Spironolactone Group Research Articles

Spironolactone Reduced Arrhythmia and Maintained Magnesium Homeostasis in Patients With Congestive Heart Failure

Patients with congestive heart failure (CHF) often have increased aldosterone activity that leads to hypomagnesemia. Hypomagnesemia can induce arrhythmias, an important cause of death in patients with CHF. We determined whether the aldosterone receptor antagonist spironolactone improved magnesium homeostasis and reduced arrhythmias in patients with CHF. We randomized 116 consecutive patients with CHF into placebo control group (n = 58) and spironolactone group (20 mg daily, n = 58) in addition to conventional therapy. Plasma magnesium concentration (PMC), erythrocyte magnesium concentration (EMC), and erythrocyte magnesium efflux were not different between the 2 groups of patients before treatment. Compared with control patients, patients treated with spironolactone for 6 months had increased PMC and EMC and decreased erythrocyte magnesium efflux. Patients on spironolactone therapy also had a marked decrease of 24-hour mean heart rate, ventricular and atrial premature beats, and the risk of atrial fibrillation/flutter. Pooled data from the 116 patients showed that patients with a higher EMC or a lower sodium-dependent erythrocyte magnesium efflux had a slower heart rate, fewer ventricular premature beats, and a lower risk of atrial fibrillation/flutter. Our results suggest that reducing cellular magnesium efflux and loss may contribute to the spironolactone-reduced arrhythmias in patients with CHF.

Effects of aldosterone receptor blockade in patients with mild–moderate heart failure taking a beta‐blocker

Spironolactone improves prognosis in severe heart failure (HF). We investigated its effects in patients with mild-moderate HF treated with an ACE inhibitor and beta-blocker. Randomised, double-blind, parallel-group, 3-month comparison of placebo and spironolactone (25 mg daily) in 40 patients in New York Heart Association (NYHA) class I (20%), II (70%) or III (10%), with a left ventricular ejection fraction of <40%. The mean (standard error) changes from baseline in the spironolactone and placebo groups were, respectively: i) B-type natriuretic peptide (BNP) -53.4(22.2) pg/mL and +3.3(12.1) pg/mL, P=0.04, ii) pro-collagen type III N-terminal amino peptide (PIIINP) -0.6(0.2) micromol/L and +0.02(0.2) micromol/L, P=0.02 and iii) creatinine +10.7(3.2) micromol/L and -0.3(2.6) micromol/L, P=0.01. Compared with placebo, spironolactone therapy was associated with a reduction in self-reported health-related quality of life: change in visual analog score: -6 (3) vs. +6 (4); P=0.01. No differences were observed on other biochemical, neurohumoral, exercise and autonomic function assessments. In patients with mild-moderate HF, spironolactone reduced neurohumoral activation (BNP) and a marker of collagen turnover (PIIINP) but impaired renal function and quality of life. The benefit-risk ratio of aldosterone blockade in mild HF is uncertain and requires clarification in a large randomised trial.

Spontaneous, L-Arginine-Induced and Spironolactone-Induced Regression of Protein Remodeling of the Left Ventricle in L-NAME-Induced Hypertension

N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension is associated with protein remodeling of the left ventricle. The aim of the study was to show, whether aldosterone receptor blocker spironolactone and precursor of NO-production L-arginine were able to reverse the protein rebuilding of the left ventricle. Six groups of male Wistar rats were investigated: control 4 (4 weeks placebo), L-NAME (4 weeks L-NAME), spontaneous-regression (4 weeks L-NAME + 3 weeks placebo), spironolactone-regression (4 weeks L-NAME + 3 weeks spironolactone), L-arginine-regression (4 weeks L-NAME + 3 weeks arginine), control 7 (7 weeks placebo). L-NAME administration induced hypertension, hypertrophy of the left ventricle (LV), and the increase of metabolic and contractile as well as soluble and insoluble collagenous protein concentration. The systolic blood pressure and relative weight of the LV decreased in all three groups with regression, while the most prominent attenuation of the LVH was observed after spironolactone treatment. In the spontaneous-regression and L-arginine-regression groups the concentrations of individual proteins were not significantly different from the control value. However, in the spironolactone-regression group the concentration of metabolic, contractile and insoluble collagenous proteins remained significantly increased in comparison with the control group. The persistence of the increased protein concentration in the spironolactone group may be related to the more prominent reduction of myocardial water content by spironolactone.

The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy

Angiotensin II can influence adipocytokine levels in adipose tissue, but the association between aldosterone, which mediates the effect of angiotensin II, and adipocytokines has yet to be fully elucidated. This study was designed to investigate the effect of spironolactone, a representative aldosterone blocker, on adipocytokines such as adiponectin, visfatin, plasminogen activator inhibitor (PAI)-1 and tumor necrosis factor α in patients with type 2 diabetic nephropathy: the study included 33 patients, 22 of whom were randomly assigned to the spironolactone (50 mg/d) group and 11 to the amlodipine (2.5 mg/d) group. Data were collected at baseline and after 3 months of treatment and compared with baseline data for 25 age-matched healthy subjects. A significant decrease in plasminogen activator inhibitor 1 in the spironolactone group was observed (22.6 ± 13.4 to 19.2 ± 11.3 ng/mL, P =.0323), but this did not occur in the amlodipine group. Adiponectin and visfatin levels did not change in the spironolactone and amlodipine groups, but significant increases in these adipocytokines were found in a subgroup of patients in the spironolactone group with glycated hemoglobin A 1c (HbA 1c) 8.0% or greater (11.8 ± 6.4 to 13.3 ± 7.4 μg/mL, P = .0344; and 1.39 ± 0.92 to 2.26 ± 0.76 ng/mL, P =.0397, respectively). The tumor necrosis factor α level at baseline exceeded the lower detection limit of the assay in only 6 patients in the spironolactone group, and no change occurred in these patients. Moreover, neither spironolactone nor amlodipine therapy caused a change in high-sensitivity C-reactive protein or soluble CD40 ligand, but a significant decrease in the level of brain natriuretic peptide was found in the spironolactone group only. Furthermore, significant increases of HbA 1c, creatinine, potassium, and aldosterone levels and plasma renin activity, and a decrease in urinary albumin excretion were also observed only in the spironolactone group. The number of patients with HbA 1c 8.0% or greater increased after spironolactone treatment. A significant decrease in systolic but not in diastolic blood pressure was observed in both treatment groups. In conclusion, our data suggest that in patients with type 2 diabetes mellitus complicated by diabetic nephropathy, spironolactone can decrease plasminogen activator inhibitor 1 and brain natriuretic peptide levels in addition to urinary albumin excretion, and systolic blood pressure, and that in patients with poor glycemic control, spironolactone can increase the levels of adiponectin and visfatin. However, the significant elevation of HbA 1c levels by spironolactone should be emphasized.

Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function

To study the effects of addition of spironolactone to angiotensin-converting enzyme (ACE) inhibition or angiotensin II (AngII) receptor antagonism on proteinuria, blood pressure (BP) and renal function in overt type 2 diabetic nephropathy. A placebo-controlled, double-blind, parallel-group trial in patients from two outpatient clinics with a follow-up of 1 year. Type 2 diabetic patients with macroalbuminuria, despite long-term use of an ACE inhibitor or AngII receptor blocker were allocated to spironolactone, 25-50 mg once daily (n = 29) or placebo (n = 30). Urinary albumin to creatinine ratio, BP and biochemical parameters were measured at regular intervals. Five patients of the spironolactone and one of the placebo group developed hyperkalemia and had to be excluded. Compared to other patients their baseline serum creatinine [161 (123-248) versus 88 (72-170) micromol/l] and potassium concentrations (4.7 +/- 0.3 versus 4.2 +/- 0.2 mmol/l) were elevated (P < 0.001). Albuminuria decreased by 40.6% [95% confidence interval (CI) 23.4-57.8%] and BP by 7 mmHg (2-12 mmHg)/3 mmHg (1-6 mmHg) with spironolactone, but did not change with placebo. Estimated glomerular filtration rate (eGFR) during the 1-year follow-up declined on average by 12.9 ml/min per 1.73 m (9.5-16.5 ml/min per 1.73 m) in the spironolactone and by 4.9 ml/min per 1.73 m (0.8-8.9 ml/min per 1.73 m) in the placebo group (P = 0.004). This decline was progressive in the placebo but leveled off in the spironolactone group. In the spironolactone group changes in albuminuria and GFR were correlated (r = 0.48, P = 0.007). Addition of spironolactone to an ACE inhibitor or AngII receptor blocker is associated with a marked and sustained antiproteinuric effect, which in part relates to the more pronounced reduction in GFR.

Aldosterone Antagonism in an Inflammatory State: Evidence for Myocardial Protection

Chagas' disease is one of the most important causes of dilated cardiomyopathy in South and Central America. It is an inflammatory cardiomyopathy. We wanted to investigate whether it could have the same response to aldosterone antagonism as demonstrated before in other dilated cardiomyopathies. To evaluate the role of spironolactone in myocardial remodelling in a Chagas cardiomyopathy model. We studied 60 Sirius Hamsters divided into: control (C) infected (Inf) and Inf plus spironolactone (Infsp, 40 mg/kg/day) groups, for 11 months. Echocardiography with colour doppler was performed. Left ventricular end diastolic diameter (LVEDD), fractional shortening (FS) and corrected isovolumic relaxation time (IRT) were evaluated, as well as interstitial collagen volume fraction (ICVF) and myocardial inflammation. The results demonstrated that survival was improved by use of spironolactone in the chronic phase (p<0.04). Body weight (BW) was C:190 g, Inf:167 g*, Infsp:198 g (*p<0.05, compared to C and Infsp), LVEDD/BW was C:0.31, Inf: 0.35*, Infsp: 0.29 (*p<0.05, compared to C and Infsp), FS was C:38, Inf: 35.5, Infsp: 38 (with no statistical difference) and IRT was C: 23 msec, Inf: 26 msec*, Infsp: 22 msec (p<0.05, compared to C and Infsp). ICVF (%) was attenuated at LV (C: 0.34+/-0.1, Inf: 1.75+/-0.7*, Infsp: 0.95+/-0.2*; *p<0.05, p<0.05). Spironolactone attenuated the myocardial remodelling in Chagas cardiomyopathy, reduced mortality during the chronic phase and reduced inflammatory infiltration.

Addition of spironolactone to an angiotensin-converting enzyme inhibitor decreases lung congestion and edema in Dahl hypertensive rats

We investigated the effect of adding spironolactone to treatment with an angiotensin-converting enzyme (ACE) inhibitor, imidapril, in Dahl salt-sensitive (DS) hypertensive heart failure rats with preserved systolic function. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Rats were divided into four groups and treated for 9 weeks with vehicle alone (water; n = 23), the ACE inhibitor imidapril (1 mg kg(-1) day(-1); n = 16), spironolactone (2 mg kg(-1) day(-1); n = 15), or a combination of imidapril and spironolactone at the doses above (n = 16). The left ventricular weight to body weight (BW) ratio was significantly lower in the imidapril group (3.28 +/- 0.30 mg g(-1)) and the combination group (3.34 +/- 0.38 mg g(-1)) than in the vehicle group (3.71 +/- 0.46 mg g(-1)). Adding spironolactone to imidapril inhibited an increase in the ratio of lung weight to BW (4.38 +/- 0.50 mg g(-1)) related to high salt intake, while monotherapy (imidapril group, 4.61 +/- 0.90 mg g(-1); spironolactone group, 5.40 +/- 2.50) did not significantly change the ratio from that seen with vehicle treatment (6.32 +/- 3.62 mg g(-1)). All active treatments (imidapril, 0.66% +/- 0.67%; spironolactone, 0.51% +/- 0.55%; both together, 0.31% +/- 0.26%) inhibited a salt-intake related increase in the percentage area representing fibrous tissue compared with vehicle treatment alone (1.81% +/- 1.51%). These findings suggest that adding spironolactone to an ACE inhibitor is more effective in improving pulmonary congestion and edema in hypertensive heart failure with preserved systolic function than an ACE inhibitor alone.

Induction of Rat Intestinal P-glycoprotein by Spironolactone and Its Effect on Absorption of Orally Administered Digoxin

The effect of the diuretic spironolactone (SL) on expression and function of intestinal P-glycoprotein (P-gp), as well as its impact on intestinal absorption of digoxin, was explored. Rats were treated with daily doses of 200 micromol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of approximately 25 cm, with segment I being the most proximal. Brush-border membranes were isolated and used in analysis of P-gp expression by Western blot analysis. P-gp content increased in the SL group by 526, 292, 210, and 622% over controls for segments I, II, III, and IV, respectively. Up-regulation of apical P-gp was confirmed by immunofluorescence microscopy. P-gp transport activity was explored in intestinal sacs prepared from segment IV using two different model substrates. Serosal to mucosal transport (efflux) of rhodamine 123 was 140% higher, and mucosal to serosal transport (absorption) of digoxin was 40% lower in the SL group, both indicating increased P-gp function. In vivo experiments showed that intestinal absorption of a single dose of digoxin administered p.o. was attenuated by SL pretreatment. Thus, concentration of digoxin in portal and peripheral blood was lower in SL versus control groups, as well as its accumulation in kidney and liver. Urinary excretion of digoxin was significantly decreased in the SL group, probably reflecting decreased systemic availability of digoxin for subsequent urinary elimination. We conclude that SL induces P-gp expression with potential impact on intestinal absorption of substrates with therapeutic application.

Aldosterone Antagonism in Chronic Kidney Disease

Angiotensin-converting enzyme (ACE) inhibitors are potent members of the arsenal to treat chronic kidney disease (CKD). By reducing blood pressure (BP) and disproportionately decreasing intraglomerular pressure, this class of drugs also reduces proteinuria and slows progression of CKD (1,2). Given the high prevalence of cardiovascular disease in this population, it is noteworthy that ACE inhibitors also decrease the incidence of stroke, myocardial infarction (MI), and cardiovascular mortality in patients who are at high cardiovascular risk (3). More recently, data reporting similar benefits of angiotensin receptor blockers (ARB) support their use in the treatment of CKD as well, especially in individuals with type 2 diabetes (4). Furthermore, one sizable study suggested that the combination of an ACE inhibitor and ARB may be more effective than either agent alone (5). Parving and colleagues (6) called attention to the effects of high-dose ARB therapy, up to three times the recommended dose, as an additional means of effectively interrupting the renin-angiotensin-aldosterone system (RAAS). By logical extension, further blockade of the RAAS by direct antagonism of aldosterone also may prove beneficial. Indeed, aldosterone seems to be a potent effector of renal injury (7–9). In the rare cases of primary aldosteronism and its functional analogue, the even more rare Liddle’s syndrome, the observed renal injury probably is independent of the more proximal elements of the RAAS (10,11). Animal models provide an expeditious tool for assessing pathophysiologic change and the efficacy of intervention. The classic model of primary aldosteronism, the mineralocorticoid–nephrectomy–high-salt model of hypertension, develops systemic and glomerular capillary hypertension and sustains renal damage (12). In the remnant kidney model of CKD, ACE inhibitors and ARB attenuate renal injury (13). However, this protection, which is associated with suppression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of …

Aldosterone Blockage in Proliferative Glomerulonephritis Prevents Not Only Fibrosis, but Proliferation as Well

Studies performed recently have determined that aldosterone has not only a major role in electrolyte and water balance and K excretion, but it also modulates myofibroblast growth in the heart and blood vessels and causes fibrosis. This study investigated the effects of aldosterone blockers in rats with anti-thy 1.1 nephritis, both on proliferation and fibrosis, by comparing it to an angiotensin receptor inhibitor valsartan. Rats with anti-thy 1.1 nephritis were randomly allocated to one of the three following groups of treatment: the control group (group 1); those treated with the aldosterone receptor blocker spironolactone (group 2); and those treated with the ATRB valsartan (group 3). On day 7, the parameters of glomerular fibrosis [transforming growth factor beta, TGF staining areas %], proliferation (Ki-67), and renal damage scores were determined. The TGF-β and Ki-67 levels of control group were significantly more than the other two groups (p<0.01). The TGF staining areas percentages were significantly decreased compared to control group. The artery, glomerular, and renal injury scores evaluated between the groups were found to be significantly decreased compared to control group. In line with previous studies, this study found that in anti–thy 1.1 mesangioproliferative glomerulonephritis, aldosterone blockage affected proliferation and fibrosis.

Comparative pilot study of repeated large volume paracentesis vs the combination on clonidine-spironolactone in the treatment of cirrhosis-associated refractory ascites

To study the usefulness of the combination of clonidine--spironolactone in refractory ascites. Twenty cirrhotic patients with refractory ascites were randomly assigned to receive repeated large volume paracentesis plus intravenous albumin (group 1), or a combination of clonidine (0.075 mg twice daily) and spironolactone (200 to 400 mg daily) (group 2). During the first hospitalisation,, the mean weight loss in group 1 was higher than in group 2 (12.4 +/- 3.2 versus 4.3 +/- 1.1 kg, P < or = 0.01). Mean stay in hospital was shorter in group 2 (20 +/- 1.5 versus 10 +/- 2.8 days; P < or = 0.01). Paracentesis did not induce changes in neuro-hormonal measurements. Oppositely, clonidine induced a decreased sympathetic activity, an increased glomerular filtration rate and a delayed reduction of the renin-aldosterone levels. During the follow-up in group 1, the number of rehospitalisations for ascites was higher than in group 2 (37 versus 3; P < or = 0.01), and the mean time to the first readmission was shorter (10 +/- 2.7 versus 23.7 +/- 5.6 days; P < or = 0.01). The total duration spent in hospital were similar in both groups. Paracentesis is more effective for short-term treatment of ascites but clonidine-spironolactone association might provide better long-term control.

Spironolactone improves diastolic function in the elderly

Diastolic dysfunction is common in the elderly. Increased myocardial fibrosis, a major determinant of diastolic function, has been observed with advancing age. Spironolactone prevents age-related increases in myocardial fibrosis in old normotensive rats. Spironolactone, via its antifibrotic activity, can improve diastolic function in the elderly with isolated diastolic dysfunction. The study was a prospective, double-blind, randomized, placebo-controlled trial. Thirty elderly subjects between 60 and 85 years of age with isolated diastolic dysfunction and no contraindications for spironolactone were randomized to 25 mg/day of spironolactone or placebo for 4 months. Mitral E/A and deceleration time, plasma levels of carboxy-terminal of procollagen type I (PICP), and brain natriuretic peptide (BNP) were measured at baseline and at the end of 4 months. Plasma level of potassium was also monitored to prevent clinically significant hyperkalemia. There was no serious adverse event or clinically significant hyperkalemia in the spironolactone group. Compared with baseline values, spironolactone significantly improved mitral E/A ratio (0.71 +/- 0.08 vs. 0.84 +/- 0.19, p = 0.025) and deceleration time (285.5 +/- 73.1 vs. 230.0 +/- 54.7, p = 0.035). There were no significant differences in the magnitude of change in the levels of PICP and BNP between the two treatment groups. Spironolactone may improve diastolic function in the elderly.

Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone

In this study, the effects of inhibition of aldosterone on regression of existing hypertension-related glomerulosclerosis were investigated. Adult male Sprague Dawley rats (220 to 250 g) underwent 5/6 nephrectomy (Nx). Severity of glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equal biopsy sclerosis and then randomized by group to 4-wk treatments as follows: Control with no further treatment (CONT; n = 6); spironolactone (SP) alone (200 mg/kg per d, by gavage, n = 6); or SP combined with nonspecific triple antihypertensive drugs (TRX; reserpine, hydralazine, and hydrochlorothiazide in drinking water; SP+TRX, n = 7) or with angiotensin type 1 receptor antagonist (AT1RA; losartan in drinking water; SP+AT1RA, n = 8). When the rats were killed 12 wk after Nx, autopsy glomerulosclerosis index (SI; 0 to 4+ scale) was compared with biopsy SI in the same rats. Systolic BP was increased at 8 wk after Nx and continued to increase at 12 wk after Nx in the CONT and SP groups but not in SP+TRX- or SP+AT1RA-treated rats. Serum creatinine at 12 wk was significantly decreased in all SP-treated groups versus CONT. CONT rats had on average a 157% increase in SI from biopsy to killing at 12 wk, compared with only 84% increase in SP rats, with regression of SI in some rats. The effects on glomerulosclerosis by SP were further enhanced (when systolic BP was controlled by TRX or by AT1RA). It is concluded that inhibition of aldosterone by SP not only slows development of glomerulosclerosis but also induces regression in some rats of existing glomerulosclerosis.

Differing Effects of Mineralocorticoid Receptor–Dependent and –Independent Potassium-Sparing Diuretics on Fibrinolytic Balance

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1+/-7.8 to 16.9+/-9.9 ng/mL at 9 am, P=0.019; from 7.6+/-5.4 to 11.5+/-7.3 ng/mL at 11 am, P=0.027; from 9.3+/-7.7 to 13.7+/-8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0+/-23.4 to 16.7+/-19.0 ng/mL at 10 am, P=0.041; from 17.5+/-21.7 to 12.7+/-16.8 ng/mL at 11 am, P=0.043; from 20.3+/-22.6 to 16.6+/-19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.

Spironolactone Does Not Prevent Restenosis After Coronary Stenting in Humans

Introduction: In animal studies, aldosterone enhanced neointimal proliferation by increasing extracellular accumulation of collagen and potentiating the effects of angiotensin II. Spironolactone, an aldosterone antagonist, is a potent inhibitor of neointimal proliferation. We conducted a placebo-controlled, double-blind, randomised study to assess the effect of spironolactone on angiographic 6-month in-stent restenosis. Materials and Methods: Of the 310 randomised patients with significant coronary artery disease, 258 patients were available for analysis: 128 constituted the placebo group and 130 were assigned to receive spironolactone. Eligible patients were randomly assigned to receive a dose of 50 mg spironolactone or placebo orally twice a day for 6 months. The primary endpoint was the angiographic restenosis (&gt;50% stenosis) rate at follow-up angiography. Results: At 6-month follow-up angiography after stenting, there was no difference between the 2 groups in minimal lumen diameter, percent diameter stenosis, late loss, and net gain. Angiographic restenosis occurred in 46 (35.4%) of 130 patients receiving spironolactone and 50 (39.0%) of 128 in the placebo group with an odds ratio (OR) of 0.85 with a 95% confidence interval (CI) of 0.49 to 1.46 (P = 0.62). Restenosis rate was found in 60 (32.9%) of 182 lesions in the spironolactone group, and 61 (35.5%) of 172 lesions in the placebo group with an OR of 0.89 with a 95% CI of 0.56 to 1.42 (P = 0.89). Conclusions: Spironolactone did not reduce the incidence of in-stent restenosis as compared with placebo in human, contrary to the fact that reduction of neointimal formation in animal models has been observed upon administration of spironolactone.

Effects of AT1 Receptor Antagonist and Spironolactone on Cardiac Expression of ET-1 mRNA in SHR-SP/Izm

Angiotensin II stimulates and angiotensin-converting enzyme inhibitor decreases endothelin-1 expression. Effects of the angiotensin-type 1 antagonist (angiotensin receptor blocker) on tissue expression of endothelin-1 in hypertension remained unknown. We investigated the effects of angiotensin-type 1 antagonist with and without co-administration of the aldosterone receptor antagonist spironolactone on cardiac expression of endothelin-1 mRNA. Angiotensin receptor blocker (candesartan, 1.0 mg/kg per day) was orally administered to male spontaneously hypertensive stroke-prone rats/Izm from 4 weeks of age for 4 weeks, 12 weeks and 28 weeks (angiotensin receptor blocker group). Lowdose spironolactone (10 mg/kg per day, s.c.), which does not affect blood pressure, was co-administered with angiotensin-type 1 antagonist for 28 weeks (angiotensin-type 1 antagonist + spironolactone group). Cardiac expression of endothelin-1 mRNA was determined. In the angiotensin receptor blocker group, although cardiac expression of endothelin-1 mRNA was significantly decreased after 4 weeks of treatment, it was significantly increased after 12 weeks and 28 weeks of treatment. In the angiotensin receptor blocker + spironolactone group, while systolic blood pressure did not show a further decrease from that in the angiotensin receptor blocker group, cardiac expression of endothelin-1 mRNA was decreased to the level in the untreated group. These results suggest that effects on endothelin-1 expression could modify the cardioprotective effects of angiotensin receptor blocker. Coadministration of angiotensin receptor blocker with low-dose spironolactone is recommended for further cardioprotection via suppression of endothelin-1 expression.

Digitalis therapy for patients in clinical heart failure.

The most commonly used preparation of digitalis is digoxin, which is obtained from the leaves of Digitalis lanata , a common flowering plant called “foxglove.” The words digitalis and digoxin in this article are used interchangeably. An exhaustive review published in 19961 cited a large number of references and had detailed data and descriptions of a large number of studies and all early trials. The present article summarizes those data but focuses on and emphasizes data collected since that time. These have been described in detail previously1 and are briefly summarized. ### Inotropic Effects The inotropic effects have been documented in the isolated papillary muscles and in the normal hearts of animals and humans. The inotropic action occurs in both ventricles and in both atria. In the normal heart and in those with coronary artery disease and normal left ventricular (LV) systolic function, with digitalis the LV function curve is moved upward and to the left.1 As a result, LV end-diastolic pressure and LV end-diastolic and end-systolic volumes are reduced, and there is an increase of LV ejection fraction (LVEF).1 ### Patients With Heart Failure In patients with heart failure (HF), digoxin slows the ventricular rate (1) in sinus rhythm because of an improvement in HF and withdrawal of sympathetic stimulation and (2) in atrial fibrillation by increasing parasympathetic tone. The combination of digoxin and carvedilol is superior to digoxin or carvedilol alone.2 ### Peripheral Vessels In normal subjects given intravenous ouabain, there is arterial and venous vasocontriction.3 The vasoconstriction is obviated by administering digoxin slowly over a period of 15 to 20 minutes1; moreover, the vasoconstriction lasts up to 30 minutes. The seminal study of Mason and Braunwald3 showed that in HF, the effects are different. Digitalis produces an increase of blood flow, a decrease of vascular resistance, venodilation, and a …

Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats

There is increasing evidence to support the importance of blocking aldosterone to prevent target-organ damage in hypertension. We recently demonstrated an aldosterone breakthrough phenomenon during administration of an angiotensin type 1 receptor blocker (ARB). To elucidate the pathophysiological significance of residual aldosterone by investigating the influence of the aldosterone antagonist on the cardioprotective effects of the ARB in hypertensive rats. Injection vehicle alone, ARB (1.0 mg/kg per day candesartan by mouth), aldosterone antagonist (10 mg/kg per day spironolactone, subcutaneously), or combined treatment were administered to male stroke-prone spontaneously hypertensive rats for 24 weeks from the age of 4 weeks. Blood pressure, plasma angiotensin II and aldosterone concentrations, left ventricular weight, expression of type I and type III collagen mRNA, and histological findings were determined. In the ARB-treated group, aldosterone concentrations remained unchanged (1.10 +/- 0.20 nmol/l, compared with 1.17 +/- 0.46 nmol/l in the control group), whereas systolic blood pressure (178 +/- 9 mmHg), left ventricular weight (0.372 +/- 0.035 g/100 g body weight), expression of collagen mRNA, and cardiac interstitial and perivascular fibrosis all decreased significantly compared with the control group (systolic blood pressure: 222 +/- 10 mmHg, P < 0.05; left ventricular weight: 0.483 +/- 0.021 g/100 g body weight, P < 0.05). Although blood pressure (217 +/- 9 mmHg) and left ventricular weight (0.467 +/- 0.027 g/100 g body weight) remained unchanged in the group receiving spironolactone, the expression of both types of collagen mRNA and cardiac interstitial and perivascular fibrosis showed a significant decrease compared with the vehicle-treated group. In the rats receiving combined treatment with the ARB and spironolactone, left ventricular weight (0.352 +/- 0.005 g/100 g body weight, P < 0.05), expression of collagen mRNA, and cardiac interstitial and perivascular fibrosis all showed a further improvement compared with both the ARB and spironolactone groups. These results demonstrate that residual aldosterone has a significant impact on target-organ damage in hypertension, even during chronic administration of an ARB. The addition of an aldosterone antagonist has an advantage in facilitating the cardioprotective effects of ARBs.

Aldosterone blockade in heart failure

Aldosterone plays a key role in the pathophysiology of heart failure. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers may not suppress aldosterone production in the long term. This allows aldosterone to exert its effects on myocardial fibrosis and cardiac remodelling, endothelial function, electrolytes and baroreceptor response. The Randomized Aldactone Evaluation Study (RALES) tested spironolactone against placebo in patients with severe heart failure. The study found a 30% reduction in the risk of death among patients treated with spironolactone and a 31% reduction in the risk of death from cardiac causes. Patients in the spironolactone group had significantly lower risks of death from progression of heart failure and sudden cardiac death. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) investigated the effects of eplerenone against placebo in patients with myocardial infarction complicated by left ventricular dysfunction. Compared to placebo, the relative risk of death from any cause was 0.85 in eplerenone-treated patients, and the relative risk of death or hospitalisation for cardiovascular events was 0.87. The reduction in the risk of sudden death from cardiac causes was statistically significant. In conclusion, aldosterone blockade should form part of optimal therapy for patients with heart failure.

A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism

To compare the clinical efficacy and safety of the combination of spironolactone (100 mg/day) plus finasteride (5 mg/day) and spironolactone (100 mg/day) alone in the treatment of hirsutism. Sixty-five hirsute women were randomly assigned to one of these two treatment groups. Hirsutism score was measured according to the modified Ferriman-Gallwey scoring system. Baseline and post-treatment assessments were carried out in each subject by an investigator blinded to the therapy. Both groups had similar demographic properties at baseline. The serum levels of total and free testosterone, dehydroepiandrosterone sulphate and sex hormone-binding globulin were measured at the beginning and after 1 year of therapy. Blood chemistry and side-effects were evaluated during the study. Hirsutism scores were decreased significantly in both groups at the end of the year. The mean percentage change in hirsutism scores from baseline in the spironolactone plus finasteride-treated group (51.3%) was significantly (P<0.005) higher than in the group treated with spironolactone alone (36.6%). Patients from both treatment groups experienced similar side-effects. We have concluded that a combination of spironolactone plus finasteride is a safe and effective therapy in the treatment of hirsutism.