrenal Cortex Hormones↗
PubMed2005

Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure.

Angiotensin-converting enzyme (ACE)-2 is a newly described enzyme with antagonistic effects to those of the classical ACE (ACE-1). Both ANG II and aldosterone play an important role in the pathophysiology of congestive heart failure (CHF) and in the adverse cardiac remodeling during its development. In this study, we examined the effects of experimental CHF induced by an aortocaval fistula (ACF) and of its treatment with ANG II and aldosterone inhibitors on the relative levels of ACE-1 and ACE-2. We also compared the effects of spironolactone, an aldosterone antagonist, and eprosartan, an ANG II receptor antagonist, on heart hypertrophy and fibrosis in rats with ACF. Spironolactone (15 mg x kg(-1) x day(-1) ip, via minipump) or eprosartan (5 mg x kg(-1) x day(-1) ip, via minipump) was administered into rats with ACF for 14 and 28 days. Specific antibodies were used to determine the protein levels of myocardial ACE-1 and ACE-2. ACF increased the cardiac levels of ACE-1 and decreased those of ACE-2. Heart-to-body weight ratio significantly increased from 0.30 +/- 0.004% in sham-operated controls to 0.50 +/- 0.018% and 0.56 +/- 0.044% (P < 0.001) in rats with ACF, 2 and 4 wk after surgery, respectively, in association with increased plasma levels of aldosterone. The area occupied by collagen increased from 2.33 +/- 0.27% to 6.85 +/- 0.65% and 8.03 +/- 0.93% (P < 0.01), 2 and 4 wk after ACF, respectively. Both spironolactone and eprosartan decreased cardiac mass and collagen content and reversed the shift in ACE isoforms. ACF alters the ratio between ACE isoforms in a manner that increases local ANG II and aldosterone levels. Early treatment with both ANG II and aldosterone antagonists is effective in reducing this effect. Thus ACE isoform shift may represent an important component of the development of cardiac remodeling in response to hemodynamic overload, and its correction may contribute to the beneficial therapeutic effects of renin-angiotensin-aldosterone system inhibitors.

Acrylates↗
PubMed2005

Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats.

Reversal by the mineralocorticoid receptor antagonist spironolactone on cardiac and renal abnormalities, associated with long-term (since weaning) administration of a high (2 and 8% NaCl chow, HS2 and HS8) sodium diet, was assessed in Sprague-Dawley rats. At the age of 5 mo, spironolactone (20 or 100 mg/kg, gavage) or placebo were given for 14 days to HS2 and HS8 rats. A group fed a regular diet (0.8% NaCl, NS) remained untreated. High sodium intake had no detectable effect on blood pressure; however, cardiac mass index and cross-sectional area of the carotid artery, as well as albuminuria, were increased only in the HS8 group compared with the control group on NS diet. In addition, a marked reduction in glomerular filtration rate (by 40%), associated with a nonproportional fall in renal plasma flow (thus resulting in a decrease in filtration fraction), was observed only in the HS8 group. No change in cardiac and renal fibrosis was detected. Production of the reactive oxygen species (ROS) by aortic tissue was increased in HS8 rats, whereas ROS production by the heart was unaffected. Only the high dose of spironolactone was effective, as it markedly reversed the cardiac hypertrophy and renal hypofiltration associated with the HS8 feeding. The changes were observed in the absence of any effect on systemic blood pressure and production of ROS. These observations favor aldosterone's role in the deleterious effects of marked and prolonged increases in sodium intake.

Administration, Oral↗
PubMed1996

Effects of aldosterone and spironolactone on the isolated perfused rat heart.

Aldosterone antagonists are used in the treatment of hypertension. However, the cardiac influences of aldosterone and its antagonists have not been thoroughly investigated. In the present study, we investigated the effects of aldosterone and spironolactone on an isolated rat working heart model. Aldosterone (10(-8) mol/l) decreased the coronary flow and increased aortic flow and cardiac output. Spironolactone (10(-5) mol/l) inhibited these effects. These results suggest that aldosterone directly influences the cardiac function. Spironolactone appears able to inhibit the adverse cardiac effects of aldosterone. The exact mechanisms remain to be elucidated, but the early effects of aldosterone under our experimental conditions on the functional parameters of the heart suggest a nongenomic response including activation of receptors different from those transmitting genomic steroid actions.

Aldosterone↗
PubMed1979

Influence of age and spironolactone on lysosomal enzyme activities, DNA and protein content of the rat liver after partial hepatectomy.

Measurements of DNA and protein content and determinations of lysosomal enzyme activities (beta-glucuronidase, beta-acetylglucosaminidase, cathepsin D) were performed in the rat liver following partial hepatectomy and spironolactone administration. The rats (SIV) were divided into three age-groups: 6 weeks old, 10 months old and 18 months old. 60 h after the administration of spironolactone (2 x 10 mg Aldactone/100 g body weight/day orally via gastric tube for 3 days) partial hepatectomy was performed. The removed two thirds of the liver and the regenerating liver (24 h after partial hepatectomy) were prepared for the biochemical examinations at 4 degrees C. The measurements of the enzyme activities were performed in liver homogenates. The results indicate that the administration of spironolactone cause (1) a weight increase in the normal as well as in the regenerating liver, especially in the older animals; (2) an increase of the protein content of the normal liver in the oldest age-group; (3) a decrease in the DNA content of the normal and regenerating liver of old rats, and (4) an age-dependent increase of decrease of the three lyososomal enzymes beta-glucuronidase, beta-acetylglucosamidase and cathepsin D.

Acetylglucosaminidase↗