Administration Of Spironolactone Research Articles

Cocaine decreases the expression of PSA‐NCAM protein and attenuates long‐term potentiation via glucocorticoid receptors in the rat dentate gyrus

The present study investigated a potential role for glucocorticoid (GR) and mineralocorticoid (MR) receptors in the detrimental effects of single cocaine (COC) administration on both the number of polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neurons and the induction of long-term potentiation (LTP) in the rat dentate gyrus (DG). The effects of COC (15 mg/kg i.p.) on the number of PSA-NCAM-positive neurons and the induction of LTP observed 2 days after COC administration were abolished either by depleting circulating corticosterone after administration of metyrapone (100 mg/kg s.c. given 3 h before COC) or by pharmacologically blocking GRs using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC). Administration of the MR blocker spironolactone (50 mg/kg s.c. given 1 h before COC) did not alter the effects of COC on the number of PSA-NCAM-positive neurons or LTP induction. Results have also shown that COC does not change the rate of cell proliferation, as measured by the presence of Ki-67 and the incorporation of bromodeoxyuridine (100 mg/kg i.p. given 2 h after COC) into the newly born cells in the DG 2 days after COC administration. Finally, we observed that GRs colocalized with some, but not all, PSA-NCAM-positive neurons, whereas MRs showed no colocalization with neurons positive for PSA-NCAM in the DG. These data indicate that a single dose of COC may arrest hippocampal susceptibility to plastic changes and lead to functional impairments through the alteration of hippocampal structure and the formation of memory traces.

Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16 INK4a

There is increasing evidence for a role of somatic cellular senescence in physiological aging but also in injury and disease. Cell cycle inhibitor p16(INK4a) is the key mediator for stress and aberrant signaling induced senescence. Here we report that elevated blood pressure markedly induced p16(INK4a) expression in rat kidneys and hearts, as well as in human kidneys. In kidneys from deoxycorticosterone acetate-salt-treated rats, p16(INK4a) induction was found in tubular, glomerular, interstitial, and vascular cells and correlated with the typical histopathologic features of hypertensive target organ damage. p16(INK4a) expression also correlated with phospho-p38, a positive upstream regulator of p16(INK4a) expression. In left ventricles, increased p16(INK4a) expression was found in myocardium and cardiac arteries. Antihypertensive medication consistent of hydrochlorothiazide, hydralazine, and reserpine ameliorated the histopathologic changes and attenuated p16(INK4a) expression in kidneys of deoxycorticosterone acetate-salt-treated rats. Nonantihypertensive administration of spironolactone also reduced kidney damage and p16(INK4a) expression. p16(INK4a) induction was further observed in kidneys from hypertensive transgenic rats heterozygous for the mouse Ren-2 gene and was prevented by the angiotensin II type 1 receptor blocker losartan. In human kidney biopsies showing hypertensive nephrosclerosis, increased p16(INK4a) expression was found compared with age-matched normotensive control subjects. Thus, hypertension induces cellular senescence via p16(INK4a), possibly through p38, thereby contributing to hypertensive target organ damage. This detrimental effect can be overcome by different therapeutic drug strategies.

Increased oxidative stress diminishes NO‐mediated vasodilatation initiated by aldosterone in arterioles

There is increasing evidence that aldosterone has a significant impact on cardiovascular function. In the present study, we investigated direct vasoreactivity to aldosterone in resistance vessels. Mesenteric arterioles were isolated from normal Wistar rats and pressurized at 80 mmHg intravascular pressure in a no‐flow condition. Aldosterone (10−12 to 10−8M) elicited a dose‐dependent vasodilator response, which was significantly inhibited by administration of spironolactone (10−7 M), mineralocorticoid receptor antagonist, removal of the endothelium or inhibition of NO synthesis by Nω‐nitro‐L‐arginine methyl ester (3×10−4M). At a concentration of 10−7M, aldosterone elicited a reduced dilation, which was converted to a vasoconstriction after removal of the endothelium and a greater dilatation after scavenging superoxide with Tempol (10−4M) or inhibition of NAD(P)H‐oxidase with apocynin (10−4M). Intraluminal administration of aldosterone (10−7M) elicited a significantly greater and prolonged vasodilatation than extraluminal administration. These data suggest that the effects of aldosterone on resistance vessels depend on its concentration. In a physiological concentration, aldosterone increases arteriolar diameter via an endothelial NO‐mediated mechanism; however, in pathological concentrations, aldosterone increases oxidative stress, which may reduce NO bioavailability. (Supported by NIH HL‐43023, HL‐68813 and HL‐070653)

Two Elderly Patients with Mineralocorticoid Excess Due to 11.BETA.-Hydroxysteroid Dehydrogenase Type 2 (11.BETA.-HSD2) Impairment

A 75-year-old woman had a low circulating level of aldosterone, despite the mineralocorticoid excess state. These abnormalities were improved by spironolactone administration. The distinct elevation of urinary cortisol/cortisone ratio revealed 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment. Moreover, slight but distinct elevation of the ratio was found in a 95-year-old woman with normotension and normopotassemia. The mineralocorticoid excess state with reduced aldosterone level appeared following with vomiting and diarrhea, exaggerating asymptomatic impairment of 11beta-HSD2 to induce apparent mineralocorticoid excess (AME)-like condition.

Effect of spironolactone on diuresis and urine sodium and potassium excretion in healthy dogs

Objectives To document the diuretic effect of different oral doses of spironolactone (SP) in healthy dogs. Background SP is currently mentioned as a diuretic agent in the dog. However, the recommended doses were empirically defined and their corresponding diuretic effect has never been documented in dogs. Animals, materials and methods Eight adult Beagle dogs were used for two separate 2 * 2 cross-over designs. In the first cross-over, 4 dogs received SP orally for 8 days at 1 and 2 mg/kg per day. In the second cross-over the 4 other dogs received SP similarly, but at 4 and 8 mg/kg per day. Dogs were weighed on the first and last day of each period. Plasma SP and canrenone (the main active metabolite of SP) were assayed by high performance liquid chromatography (HPLC). Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium and potassium were measured during the SP treatment. Results Two hours after SP administration, SP was metabolized into canrenone. A significant 14 and 22% decrease in urine potassium excretion was observed at 1 and 2 mg/kg, respectively, but not at the two other dose levels. Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium were not significantly altered by the SP treatment regardless of dose. Conclusions Repeated oral administration of SP at 1, 2, 4 or 8 mg/kg for 8 days had no effect on water and sodium diuresis in healthy dogs.

The tubulogenic effect of aldosterone is attributed to intact binding and intracellular response of the mineralocorticoid receptor

Abstract Little is known about the extra- and intracellular stimuli inducing renal stem/progenitor cells to develop into three-dimensionally structured tubules. To study this specific development in a controlled environment, we used an advanced culture technique. Embryonic tissue derived from neonatal rabbit kidney was placed in a perfusion culture container at the interface of an artificial interstitium made of a polyester fleece. Culture was carried out in chemically defined Iscove’s Modified Dulbecco’s Medium (IMDM) for 13 days. Development of tubules was histochemically detected on cryosections labeled with Soybean Agglutinin (SBA). The experiments showed that aldosterone exerts a specific tubulogenic effect. Application of aldosterone (1 × 10−7 M) raised numerous SBA-labeled tubules, while in the absence of the steroid hormone the development of tubules was lacking. Specificity of hormone action was analyzed by the use of aldosterone antagonists. Administration of spironolactone (1 × 10−4 M) and canrenoate (1 × 10−5 M) completely inhibited the development of tubules. Finally, disrupting the intracellular molecular complex of the mineralocorticoid receptor (MR) and heat shock proteins by geldanamycin (2 μg/ml) prevented the development of tubules. Our results suggest that the tubulogenic effect induced by aldosterone is attributed to both hormone binding and an undisturbed intracellular response of the MR.

Beneficial Effect of Spironolactone Administration on Ethynylestradiol-Induced Cholestasis in the Rat: Involvement of Up-Regulation of Multidrug Resistance-Associated Protein 2

The effect of spironolactone (SL) administration on 17alpha-ethynylestradiol (EE)-induced cholestasis was studied, with emphasis on expression and activity of Mrps. Adult male Wistar rats were divided into the following groups: EE (5 mg/kg daily for 5 days, s.c.), SL (200 micromol/kg daily for 3 days, i.p.), EE+SL (same doses, SL administered the last 3 days of EE treatment), and controls. SL prevented the decrease in bile salt-independent fraction of bile flow induced by EE, in association with normalization of biliary excretion of glutathione. Western blot studies indicate that EE decreased the expression of multidrug resistance-associated protein 2 (Mrp2) by 41% and increased that of Mrp3 by 200%, whereas SL only affected Mrp2 expression (+60%) with respect to controls. The EE+SL group showed increased levels of Mrp2 and Mrp3 to the same extent as that registered for the individual treatments. Real-time polymerase chain reaction studies indicated that up-regulation of Mrp2 and Mrp3 by SL and EE, respectively, was at the transcriptional level. To estimate Mrp2 and Mrp3 activities, apical and basolateral excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, was measured in the recirculating isolated perfused liver model. Biliary/perfusate excretion ratio was decreased in EE (-88%) and increased in SL (+36%) with respect to controls. Coadministration of rats with SL partially prevented (-53%) impairment induced by EE in this ratio. In conclusion, SL administration to EE-induced cholestatic rats counteracted the decrease in bile flow and biliary excretion of glutathione and APAP-glu, a model Mrp substrate, findings associated with up-regulation of Mrp2 expression.

Aldosterone upregulates vascular endothelial growth factor expression in mouse cortical collecting duct epithelial cells through classic mineralocorticoid receptor

Accumulating evidence shows that aldosterone plays an important role in the pathogenesis of renal fibrosis but its mechanism has not been completely defined. Recently, exogenous administration of aldosterone significantly alleviated ischemic states in a model of femoral artery ligated rats, accompanied by an obvious enhancement of VEGF upregulation. We hypothesized that aldosterone may also regulate the expression of VEGF in the kidney. To confirm this, cultured cortical collecting duct epithelial cells (M-1 cell line) were incubated with aldosterone and control media, respectively. The pathway by which aldosterone regulates VEGF expression was tested by the administration of spironolactone, a specific mineralocorticoid receptor (MR) antagonist. VEGF expression was detected by immunofluorescence staining, ELISA, Western blot and RT-PCR. Aldosterone induced an elevation of VEGF excretion in a time- and dose-dependent manner. Western blotting showed a 1.4-fold elevation in cytosolic VEGF expression following aldosterone (10 − 8 M) incubation for 48 h ( p < 0.01). After aldosterone (10 − 7 M) incubation for 48 h, the mRNA level of VEGF164 and VEGF120 showed 1.8- and 1.7-fold increases, respectively ( p < 0.01). This upregulation was almost completely blocked by spironolactone as shown both by mRNA levels and cytosolic protein levels. In addition, the mRNA of aldosterone receptor was detected in M-1 cells. We demonstrated for the first time that aldosterone induced VEGF expression in M-1 cells, an effect mediated by classic mineralocorticoid receptor. This finding provides experimental evidence for the local non-hemodynamic action of aldosterone.

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

Mesangial proliferative glomerulonephritis with aldosterone-producing adenoma

We describe a case of mesangial proliferative glomerulonephritis (MesPGN), the clinical symptoms of which were exacerbated by aldosterone-producing adenoma (APA). A 45-year-old man, who had had a history of hypertension for several years, presented with renal derangement, with serum creatinine at its upper normal limit and with microhematuria and proteinuria. He also presented with hypokalemia, with a plasma aldosterone concentration at its upper normal limit and plasma renin activity at its lower normal limit. After the administration of spironolactone, we resected his left adrenal gland, which had a nodular lesion as well as aldosterone hypersecretion. The treatment normalized his arterial blood pressure and serum potassium concentration. Although his proteinuria disappeared with the reduction in arterial blood pressure, the microhematuria continued. The administration of losartan because of the histological finding of MesPGN reduced the amount of hematuria. A dissociated response of hematuria and proteinuria to antihypertensive treatment indicated that MesPGN was coincidental with APA.

Spironolactone is not Effective for the Treatment of Hypokalemia in Peritoneal Dialysis Patients

Hypokalemia is a common problem in patients on continuous ambulatory peritoneal dialysis (CAPD). We evaluated the efficacy and safety of spironolactone in CAPD patients with hypokalemia. We reviewed the clinical response of 12 consecutive hypokalemic CAPD patients treated with spironolactone in our dialysis center. All patients received spironolactone 25 mg daily. There was no significant change in the serum potassium level after administration of spironolactone (3.30 ± 0.26 vs. 3.46 ± 0.38 mmol/L, p = 0.28), even though three patients required regular oral potassium supplementation. There was also no significant change in arterial blood pressure or urine output after spironolactone treatment. Spironolactone was well tolerated and no hyperkalemia was recorded. Spironolactone is not effective in the treatment of hypokalemia in stable CAPD patients, but the agent is well tolerated, at least in CAPD patients with little residual renal function. Future studies are warranted to determine the therapeutic role of spironolactone in CAPD patients with concomitant congestive heart failure or cardiovascular disease.

Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone

Renal ischemia and reperfusion (I/R) injury is the major cause of acute renal failure and may also be involved in the development and progression of some forms of chronic kidney disease. We previously showed that a mineralocorticoid receptor (MR) blockade prevents renal vasoconstriction induced by cyclosporine that leads to acute and chronic renal failure (Feria I, Pichardo I, Juarez P, Ramirez V, Gonzalez MA, Uribe N, Garcia-Torres R, Lopez-Casillas F, Gamba G, Bobadilla NA. Kidney Int 63: 43-52, 2003; Perez-Rojas JM, Derive S, Blanco JA, Cruz C, Martinez de la Maza L, Gamba G, Bobadilla NA. Am J Physiol Renal Physiol 289: F1020-F1030, 2005). Thus we investigated whether spironolactone administration prevents the functional and structural damage induced by renal ischemia-reperfusion (I/R). Five groups were studied: sham-operated animals, rats that underwent 20 min of ischemia and 24 h of reperfusion, and three groups that received spironolactone 1, 2, or 3 days before I/R, respectively. Renal I/R produced significant renal dysfunction and tubular damage. Spironolactone administration completely prevented a decrease in renal blood flow, the development of acute renal failure, and tubular apoptosis. The protection conferred by spironolactone was characterized by decreasing oxidative stress, as evidenced by a reduction in kidney lipoperoxidation, increasing expression of antioxidant enzymes, and restoration of urinary NO(2)/NO(3) excretion. Endothelial nitric oxide synthase expression was upregulated by a mineralocorticoid receptor blockade in I/R groups; in addition, an increase in activating phosphorylation of this enzyme at residue S1177 and a decrease in inactivating phosphorylation at T497 were observed. In conclusion, our study shows that spironolactone administration prevents the renal injury induced by I/R, suggesting that aldosterone plays a central role in this model of renal injury.

Treatment of heart failure with ACE inhibitors and beta-blockers

Angiotensin converting enzyme (ACE) inhibitors and beta-blockers have together become the backbone of the treatment of chronic heart failure (CHF) as both classes of drugs have been shown to reduce morbidity and mortality [1]. In addition, patients with CHF generally receive a number of other drugs, which include diuretics, digoxin, vasodilators (like nitrates, and calcium channel blockers), anti-arrhythmic drugs, anticoagulants, and more recently statins. Although these latter classes of drugs may be indicated for special indications (such as atrial fibrillation) none of them has been overall shown to improve outcome. This is in contrast with two other classes of drugs which were found to further reduce morbidity and mortality in patients with CHF when added to maximal medication, i.e. angiotensin II receptor blockers (ARBs) and aldosterone receptor antagonists (ARAs) [2–5].

Severe Hypokalemia, Rhabdomyolysis, Muscle Paralysis, and Respiratory Impairment in a Hypertensive Patient Taking Herbal Medicines Containing Licorice

A 93 year-old hypertensive woman was found to have severe hypokalemia (as low as 1.3 mEq/L) and developed paralysis of the all extremities associated with metabolic alkalosis, hypoxemia, hypercapnea, extremely high levels of creatine phosphokinase (up to 9280 U/L), myoglobin and myoglobinuria compatible with rhabdomyolysis. Plasma renin activity and aldosterone levels were below normal. She was found to have been taking licorice-containing herbal medicines for the last 7 years. With the discontinuation of the licorice-containing medicines and administration of spironolactone together with intravenous and oral potassium supplement, her serum potassium level was normalized and her clinical symptoms and hypertension improved within 2 weeks.

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

Aldosterone antagonists have been reported to prevent ventricular remodeling after myocardial infarction (MI) via their action to extracellular matrix (ECM). However, it remains largely unknown whether aldosterone antagonists attenuate myocyte loss in the remodeling process. The present study examined whether spironolactone prevents myocyte apoptosis and improves post-infarct ventricular remodeling in rats. MI was achieved by permanent occlusion of the left coronary artery. Administration of spironolactone (100 mg/kg/day) was started immediately after MI. Sprague-Dawley rats were divided into four groups: 1) sham, 2) spironolactone-treated sham, 3) untreated MI, 4) spironolactone-treated MI. Echocardiographic parameters (left ventricular [LV] diastolic dimension [LVDd], fractional shortening [%FS]), hemodynamic parameters (LV systolic pressure [LVSP], LV end-diastolic pressure [LVEDP], dP/dt(max) and dP/dt(min)) and collagen accumulation quantitated by Masson's Trichrome staining were significantly improved in the spironolactone-treated MI group on the 14th day, compared with the untreated MI group. Moreover, the percentage of apoptotic myocytes evaluated by terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay was significantly lower in the spironolactone-treated MI group on the 2nd (3.54% vs. 5.79% in untreated MI group), 7th (0.65% vs. 1.37% in untreated MI group) and 14th days (0.11% vs. 0.16% in untreated MI group). Real time reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mineralocorticoid receptor (MR) mRNA and that of 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) mRNA, which is known to confer aldosterone selectivity on MR, were upregulated in the untreated MI group, and that spironolactone significantly suppressed the expression of these genes. Moreover, spironolactone significantly inhibited aldosterone-induced apoptosis in cultured rat cardiac myocytes in a dose-dependent fashion. Our study demonstrates that, in addition to their effect on ECM, aldosterone antagonists inhibit myocyte apoptosis and prevent post-infarct ventricular remodeling by modulating the expression levels of MR and 11beta-HSD2, which are enhanced in the remodeling heart.

Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders

Multiple studies now demonstrate that autism is medically characterized, in part, by immune system dysregulation, including evidence of neuroglial activation and gastrointestinal inflammation. This neuroglial process has further been characterized as neuroinflammation. In addition, a subset of autistic children exhibit higher than average levels of androgens. Spironolactone is an aldosterone antagonist and potassium-sparing diuretic with a desirable safety profile. It possesses potent anti-inflammatory and immune modifying properties that might make it an excellent medical intervention for autism spectrum disorders. Furthermore, spironolactone demonstrates substantial anti-androgen properties that might further enhance its appeal in autism, particularly in a definable subset of hyperandrogenic autistic children. One case report is briefly reviewed demonstrating objective clinical improvements in an autistic child after spironolactone administration. Additional research in controlled trials is now needed to further define the risks and benefits of spironolactone use in children with autism.

The effect of aldosterone blockade in patients with Alport syndrome

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.

Eplerenone relieves spironolactone-induced painful gynaecomastia in a patient with primary aldosteronism

Sir, Eplerenone is the second oral aldosterone antagonist available for the treatment of essential hypertension and congestive heart failure. Spironolactone, the first aldosterone antagonist, although effective for the above conditions, has progestational and antiandrogenic adverse effects due to its non-specific binding to various steroid receptors. We report the case of a 54-year-old Caucasian man, who was admitted to hospital because of severe hypertension and hypokalaemia. The plasma aldosterone/plasma renin activity ratio was well above the cut-off level of 30 ng/dl/ng ml � 1 h � 1 . The acute intravascular volume expansion with the intravenous administration of isotonic saline showed autonomous aldosterone production. The aforementioned results were considered diagnostic of primary aldosteronism. A computerized tomography scan with fine cuts (2.5–3 mm) showed bilateral adrenal gland hyperplasia. Therefore, the patient was started on spironolactone 100 mg t.d.s., and in the following days normokalaemia was restored and blood pressure was well-controlled. Two months later, the patient presented with bilateral painful gynaecomastia. We switched spironolactone to eplerenone 25 mg t.d.s., and the patient was completely relieved within 1 month, while his blood pressure remained well-controlled and serum potassium was normal. Spironolactone is the drug of choice for the treatment of primary aldosteronism, but presents sexual side effects, such as impotence, painful gynaecomastia and menstrual disturbances in pre-menopausal women. Several mechanisms have been proposed for these side effects, such as a dosedependent reduction of microsomal cytochrome P-450, alterations of the testosterone–estrogen ratio, a fall in plasma testosterone or a significant increase in its metabolic clearance, and the peripheral conversion of testosterone to estradiol or increased serum levels of estrone and estradiol [1]. Gynaecomastia may be quite remarkable and its occurrence is dose- and time-dependent. Eplerenone is a highly selective aldosterone antagonist. Spironolactone is approximately 40-fold more potent than eplerenone in blocking aldosterone activation of mineralocorticoid receptor. However, the selectivity of eplerenone is significantly greater than spironolactone at androgen, progesterone and glucocorticoid receptors. Eplerenone is 370-fold less potent at blocking dihydrotestosteroneactivation of androgen receptors compared with spironolactone [2]. Two large clinical studies have evaluated the efficacy and tolerability of these aldosterone antagonists. The Randomized Aldactone Evaluation Study (RALES) found that the administration of spironolactone 12.5–50 mg/day,

Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats

Administration of spironolactone provides a beneficial effect in various animal models of renal injury. In this study, we investigated whether spironolactone prevents the progression of diabetic nephropathy through reduction of connective tissue growth factor (CTGF) synthesis in type II diabetic rats. In addition, we evaluated the effect of aldosterone and spironolactone on CTGF and collagen production in cultured cells. Renal functional and morphologic changes were examined in Otsuka Long-Evans Tokushima Fatty rats with or without spironolactone treatment (20 mg/kg/day) for 8 months, as well as in non-diabetic age-matched Long-Evans Tokushima Otsuka rats. Spironolactone treatment did not induce any significant differences in body weight, kidney/body weight ratio, serum creatinine concentration, blood glucose levels, or systolic blood pressure. However, urinary protein and albumin excretion were significantly decreased in the spironolactone treatment group, which was associated with amelioration of glomerulosclerosis. In addition, renal CTGF, collagen synthesis demonstrated marked decreases in the spironolactone treatment group. In cultured MC and PTC, aldosterone induced significant increases in CTGF gene expression and protein synthesis associated with increased collagen synthesis, which was abolished by prior treatment with spironolactone. However, aldosterone treatment did not induce transforming growth factor (TGF)-beta1 overproduction, and inhibition of TGF-beta1 by neutralization of TGF-beta1 protein did not significantly prevent aldosterone-induced CTGF production. These results suggest that the antifibrotic effects of spironolactone may be mediated by CTGF through a TGF-beta1-independent pathway in this animal model of diabetic nephropathy.

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 …