Low-dose Spironolactone Research Articles

The Effects of Spironolactone Monotherapy on Blood Pressure and Myocardial Remodeling in Spontaneously Hypertensive Rats: A Stereological Study

The aim of this study was to evaluate the cardiac structure of spontaneously hypertensive rats (SHRs) treated with different doses of spironolactone. Twenty SHRs were separated into four groups and treated for 13 weeks, as follows: one control group and three spironolactone treatment groups receiving doses of 5, 10 or 30 mg/kg/day. The spironolactone treatment either attenuated or prevented the tendency for increased blood pressure. However, the myocardial structure was not significantly affected by the spironolactone monotherapy treatment (all doses); it showed hypertrophied cardiac myocytes, focal areas of reactive fibrosis, inflammatory infiltrate and a decrease in the density of intramyocardial microvessels. None of the cardiac myocyte stereological parameters in the left ventricular myocardium showed significant differences among the SHR groups. The cardiac myocyte volume density was around 80%, the cardiac myocyte surface density varied from 3.6 to 4.1 × 10⁴ mm²/mm³ and the cardiac myocyte mean cross-sectional area varied from 351 to 415 µm². The connective tissue volume density of the SHRs treated with the highest dose of spironolactone was 75% lower than in the control SHRs, and this was the only significant difference found for this parameter among SHR groups. The intramyocardial vessels showed some differences when the control SHRs and the other SHRs were compared. The lowest intramyocardial vessel volume density was found in the control group (more than 20% lower than that in the treated SHRs), but no significant difference was detected among the treated SHRs (all doses). The intramyocardial vessel length density (Lv[v]) and surface density (Sv[v]) showed a similar tendency, being significantly greater in the treated SHRs than in the control rats. The Lv[v] was 45% greater in the high-dose spironolactone group than in the control group, and it was 28% greater in the high-dose spironolactone SHRs than in the other treated SHRs. The Sv[v] was 50% greater in the high-dose spironolactone SHRs than in both control and low-dose spironolactone SHRs. Long-term spironolactone monotherapy showed a partial effect in the preservation of intramyocardial vessels and also in the attenuation of interstitial fibrosis.

The effects of spironolactone monotherapy on blood pressure and myocardial remodeling in spontaneously hypertensive rats: a stereological study.

The aim of this study was to evaluate the cardiac structure of spontaneously hypertensive rats (SHRs) treated with different doses of spironolactone. Twenty SHRs were separated into four groups and treated for 13 weeks, as follows: one control group and three spironolactone treatment groups receiving doses of 5, 10 or 30 mg/kg/day. The spironolactone treatment either attenuated or prevented the tendency for increased blood pressure. However, the myocardial structure was not significantly affected by the spironolactone monotherapy treatment (all doses); it showed hypertrophied cardiac myocytes, focal areas of reactive fibrosis, inflammatory infiltrate and a decrease in the density of intramyocardial microvessels. None of the cardiac myocyte stereological parameters in the left ventricular myocardium showed significant differences among the SHR groups. The cardiac myocyte volume density was around 80%, the cardiac myocyte surface density varied from 3.6 to 4.1 x 10(4) mm2/mm3 and the cardiac myocyte mean cross-sectional area varied from 351 to 415 micro m2. The connective tissue volume density of the SHRs treated with the highest dose of spironolactone was 75% lower than in the control SHRs, and this was the only significant difference found for this parameter among SHR groups. The intramyocardial vessels showed some differences when the control SHRs and the other SHRs were compared. The lowest intramyocardial vessel volume density was found in the control group (more than 20% lower than that in the treated SHRs), but no significant difference was detected among the treated SHRs (all doses). The intramyocardial vessel length density (Lv[v]) and surface density (Sv[v]) showed a similar tendency, being significantly greater in the treated SHRs than in the control rats. The Lv[v] was 45% greater in the high-dose spironolactone group than in the control group, and it was 28% greater in the high-dose spironolactone SHRs than in the other treated SHRs. The Sv[v] was 50% greater in the high-dose spironolactone SHRs than in both control and low-dose spironolactone SHRs. Long-term spironolactone monotherapy showed a partial effect in the preservation of intramyocardial vessels and also in the attenuation of interstitial fibrosis.

Monitoring of transtubular potassium gradient in the diuretic management of patients with cirrhosis and ascites.

Aldosterone antagonists are the diuretics of first choice in the treatment of cirrhotic ascites. However, there is still no reliable clinical parameter to evaluate their efficacy. Transtubular potassium gradient (TTKG), the accurate indicator of aldosterone bioactivity, may serve as a guide for the proper use of the aldosterone antagonists. In 23 patients with cirrhotic ascites, the daily administered initial dosage of 100 mg of spironolactone was increased by 100 mg/day at intervals of 5 days until either diuresis commenced or TTKG fell below 3.0, the value indicating complete blockade of aldosterone bioactivity. For the non-responders with TTKG lower than 3.0, furosemide was given in addition to spironolactone. Basal TTKG correlated significantly with plasma aldosterone concentration (r = 0.60, P = 0.002). Spironolactone induced the decrease of TTKG in 20 patients, from 5.3 +/- 0.5 to 2.9 +/- 0.2 (mean +/- SE, P < 0.001). A TTKG value of 3.0 could classify seven patients, who did not respond to low dose spironolactone, into two distinct groups at that time, indicating different further diuretic regimen. All patients achieved diuretic responses without complication by this TTKG-guided modification of diuretics. TTKG may be a suitable guide for the diuretic management of cirrhotic ascites by accurately reflecting the effect of aldosterone antagonists.

Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system.

For almost 40 years since its discovery in 1953, the mineralocorticoid hormone, aldosterone, was considered to affect blood volume, and thus blood pressure, by its action to retain sodium at epithelial tissues. Over the past decade, direct effects of aldosterone on the heart and blood vessels, and on the cerebral control of blood pressure, have been established in experimental animals. Simultaneously, the incidence of primary aldosteronism in essential hypertension is now acknowledged to be 10-20%, rather than <or= 1%, underscoring a previously unrecognized role for aldosterone in hypertension. The 30% improvement in mortality (and 35% in morbidity) seen in the RALES trial with the addition of low-dose spironolactone to best practice therapy in moderate to severe heart failure, similarly points to an unrecognized role for aldosterone in the pathophysiology of heart failure. Currently, both experimental and clinical studies are directed towards establishing the mechanisms involved in these pathophysiological effects of aldosterone in the cardiovascular system, and of the role of mineralocorticoid receptor antagonists in offsetting or blocking such effects. A brief account of the current state of these mechanisms in at a cellular and tissue level forms the basis of this review.

Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats.

Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 microg/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.

Spironolactone therapy in older patients—the impact of renal dysfunction

Low dose spironolactone reduces the risk of death from heart failure. We examined the effects of spironolactone on potassium homeostasis in a cohort of elderly patients with congestive heart failure (CHF). Eighteen patients >70 years, mean 80.5 (±SD 6.3) with New York Heart Association CHF Grade II–IV were enrolled. All patients were commenced on 25 mg spironolactone daily. The dose was reduced to 12.5 mg daily when hyperkalemia (potassium >5.0) occurred. A serum creatinine of >150 μmol/l was defined as indicating renal impairment (RI). Blood pressure, pulse rate, urea, creatinine, Na + and K + were measured at baseline, day 2–5, day 28 and more often if clinically indicated. Nine of those recruited had RI. Baseline serum potassium was significantly higher in those with RI, mean 4.56 (±0.30) vs. 4.04 (±0.30) mmol/l ( P<0.01). Six patients with RI developed hyperkalemia versus one of those with serum creatinine <150 μmol/l ( P<0.05). Serum K + returned to normal in all patients when the dose of spironolactone was reduced to 12.5 mg daily with one exception in whom the medication was withdrawn. When spironolactone is prescribed to older patients with CHF, hyperkalemia appears more likely in those with RI. Halving the dose to 12.5 mg daily results in normalisation of serum potassium. Older patients commencing spironolactone therapy should have serum potassium monitored frequently, particularly in the presence of RI.

A review of the medical treatment of primary aldosteronism.

Use of the aldosterone-to-renin ratio (ARR) has suggested that at least one in 10 hypertensive subjects have primary aldosteronism (PA). There is thus a timely need to review the literature for effective drug therapies and to speculate on other therapeutic options by taking into account recent advances in understanding of the PA disease pathophysiological process. A MEDLINE and EMBASE search of all articles published from the start of the databases until July 1999 and reviews of the bibliographies of textbooks. Primary research articles on the medical treatment of PA with emphasis on diagnosis, treatment option, drug dosage, therapeutic response and adverse drug effect. Study design and quality were assessed. Relevant data on diagnostic methodology, drug usage and response were analysed and compared. A select number of subjects with aldosterone-producing adenoma (APA) can be expected to respond well to surgical treatment For the majority of PA cases especially subjects with idiopathic hyperaldosteronism (IHA), long-term medical treatment is now safe and feasible although no randomized controlled trials have been carried out to date. The best therapeutic response is obtained by directly antagonizing aldosterone at the receptor level using medium to low dose spironolactone and this response can be predicted by a raised ARR. The response to other potassium-sparing diuretics and calcium channel blockers are modest. IHA responds better than angiotensin II-unresponsive APA to angiotensin converting enzyme inhibitors and this may also be true with angiotensin II receptor blockers. The discovery of the aldosterone synthase gene opens up the possibility for gene therapy. The diagnosis of PA allows appropriate management with resultant blood pressure control in many hypertensive subjects who otherwise have resistant hypertension despite multiple drug therapy.

Increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE-inhibition Michael Christ, Daniela Fraccarollo, Georg Ertl, Norbert Gretz, Martin Wehling, Johann Bauersachs. Institute of Clin. Pharmacology, Mannheim, Germany, Med. Universit�tsklinik, Wuerzburg, Germany

Increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE-inhibition Michael Christ, Daniela Fraccarollo, Georg Ertl, Norbert Gretz, Martin Wehling, Johann Bauersachs. Institute of Clin. Pharmacology, Mannheim, Germany, Med. Universit�tsklinik, Wuerzburg, Germany

Clinical pearl #1: diuretic- induced-K + depletion may be hazardous: the “miracle” of low-dose spironolactone

Clinical pearl #1: diuretic- induced-K + depletion may be hazardous: the “miracle” of low-dose spironolactone

Striking Increase of Natriuresis by Low-Dose Spironolactone in Congestive Heart Failure Only in Combination With ACE Inhibition

A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the mineralocorticoid receptor antagonist spironolactone to ACE inhibition. The aim of the present study was to examine a hypothesized interaction of spironolactone and ACE inhibitors in renal electrolyte and volume regulation. Wistar rats with extensive myocardial infarction or sham operation were treated with either placebo, the ACE inhibitor trandolapril, low-dose spironolactone, or a combination of the 2. Twelve weeks after infarction, rats were housed in metabolic cages. Urinary volume and sodium excretion were significantly increased in CHF rats on a combined treatment with spironolactone and trandolapril (21.2+/-2.6 mL/d, 2489+/-320 mmol/d, mean+/-SD; P<0.05 versus other experimental groups) versus placebo-treated rats (16.7+/-5.6 mL/d, 1431+/-458 mmol/d),whereas these parameters were not affected in rats on either spironolactone (16.1+/-6.6 mL/d, 1153+/-273 mmol/d) or trandolapril alone (15.9+/-4.2 mL/d, 1392+/-294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone (10.8+/-8.2 mm Hg; P:<0.05 versus CHF placebo: 23.3+/-7.2 mm Hg; sham-operated rats: 5.1+/-0.9 mm Hg), whereas LVEDP remained elevated in rats treated with either compound alone. In the present study, we found an unexpected interaction of low-dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may explain the beneficial effects of spironolactone in CHF patients.

Low-dose adjunctive spironolactone in the treatment of acne in women: A retrospective analysis of 85 consecutively treated patients

Background: Despite advances in acne therapy in recent years, treatment failures are common, especially in adult women. Spironolactone, an established androgen receptor blocker, is successful in treating adult women with acne, but side effects are common at the doses reported in published studies to date. Objective: The purpose of this study was to assess the therapeutic effect and tolerance of low doses of spironolactone used alone or as an adjunct in the treatment of acne in adult women. Methods: Records were reviewed from 85 women with acne treated consecutively with spironolactone 50 to 100 mg/day, administered either as single-drug therapy or as an adjunct to standard therapies. The maximum length of treatment was 24 months. Results: Clearing of acne occurred in 33% of patients treated with low doses of spironolactone; 33% had marked improvement, 27.4% showed partial improvement, and 7% showed no improvement. The treatment regimen was well tolerated, with 57.5% reporting no adverse effects. Conclusion: Spironolactone can be used in low doses as a single drug or as an adjunct to standard acne therapies in women with adult acne. When used in this fashion, treatment outcomes are favorable, and the drug is well tolerated. (J Am Acad Dermatol 2000;43:498–502.)

The promise of selective aldosterone receptor antagonists for the treatment of hypertension and congestive heart failure.

Inappropriate elevations in plasma aldosterone levels have multiple actions that play an important role in the pathophysiology of hypertension and heart failure. Patients with hypertensive cardiovascular disease are at increased risk for coronary artery disease, myocardial infarction, congestive heart failure, and sudden cardiac death. Despite long-term treatment with an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, aldosterone levels usually remain high in these patients. The effectiveness of low-dose spironolactone raises the possibility that a nonselective aldosterone antagonist can block the deleterious effects of aldosterone on the cardiovascular system. However, side effects limit the use of this drug in many patients. The advent of selective aldosterone antagonists, which have a lower affinity for androgen and progesterone receptors, should minimize these side effects, leading to better compliance.

Primary aldosteronism.

The basic clinical pathophysiology of primary aldosteronism (PAL) was described by Conn in terms of autonomous production of aldosterone, secondary suppression of renin and development of hypertension with hypokalaemic alkalosis. Conn recognised a normokalaemic form of the syndrome and suggested that it might masquerade as essential hypertension and be not uncommon. This was hotly disputed at the time, and normokalaemic PAL considered rare until recently, and, as a consequence, overlooked. The advent of a simple screening test, the aldosterone-renin ratio, led to recognition that normokalaemic forms are not uncommon. In fact, PAL may be the commonest specifically treatable and potentially curable form of hypertension so far identified. In all patients with PAL confirmed by lack of suppressibility ("autonomy") of aldosterone production, Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-remediable hyperaldosteronism, reviewed elsewhere in this issue) should first be excluded by dexamethasone suppression or genetic testing. Capable of causing fatal stroke in young people affected by this dominantly inherited disorder, it can be reversed by doses of glucocorticoids such as dexamethasone which partially suppress endogenous ACTH without producing "steroid" side-effects. The remaining varieties of PAL may eventually also be shown to have a genetic basis, but are currently treated either by excision of a solitary aldosterone-secreting tumour or by antagonism of aldosterone's action in the renal tubule. It is possible that both adrenal cortices are genetically predisposed to overproduction of aldosterone in all varieties of PAL, whether because of anomalous regulation of aldosterone secretion or because of a tendency towards hyperplasia and neoplasia. Aldosterone-producing adenomas (APA's) can be divided into two main subtypes based on morphology and biochemical behaviour. The first subtype to be morphologically and biochemically characterised is composed predominantly of fasciculata-like cells and is unresponsive to angiotensin II (ALL-U-APA). The more recently characterised subtype is composed predominantly of glomerulosa-like cells, is responsive to angiotensin II (AII-R-APA) and could previously have been misdiagnosed as bilateral hyperplasia. The renin gene is often overexpressed in the second variety of adenoma, and in surrounding non-tumorous cortex, and the two subgroups show different allelic frequencies for RFLP's of the constitutive renin gene and the constitutive ANP gene locus. Unilateral, solitary, benign adrenal cortical adenomas producing aldosterone (APA's) represent a potentially surgically curable form of hypertension. Adrenal venous sampling (AVS) should always be performed because APA's are biochemically recognisable by adrenal venous steroid measurement before they are identifiable by computerised tomography or scintigraphy, and adrenal masses seen on CT may not be responsible for PAL. The secretory activity of adrenal masses must therefore be established by AVS before surgical removal. Discovery of an adrenal mass on CT requires formulation of a plan, whether or not it is found to be secreting hormones in excess. Independently of the treatment of the patient's hypertension, an apparently nonfunctioning adrenal mass ("incidentaloma") should be removed if 2.5 cm or more in diameter, because of the risk of cancer. Smaller masses require long-term follow-up. Primary aldosteronism not lateralising on AVS should be treated with low dose spironolactone, or with amiloride. For any such patients intolerant of medical treatment, laparoscopic removal of the adrenal showing higher production of aldosterone on AVS is an option worthy of consideration.The resultant reduction in mass of tissue autonomously secreting aldosterone should improve hypertension, as aldosterone productions falls below a critical level, and may even be curative in the short, medium or long term, depending on the rate of growth and activity of au

Anti-Aldosterone Treatment and the Prevention of Myocardial Fibrosis in Primary and Secondary Hyperaldosteronism

In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 μg/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antogonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT an AL (202 ± 12 and 193 ± mmHg, respectively; P < 0.0005 vs C); it remained clevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVP, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.

Predictors of clinical response in hirsute women treated with spironolactone

To examine the clinical efficacy of low dose spironolactone in hirsute women. Retrospective. Outpatient endocrinology clinic. One hundred nine consecutive women prescribed 75 to 100 mg/d spironolactone for at least 4 months in whom adequate follow-up data were available. Hirsutism improved in 72% of the women. Women with regular menses, whether or not they used oral contraceptives (OCs), had the highest response rate to spironolactone (78%), whereas women with irregular menses who did not use an OC had the lowest response rate (55%). Favorable responses were associated with increased severity of hirsutism (P = 0.04) and lower serum dehydroepiandrosterone sulfate levels (P = 0.05). Responders and nonresponders did not differ significantly in age (P = 0.10), duration of hirsutism (P = 0.14), pretreatment serum testosterone (T) (P = 0.48), or body mass index (P = 0.11). However, when each parameter was divided into subsets, trends toward decreasing response were observed with increasing age, duration of hirsutism over 15 years, and increasing serum T level. Low-dose spironolactone improves hirsutism in a majority of hirsute women, irrespective of age, severity or duration of hirsutism, menstrual status, or serum hormone levels.

Hirsutism in a Gynaecological Context

Investigation of patients presenting with hirsutism to a gynaecological endocrine clinic revealed a high incidence of anovulation, obesity and elevated androgen levels. The underlying abnormality was polycystic ovarian syndrome (PCOS) in the majority of patients. Low levels of sex hormone binding globulin were common; these increased with oestrogen treatment. Treatment with a combined oral contraceptive pill and low dose spironolactone was often effective in reducing symptoms.

Hirsutism: Evaluation and treatment

Hirsutism, a troublesome cosmetic problem, may also be a sign of serious systemic disease that can be screened for by means of the patient's history, physical examination, and certain basic blood tests. Most patients with functional hirsutism have elevated production rates of testosterone, elevated metabolic clearance rates of testosterone, depressed levels of sex hormone-binding globulin, and elevated levels of serum-free testosterone and hair follicle sensitivity. Once a neoplastic source is ruled out and hirsutism established as functional, essentially empiric treatment, including low-dose dexamethasone, oral contraceptives, and spironolactone, has proved to be effective.

Unilateral Gynecomastia and Impotence During Low-dose Spironolactone Administration in Men

Unilateral Gynecomastia and Impotence During Low-dose Spironolactone Administration in Men