Administration Of Spironolactone Research Articles

Effect of aldosterone on the excretion of lithium in the adrenalectomized rat

The effect of aldosterone (1 microgram/kg X h) on the urinary excretion of lithium (Li) was measured by clearance studies in adrenalectomized rats receiving a glucocorticoid substitution (dexamethasone 6.6 micrograms/kg). Aldosterone induced significant anti-natriuresis and kaliuresis. The fractional excretion of Li remained constant around 28% and was not modified by aldosterone during the experiment (4 h). These results indicate that the tubular reabsorption of Li is not directly dependent on mineralocorticoid hormones. The previously reported effects of long term administration of DOCA or spironolactone of Li excretion are probably secondary to modifications of the sodium balance which, in turn, influences the proximal Li reabsorption rate.

Possible new relief for premenstrual syndrome

Treatments for premenstrual syndrome, or PMS, seem as varied as the symptoms themselves. Now to add to this diversity, Carlos Soto-Albors, MD, director of the PMS clinic and research fellow in reproductive endocrinology at the University of Connecticut Health Center, Farmington, has found in preliminary studies that 80% of 50 patients who suffer from PMS obtain relief from a new treatment, administration of spironolactone, an aldosterone antagonist. Premenstrual discomfort is characterized by one or more symptoms ranging from breast tenderness, weight gain, abdominal bloating, and headache to anxiety, irritability, crying spells, depression, and even violence ( JAMA [MEDICAL NEWS] 1981;245:1393-1396). These symptoms occur up to two weeks before menstruation in 70% to 90% of all women of childbearing age. In 5% to 40% of these women, symptoms are severe enough to substantially interfere with their lives and warrant the designation PMS. There are also connections between PMS and psychiatric illnesses ( JAMA

Enhancement of oral bioavailability of spironolactone by beta- and gamma-cyclodextrin complexations.

Inclusion complex formations of spironolactone (SP) with three cyclodextrins (α-, β-, γ-CyDs) in aqueous solution and in the solid state were studied by the solubility method, by spectroscopic methods (UV, CD, IR) and by X-ray diffractometry, and their modes of interaction were assessed. The solid complexes of SP with β- and γ-CyDs were obtained in molar ratios of 1 : 2 and 2 : 3, respectively, and their dissolution, membrane permeation and oral absorption properties were examined. The rates of dissolution and permeation through a cellophane membrane in water were significantly increased by inclusion complexation (γ-CyD complex>β-CyD complex>SP alone), depending upon the solubility of the test samples. The serum levels of SP following oral administration of CyD complexes were found to be greater than those after administration of SP alone. The results indicated that the γ-CyD complex rather than β-CyD complex may have great utility as a faster dissolving form of SP able to produce higher serum levels.

The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.

1 Canrenone, the major active metabolite of spironolactone, decreased [3H]-progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration-dependent. 2 Canrenone did not alter [3H]-oestradiol binding to isolated uterine cytosolic oestrogen receptors. 3 Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration-dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. 4 Kd for progesterone was 3.2 X 10(-9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 X 10(-9)M. Reports in the literature suggest that, following spironolactone administration, canrenone may rise to concentrations sufficiently high to inhibit progesterone binding. This action may contribute to the effect of spironolactone in inducing menstrual disturbances in female patients.

Pharmacokinetics of canrenone after oral administration of spironolactone and intravenous injection of canrenoate-K in healthy man.

Five healthy male volunteers received canrenoate-K 200 mg (Sincomen pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066 +/- 876 ng/ml was found after 29 +/- 15 min and thereafter the concentration declined with a half-life of 3.7 +/- 1.2 h. Total clearance was 4.2 +/- 1.7 ml/min . kg. After oral ingestion, the maximum concentration of 177 +/- 33 ng/ml was observed at 4.4 +/- 0.9 h. The absolute bioavailability of canrenone was 25 +/- 9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9 +/- 1.8 h (i.v.) and 3.9 +/- 1.2 h (p.o.).

Adrenal scintigraphy in primary aldosteronism. Spironolactone as a cause of incorrect classification between adenoma and hyperplasia.

In primary aldosteronism the type of adrenal lesion was correctly identified in 28 of 40 patients (70%) by standard adrenal scintigraphy. Suppression scintigraphy did not improve the validity of the method. In all patients the diagnosis was confirmed by surgery (unilateral adenoma n = 32; bilateral adrenal hyperplasia n = 11). False classification of the adrenal lesion(s) by standard scintigraphy was mostly due to a bilateral adrenal isotopic uptake in patients with an unilateral aldosteronoma. However, a substantial number of these patients (6 of 11 patients) received long-term spironolactone treatment prior to the examination. Thus, in primary aldosteronism adrenal changes induced by chronic spironolactone administration are probably a major cause for incorrect differentiation between adenoma and hyperplasia by adrenal scintigraphy.

Hypertension in a Patient With Hypercalcemia

A 38-year-old woman with hypercalcemia, severe hypertension, and high renin levels was treated with the angiotensin-converting enzyme inhibitor captopril. This therapy, together with spironolactone, normalized blood pressure (BP), but even with three daily administrations of the converting enzyme inhibitor, intermittent rebound hypertension could not be avoided. The administration of only verapamil, an antagonist of calcium transport, did not induce BP control, but when verapamil therapy was combined with administration of captopril and spironolactone, BP could be normalized with only twice-daily administration of the converting enzyme inhibitor. Thus, high plasma calcium levels seem to sensitize the arterioles to the intermittent increase of angiotensin II levels that accompanies captopril therapy.

Plasma active and inactive renin and urinary kallikrein in normal subjects in response to hydrochlorothiazide, spironolactone or aldosterone administration.

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.

Prazosin and congestive heart failure: Short- and long-term therapy

Reviewed here are the data from 34 patients given prazosin for chronic intractable heart failure. In 13 patients in whom hemodynamics were measured after the fifth 3 mg dose of prazosin was given, no attenuation was found. The cardiac index increased from 1.77 ± 0.13 to 2.5 ± 0.13 liters/min/m 2 (p < 0.001), and the pulmonary capillary wedge pressure decreased from 31.46 ± 1.56 to 23.54 ± 1.11 mg Hg (p < 0.001). During long-term follow-up (15.9 ± 1.5 months) the administration of spironolactone proved to be very useful. Within three months of starting prazosin therapy, none of the 15 patients discharged on a regimen of spironolactone needed readmission for edema, but 11 of the 13 patients discharged without a spironolactone regimen did. The addition of spironolactone or an increase in furosemide to the therapeutic regimen was helpful but a change to hydralazine was not. We conclude that prazosin causes short-term hemodynamic and long-term clinical improvement in patients with intractable heart failure; that spironolactone helps to prevent clinical attenuation but that more detailed studies are required to better characterize the attenuation to vasodilators seen in patients with congestive heart failure.

Plasma corticosteroid concentrations during spironolactone administration: evidence for adrenal biosynthetic blockade in man.

Spironolactone, a mineralocorticoid antagonist, may also inhibit aldosterone biosynthesis. In vitro studies suggest that spironolactone and its major metabolites inhibit adrenal 18- and 11 beta-hydroxylase activity. We examined various adrenal corticosteroids and their precursors, plasma renin activity, aldosterone excretion rate, and serum and urine electrolytes in normal subjects before and on days 5 and 10 of spironolactone administration (400 mg/day). Plasma corticosteroids were also examined 60 min after ACTH (Cortrosyn) 0.25-mg iv bolus. RIAs were performed after extensive chromatography; there was no interference of spironolactone and its metabolites in the assays. All studies were performed in supine subjects in metabolic balance on a constant 120-meq sodium intake. Plasma renin activity was increased (P less than 0.001) on both days 5 and 10 of spironolactone. Plasma aldosterone (PA) and the aldosterone excretion rate increased (P less than 0.01) on day 5 of spironolactone but decreased (P less than 0.01) from day 5 to 10. Both 11-deoxycorticosterone and 18-hydroxycorticosterone were increased from day 5 to 10. Corticosterone, progesterone, and dehydroepiandrosterone did not increase significantly during spironolactone administration. Incremental PA response to ACTH was less than control on day 10 of spironolactone, but other corticosteroid responses to ACTH were not different during control and days 5 or 10 of treatment. Reduction in PA and further elevation in its precursors during the second 5-day period of spironolactone therapy suggests inhibition of aldosterone biosynthesis during this phase of treatment in normal man. The disproportionate increments in 18-hydroxycorticosterone and 11-deoxycorticosterone suggest biosynthetic inhibition at the 18-dehydrogenase and 11 beta-hydroxylase sites.

Renal and systemic acid-base effects of chronic spironolactone administration.

Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.

Effect of Spironolactone Administration on Plasma Aldosterone and Plasma Renin Activity in Primary Aldosteronism

Effect of Spironolactone Administration on Plasma Aldosterone and Plasma Renin Activity in Primary Aldosteronism

Results of treatment in 68 patients with idiopathic aldosteronism in Japan.

Based on the results of a nationwide questionaire survey during the decade from 1963 in Japan, 68 cases of idiopathic aldosteronism were collected in order to investigate the actual treatment for this disorder performed in Japan. Idiopathic aldosteronism was usually treated by unilateral or subtotal adrenalectomy. Unlike resection of adenoma, adrenals surgery were not so effective and only 50% of cases obtained a favourable result. Surgical treatment was effective in 60.5% of cases of nodular hyperplasia while effective only in 26.3% of cases of diffuse hypreplasia. Opinions from answers to the questionaires favoured total bilateral adrenalectomy or subtotal adrenalectomy either with or without spironolactone administration.

Bartter's syndrome with normal urinary excretion of prostaglandin E: therapeutic effects of propranolol, spironolactone, indomethacin and potassium chloride.

Urinary excretion of prostaglandin E (PGE) in 8 patients with Bartter's syndrome measured by the radioimmunoassay method was not augmented over the normal values. In one of them, urinary excretion of sodium, potassium, chloride and PGE, serum sodium, potassium and chloride, plasma renin activity and plasma aldosterone concentration were studied before and after the administration of propranolol, spironolactone, indomethacin and potassium chloride. Neither propranolol nor spironolactone affected any of these parameters. Indomethacin promptly reduced urinary excretion of sodium, potassium, chloride and PGE, and markedly suppressed the renin-aldosterone system. Serum potassium was elevated, but remained still in hypokalemic range. Potassium chloride was most effective in raising the serum potassium level during the first 4 weeks of administration. These results suggest that overproduction of renal PGs is not the primary cause of Bartter's syndrome, and that the renal potassium wastage is one of the etiological factors in this syndrome. It has also been suggested that hyperreninemia in this syndrome was associated in some way with renal PGs, not PGE but other series of PGs.

The effect of mineralocorticoid administration on urine free dopamine in man.

1. Five normal subjects were studied under metabolic conditions on a controlled sodium and potassium intake. 2. Plasma and urine free dopamine concentrations were measured in these subjects before, during and after 5 days administration of fludrocortisone (0.2 mg twice daily). 3. Urine free dopamine showed a tendency to fall during the early phase of fludrocortisone administration and then rose towards normal. 4. In a patient with primary hyperaldosteronism there was no evidence of increased renal production of dopamine. Urine dopamine fell when plasma renin activity rose as a result of spironolactone administration (200 mg three times a day for 5 days). 5. If renal dopamine has a role in mineralocorticoid 'escape' then it may be permissive only. The mechanisms of control of dopamine production could include tubular sodium concentration, tubular chloride concentration and intrarenal renin activity.

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.

Comparison of the urinary excretion of free aldosterone and its acid-labile conjugate in rats during experimental hyperaldosteronism

A commercial antiserum was used in the development of a sensitive radioimmunoassay for the determination of free aldosterone as well as its acid-labile conjugate in rat urine. To determine which of the two products might best reflect variations of aldosterone secretion, they were both measured in the urine of rats with hyperaldosteronism induced by Na + depletion. K + loading. ACTH administration or spironolactone administration. Under each of these experimental conditions the excretion rate of both the free aldosterone and its acid labile conjugate increased. Since in the urine, free aldosterone has a higher concentration than the conjugate, a more rapid response to stimuli and is less time consuming to measure, it can be considered the compound of choice for the study of variations of aldosterone secretion in the rat.

TREATMENT OF PREMENSTRUAL SYNDROME BY SPIRONOLACTONE

Spironlactone was given to 28 women in a double blind cross over trial during four menstrual cycles. Hormonal profiles were measured during the first two cycles. Plasma aldosterone was elevated in the premenstrual phase of the cycles but there was no significant difference between symptomatic and asymptomatic groups. The rise in serum progesterone was higher in the symptomatic group during the postovulatory phase. The administration of spironolactone reduced weight and relieved psychological symptoms in more than 80 per cent of the symptomatic group.

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.

Relation of Canrenone to the Actions of Spironolactone on Adrenal Cytochrome P-450-Dependent Enzymes*

Studies were carried out to determine the actions of spironolactone (SL) and its metabolite, canrenone, on adrenal mixed function oxidases in the guinea pig. Administration of SL (25 mg/kg day for 3 days) to adult male guinea pigs decreased adrenal mitochondrial and microsomal cytochrome P-450 concentrations. The activities of various cytochrome P-450- dependent enzymes, including mitochondrial 11β-hydroxylase and microsomal 21-hydroxylase, benzo(a)-pyrene (BP) hydroxylase and ethylmorphine (EM) demethylase, were also reduced by SL treatment. Canrenone, when given at the same dose, had no effect on mitochondrial or microsomal cytochrome P-450 levels. Pretreatment with canrenone decreased 11β- and 21- hydroxylase activities but did not affect BP hydroxylation or EM demethylation. Addition of SL or canrenone to isolated adrenal mitochondria or microsomes produced typical type I difference spectra. Both compounds inhibited the binding of steroid substrates to cytochrome P-450 in isolated mitochondria and mic...