SEARCH · Search PubMed

Results for “SPIRONOLACTONE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources

PubMed2006

Mineralocorticoid receptor antagonist spironolactone prevents pig serum-induced hepatic fibrosis in rats.

Mineralocorticoid receptor (MR) antagonist spironolactone (SPL) is an effective agent for prevention of cardiovascular injury. However, whether and how SPL ameliorates hepatic fibrosis in rats is unknown. Pig serum (PS) (0.5 mL, twice a week, ip) or vehicle-administered rats for 12 weeks were used as rats with hepatic fibrosis or control rats, respectively. Rats given PS were treated with SPL (50 mg/kg/day, sc) for 12 weeks. Hepatic fibrosis, using picro-sirius red staining and determination of hydroxyproline content, immunohistochemistries of alpha-smooth muscle actin (alpha-SMA)-positive hepatic stellate cells (HSCs), Na/H exchange isoform-1 (NHE-1) protein, CYP11B2 aldosterone synthase protein for liver tissues, and plasma aldosterone concentrations were compared among the 3 groups of rats. Rats given PS alone exhibited hepatic fibrosis as well as increases in the number of the alpha-SMA-positive HSCs and NHE-1 protein expression in HSCs and hepatocytes, all of which were suppressed by SPL. Rats given PS alone revealed increased CYP11B2 protein expression in HSCs and hepatocytes, which was not inhibited by SPL. Plasma aldosterone concentrations were significantly greater in rats given PS and SPL than in control rats and rats given PS alone, although they were not different between control rats and rats given PS alone. PS-induced hepatic fibrosis together with HSC activation and NHE-1 protein expression occurs via MRs, and SPL ameliorates hepatic fibrosis presumably via the inhibition of HSC activation and NHE-1 protein expression in PS-induced liver injuries. The aldosterone produced in the injured liver contributes to the PS-induced hepatic fibrosis.

Actins↗

PubMed2003

Effect of spironolactone on the expression of rat hepatic UDP-glucuronosyltransferase.

Spironolactone (SL) increases the glucuronidation rate of several compounds. We analyzed the molecular basis of changes occurring in major rat liver UDP-glucuronosyltransferase (UGT) family 1 isoforms and in UGT2B1, a relevant isoform of family 2, in response to SL. UGT activity toward bilirubin, ethynylestradiol and p-nitrophenol was assayed in native and activated microsomes. Protein and mRNA levels were determined by Western and Northern blotting. The lipid composition and physicochemical properties of the microsomal membrane were also analyzed. Glucuronidation rates of bilirubin and ethynylestradiol (at both 3-OH and 17 beta-OH positions), determined in UDP-N-acetylglucosamine-activated membranes, were increased in SL group. Western blot analysis revealed increased levels of UGT1A1 and 1A5 (bilirubin and 3-OH ethynylestradiol conjugation), and 2B1 (17 beta-OH ethynylestradiol conjugation). Northern blot studies suggested transcriptional regulation by the steroid. Analysis of UGT activity in native vs. alamethicin-activated microsomes indicated increased latency, which was not associated to changes in physicochemical properties of the microsomal membrane. p-Nitrophenol glucuronidation rate and mRNA and protein levels of UGT1A6, the main isoform conjugating planar phenols, were not affected by the inducer. The data suggest transcriptional regulation of specific isoforms of hepatic UGT by SL, thus explaining previously reported increases in UGT activity toward selective substrates.

Animals↗

PubMed1984

Serum estradiol and danazol. I. Endometriosis response, side effects, administration interval, concurrent spironolactone and dexamethasone.

Serum estradiol (E2) levels and resolution of endometriosis were evaluated in 42 women after 75 days of danazol treatment. Complete or almost complete remission occurred when radioimmunoassay E2 levels were less than 15 pg/ml in extensive, less than 22 pg/ml in severe, and less than 41 pg/ml in moderate endometriosis. E2 less than or equal to 20 pg/ml occurred in 23% of 104 patients given 400 mg every 12 hours but in none weighing over 150 pounds (68 kg). E2 greater than 100 pg/ml occurred in 7%. The mean E2 levels were identical with 400 mg every 12 hours and 200 mg every 8 hours. The E2 level was 40% lower with 200 mg every 6 hours than with 400 mg every 12 hours (P less than 0.001). Dexamethasone further decreased E2 levels by 61% (P less than 0.001). Spironolactone decreased androgen symptoms but increased E2 levels by 49% (P less than 0.01).

Adult↗

PubMed1985

The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women.

Spironolactone (S) has been used successfully for the treatment of hirsutism. We evaluated whether the effects of S on serum androgens and hair growth are dose-related and whether S affects secreted androgens to the same degree as peripherally derived androgens. Two groups of 15 hirsute patients, similarly matched, received either 100 or 200 mg S daily for 3 months. Serum total testosterone (T) decreased significantly (P less than 0.05) and to a similar degree with both dosages, whereas unbound T was unaltered. Dehydroepiandrosterone sulfate was unaltered, whereas androstenedione decreased with 200 mg S (P less than 0.05). Peripherally derived serum dihydrotestosterone decreased to a similar degree with 100 and 200 mg S (P less than 0.05), whereas 5 alpha-androstane-3 alpha-17 beta-diol (3 alpha-diol) increased (P less than 0.05) similarly with both dosages. Serum 3 alpha-diol glucuronide (3 alpha-diol-G) increased with both dosages, but not significantly. Anagen hair shaft diameters decreased significantly in both groups by 19% +/- 8% and 30% +/- 4% (P less than 0.05). No correlation was found between hair growth and serum androgens. Because serum unbound T was largely unaltered by S, it is suggested that the antiandrogenic effects of S are primarily related to its peripheral effect. However, there is no good clinical marker for this effect as levels of 3 alpha-diol and 3 alpha-diol-G increase.

Adult↗

PubMed1997

Prevention of portal hypertension by propranolol and spironolactone in rats with bile duct ligation.

BACKGROUND/AIMS: It has been suggested that the early administration of propranolol (PR) and a low sodium diet may prevent the development of portosystemic shunts in animals with presinusoidal portal hypertension. Our aim was to study the hemodynamic effects of the early and chronic administration of PR and spironolactone (SPN), alone or in combination, in a model of hepatic fibrosis and sinusoidal portal hypertension induced in rats by bile duct ligation. METHODS: A blind study was performed in 40 Sprague-Dawley rats divided into four groups: placebo (PL), PR (75 mg/kg per day), SPN (100 mg/kg per day), and PR+SPN at the same doses. Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the splanchnic and systemic hemodynamics (radiolabeled microspheres) were evaluated. RESULTS: a) Systemic hemodynamics: PR significantly reduced cardiac index and increased vascular resistance, SPN had no significant effect and PR+SPN significantly decreased mean arterial pressure. b) Splanchnic hemodynamics: portal venous pressure (PL: 15.5 +/- 1.5, PR: 14.8 +/- 1.0, SPN: 13.5 +/- 2.1, PR+SPN: 15.0 +/- 1.3 mmHg, p < 0.05) and portosystemic shunts (PL: 30 +/- 31, PR: 13 +/- 14, SPN: 5 +/- 4, PR+SPN: 29 +/- 33%, p < 0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. In multivariate analysis, the only determinant of portosystemic shunts was portal pressure but with a low R2 (0.2). CONCLUSIONS: In this model, the early administration of PR, alone or in combination with SPN, had no beneficial hemodynamic effects. On the other hand, SPN alone decreased portal pressure and prevented portosystemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

Animals↗

PubMed2001

Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice.

Surveys of prescribing in both hospitals and primary care have shown delays in translating improved survival data from clinical trials into clinical practice thereby denying patients the benefits of proven treatments, such as the angiotensin converting enzyme inhibitors. This may be due to unfamiliarity with clinical guidelines and concerns about adverse events. Recent trials have shown that substantial improvements in survival are associated with spironolactone and beta-blocker therapy. In order to accelerate the uptake of these treatments, and to ensure that all eligible patients should receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of heart failure. The objective of these recommendations is to provide practical guidance for non-specialists in order to support the implementation of evidenced-based therapy for heart failure. These practical recommendations are meant to supplement rather than replace existing guidelines.

Adrenergic beta-Antagonists↗

PubMed1989

Oxidative metabolism of spironolactone: evidence for the involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450.

In a preliminary paper [Decker et al. (1986) Biochem. Biophys. Res. Commun. 136, 1162] we have shown that the antimineralocorticoid spironolactone (SPL) preferentially inactivates dexamethasone (DEX) inducible rat hepatic cytochrome P450p isozymes in a suicidal manner. These findings are now confirmed, and the kinetic characteristics of such a process are detailed. In an effort to elucidate the mechanism of SPL-mediated inactivation of cytochrome P450, we have examined the metabolism of SPL in vitro. Incubation of [14C]SPL and NADPH with liver microsomes prepared from DEX-pretreated rats results in the formation of several polar metabolites separable by HPLC with UV detection. This process is found to be dependent on NADPH, O2, SPL, and enzyme concentration, as well as temperature. Furthermore, metabolite formation was significantly attenuated by P450 inhibitors CO and n-octylamine. Mass spectral analysis (thermospray LC/MS, FAB/MS, and FAB/MS/MS) of the two most prominent polar metabolites indicated that these compounds had molecular weights that corresponded to the sulfinic and sulfonic acid derivatives of deacetyl-SPL (SPL-SH). These findings document the formation of previously unreported polar metabolites of SPL by rat liver microsomes enriched in cytochrome P450p and implicate a role for this isozyme in the oxidation of the thiol moiety of deacetyl-SPL. The detection of such metabolites also implicates a catalytic trajectory that includes the thiyl radical and/or sulfenic acid species as a plausible protagonist in drug-mediated inactivation of cytochrome P450p.

Animals↗

PubMedDate not supplied

Formation of glutathionyl-spironolactone disulfide by rat liver cytochromes P450 or hog liver flavin-containing monooxygenases: a functional probe of two-electron oxidations of the thiosteroid?

We have previously reported that the diuretic thiosteroid spironolactone (SPL) inactivates rat liver microsomal cytochromes P450 [P450 (P450 3A and P450 2C11)] in a in a mechanism-based fashion, and we have identified two polar SPL metabolites (SPL-sulfinic acid and -sulfonic acid), formed in a partition ratio of approximately 20:1 in such rat liver microsomal incubations [Decker et al. (1989) Biochemistry 28, 5128-5136]. We proposed at the time that these metabolites were most likely derived from further enzymatic (or nonenzymatic) oxidations of the one-electron oxidation product [SPL-thiyl radical (SPL-S.)] and/or the two-electron-oxidized species [SPL-sulfenic acid (SPL-SOH)]. In those studies, glutathione (GSH) was found to attenuate both SPL-mediated P450 loss as well as polar metabolite formation by approximately 40%. We have now reexamined this in greater detail and report that it is due to GSH trapping of an electrophilic oxidized SPL species to form an adduct that we have isolated and unambiguously characterized by mass spectral analyses as the glutathionyl-SPL adduct (SPL-SSG). Moreover, we have found not only that rat liver microsomal formation of this adduct is enhanced at pH 9.0, the pH optimum for flavin-containing monooxygenase (FMO), but also that such adduct formation was indeed efficiently catalyzed by purified hog liver FMO. Because FMO oxidations of thiols are thought to entail a two-electron process to form the corresponding sulfenic acids, we infer that such a SPL-SSG adduct most likely reflects FMO-catalyzed oxidation of SPL to SPL-SOH, which on leaving the FMO active site is then trapped by GSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Dose-response relationships for spironolactone at steady state.

The overnight urine electrolyte and plasma potassium responses to spironolactone (25, 50, 100, and 200 mg daily) at steady state were investigated in 11 healthy subjects after fludrocortisone challenge. For sodium excretion and urine log10 10 Na/K, log dose-response relationships were defined (P less than 0.001 in each case), but there was little evidence of dose-related influences on potassium excretion or plasma potassium. The findings confirm the limitations of the fludrocortisone model in evaluating the potassium-sparing properties of aldosterone antagonists at steady state and of the urine sodium; potassium ratio as an overall index of renal antimineralocorticoid activity.

Adult↗

PubMed2005

Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1 + minK channels.

Both spironolactone (SP) and its main metabolite, canrenoic acid (CA), prolong cardiac action potential duration and decrease the Kv11.1 (HERG) current. We examined the effects of SP and CA on cardiac hKv1.5, Kv4.3 and Kv7.1+minK channels that generate the human I(Kur), I(to1) and I(Ks), which contribute to the control of human cardiac action potential duration.hKv1.5 currents were recorded in stably transfected mouse fibroblasts and Kv4.3 and Kv7.1 + minK in transiently transfected Chinese hamster ovary cells using the whole-cell patch clamp. SP (1 microM) and CA (1 nM) inhibited hKv1.5 currents by 23.2 +/- 3.2 and 18.9 +/- 2.7%, respectively, shifted the midpoint of the activation curve to more negative potentials and delayed the time course of tail deactivation.SP (1 microM) and CA (1 nM) inhibited the total charge crossing the membrane through Kv4.3 channels at +50 mV by 27.1 +/- 6.4 and 27.4 +/- 5.7%, respectively, and accelerated the time course of current decay. CA, but not SP, shifted the inactivation curve to more hyperpolarised potentials (V(h)-37.0 +/- 1.8 vs -40.8 +/- 1.6 mV, n = 10, P < 0.05).SP (10 microM) and CA (1 nM) also inhibited Kv7.1 + minK currents by 38.6 +/- 2.3 and 22.1 +/- 1.4%, respectively, without modifying the voltage dependence of channel activation. SP, but not CA, slowed the time course of tail current decay.CA (1 nM) inhibited the I(Kur) (29.2 +/- 5.5%) and the I(to1) (16.1 +/- 3.9%) recorded in mouse ventricular myocytes and the I(K) (21.8 +/- 6.9%) recorded in guinea-pig ventricular myocytes.A mathematical model of human atrial action potentials demonstrated that K(+) blocking effects of CA resulted in a lengthening of action potential duration, both in normal and atrial fibrillation simulated conditions. The results demonstrated that both SP and CA directly block hKv1.5, Kv4.3 and Kv7.1 + minK channels, CA being more potent for these effects. Since peak free plasma concentrations of CA ranged between 3 and 16 nM, these results indicated that blockade of these human cardiac K(+) channels can be observed after administration of therapeutic doses of SP. Blockade of these cardiac K(+) currents, together with the antagonism of the aldosterone proarrhythmic effects produced by SP, might be highly desirable for the treatment of supraventricular arrhythmias.

Animals↗

PubMed2000

Use of partial least-squares regression for multicomponent determinations based on kinetic spectrofluorimetric data. Simultaneous determination of canrenone and spironolactone in urine.

A new spectrofluorimetric method for the simultaneous determination of canrenone and spironolactone in urine is proposed. The method is based on the different rates at which the two analytes react with hot sulfuric acid to form a trienone. The kinetic spectrofluorimetric data are processed by partial least-squares regression. The effects of sulfuric acid concentration and temperature on the system under study were also evaluated and the optimum values for carring out the reaction were 50% and 50 degrees C, respectively. The method was checked by analyzing urine samples that they contained both diuretics. The accuracy and the precision of the method were tested. The relative standard errors in the quantification of each analyte in all tested samples were 3.69 and 3.59%. The proposed method was validated by comparison with a high performance liquid chromatographic method for urine samples.

Canrenone↗

PubMed1976

The effects of aldosterone and spironolactone on renal kallikrein in the rat.

1. A technique has been developed for the measurement of kallikrein 'production' in rat renal cortical cells in suspension. 2. After preparative steps, column chromatography on DEAE-cellulose yielded a peak of alpha-N-tosyl-L-arginine methyl ester (Tos-Arg-OMe) esterase activity identical with kallikrein isolated from rat urine in respect of pH optimum, effects of inhibitors, biological activity and immunological properties. 3. The nutrient medium surrounding incubated cells contained measurable kallikrein activity, which was increased by aldosterone and decreased by spironolactone. 4. The results raised the possibility that kallikrein could be an aldosterone-induced protein.

Aldosterone↗

PubMed2000

Spironolactone in heart failure--a revived role for an old drug.

Spironolactone is an aldosterone antagonist which has been used as a mild potassium-sparing diuretic and in treatment of ascites in liver failure. Recent studies have shown that it has an additive effect to those of ACE inhibitors in heart failure treatment.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1978

[Treatment of essential hypertension with a combination of propranolol, spironolactone-thiabutazide and dihydralazine (author's transl)].

In 61 out-patients with essential hypertension, grade I or II, propranolol was administered alone in increasing doses (3 x 40 mg/d or 3 x 80 mg/d) or, if there was insufficient response, with a double or triple combination consisting additionally of spironolactone (50 mg/d)-thiabutazide (5 mg/d) and dihydralazine (3 x 25 mg/d). This treatment schedule achieved normal pressures in 51 patients, in 22 on 40 mg, in 7 on 80 mg propranolol, in 16 after the addition of the diuretic, and in 6 with the triple combination. Four patients had to be excluded from the study because they developed either marked bradycardia or anxiety states or paraesthesias after propranolol (3 x 40 mg/d). On chronic beta-adrenergic blockade the serum potassium level increased slightly, but remained within normal limits. The initial value of plasma-renin activity was highest in the group of those who responded to the propranolol treatment.

Anxiety↗

PubMed1990

Spironolactone inhibition of cortisol production by guinea pig adrenocortical cells.

Prior investigations with adrenal subcellular fractions demonstrated that the diuretic, spironolactone (SL), was converted to a reactive metabolite by adrenal microsomes, resulting in the degradation of microsomal cytochrome(s) P-450. Studies were done to evaluate the effects of SL and 7 alpha-thio-SL, a putative intermediate in the activation pathway, on cortisol production by intact guinea pig adrenocortical cells. Preincubation of adrenal cells with SL or 7 alpha-thio-SL caused time-dependent and concentration-dependent decreases in subsequent ACTH-stimulated cortisol production. 7 alpha-Thio-SL was a far more potent inhibitor than SL. In the absence of a preincubation period, neither SL nor 7 alpha-thio-SL affected cortisol production. The results indicate that the effects of SL on adrenal microsomal cytochrome(s) P-450 compromise steroid synthesis by intact adrenal cells and lend support to the hypothesis that metabolism of the drug is required for the inhibition of steroidogenesis.

Adrenal Cortex↗

PubMed1980

[Effect of spironolactone on intraocular pressure in glaucoma patients].

In order to eliminate a previously reported stimulation of aqueous humor production by aldosterone, 22 glaucoma patients were treated for two weeks with 200 mg Spironolactone daily. The intra-ocular pressure decreased significantly and was still distinctly below the original values 14 days after termination of treatment.

Glaucoma↗

PubMed1983

[Pigmented exanthema after spironolactone allergy in progressive systemic scleroderma].

A 37-year-old man developed generalized medium-brown hyperpigmentation in the course of progressive systemic scleroderma. Histologically there were numerous Melanin granules in the basal epidermis, but also in the upper Malpighian layer and in corneocytes. An allergic rash developed on administration of spironolactone given for the scleroderma. After healing there remained slate-grey spots. As a consequence of the drug rash the already present hyperpigmentation was aggravated by marked pigment deposition in the upper corium. At the same time there were numerous melanophages as sign of an absorptive removal of the melanin granules. The drug allergy was thus the occasion for the persisting pigment deposition with circumscribed spotty pigmentation of the skin.

Adult↗

PubMed1996

Stability of labetalol hydrochloride, metoprolol tartrate, verapamil hydrochloride, and spironolactone with hydrochlorothiazide in extemporaneously compounded oral liquids.

The stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Labetalol hydrochloride 40 mg/mL, metoprolol tartrate 10 mg/mL, verapamil hydrochloride 50 mg/mL, and spironolactone 5 mg/mL plus hydrochlorothiazide 5 mg/ mL were prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in polyethylene terephthalate bottles. The sources of the drugs were tablets. Six bottles were prepared per liquid; three were stored at 5 degrees C and three at 25 degrees C, all in the dark. A sample was removed from each bottle initially and at intervals up to 60 days and analyzed for drug concentration by stability-indicating high-performance liquid chromatography. At least 91% of the initial drug concentration was retained in all the oral liquids for up to 60 days. There were no substantial changes in the appearance or odor of the liquids, or in the pH. Labetalol hydrochloride 40 mg/mL, metoprolol tartrate 10 mg/mL, verapamil hydrochloride 50 mg/mL, plus hydrochlorothiazide 5 mg/ mL in three oral liquids compounded extemporaneously from sweetened vehicles and tablets were stable for up to 60 days when stored without light at 5 and 25 degrees C.

Antihypertensive Agents↗