Aldosterone receptor blockade and the role of eplerenone: evolving perspectives

Murray Epstein

Department of Medicine, University of Miami, School of Medicine, Miami, FL, USA

Correspondence and offprint requests to: Murray Epstein, MD, Professor of Medicine, Nephrology Section, VA Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA. Email: murraye{at}gate.net

Keywords: aldosterone; cardiovascular disease; eplerenone; mineralocorticoid receptor; renal disease; selective aldosterone blockade

Introduction

Aldosterone is a major regulator of extracellular fluid volume and the major determinant of potassium metabolism [15]. These effects are mediated by the binding of aldosterone to the mineralocorticoid receptor in target tissues, primarily the kidney. Volume is regulated through a direct effect on the collecting duct, where aldosterone causes an increase in sodium retention and an increase in potassium excretion. The reabsorption of sodium ions produces a fall in the transmembrane potential, thus enhancing the flow of positive ions, such as potassium, out of the cell into the lumen. The reabsorbed sodium ions are transported out of the tubular epithelium into the renal interstitial fluid and from there into the renal capillary circulation.

Three primary mechanisms control aldosterone release: the renin–angiotensin system, potassium and adrenocorticotropic hormone. The renin–angiotensin system controls extracellular fluid volume via regulation of aldosterone secretion. In effect, the renin–angiotensin system maintains the circulating blood volume constant by causing aldosterone-induced sodium retention during volume deficiency and, conversely, by decreasing aldosterone-dependent sodium retention when volume is ample.

In recent years, there has been a paradigm shift with respect to our understanding of aldosterone’s widespread effects on the heart, the vasculature and the kidney [69]. Aldosterone’s endocrine properties have taken on a broader perspective involving non-classic actions in non-epithelial cells found in non-classic target tissues, including the heart and vasculature [6,1015]. Furthermore, the traditional concept that aldosterone is synthesized only in the adrenal glomerulosa cell and acts almost exclusively on the kidney to modify sodium and potassium homeostasis needs to be expanded. There is increasing evidence that aldosterone can have an effect on vascular remodelling and collagen formation and has a non-genomic action to modify endothelial function. Among the most intriguing effects of aldosterone are its impact on fibrosis and activity associated with a cell surface receptor in certain target tissues, including endothelial cells [6,7,1619]. These actions contribute substantively to the pathophysiology of congestive heart failure, including its progressive nature, as well as progressive renal dysfunction. This new information has spurred interest in the development of a selective antagonist to block aldosterone’s effect, not just because of its diuretic effect, but primarily because of its potential cardiovascular and renal protective effects.

In this review, I will briefly consider the expanding role of aldosterone and the broad spectrum of non-genomic effects. It is becoming increasingly evident that these effects, occurring independently of haemodynamic factors, contribute to enhanced cardiovascular risk manifested by congestive heart failure and progressive renal disease. On an optimistic note, I will review the recent clinical and experimental trials with the selective aldosterone blocker (SAB) eplerenone (Inspra®). Such trials have enhanced our understanding of the role of aldosterone in the pathophysiology of cardiovascular and renal disease. Hopefully, these studies with eplerenone hold promise for a further reduction in cardiovascular and renal disease morbidity and mortality and for enhancing patient well-being.

Traditional concept

In its capacity as a mineralocorticoid hormone, aldosterone has receptor–ligand endocrine properties on epithelial cell sodium and potassium exchange in classic target tissues, such as the kidneys, colon and salivary and sweat glands [13]. Its significance during dietary sodium deprivation or in response to salt and water loss is clear and can be life-saving. By virtue of its effects on the distal renal tubular cell, aldosterone is involved in the regulation of sodium and body water homeostasis and, consequently, participates in the regulation of blood pressure [4]. Figure 1 summarizes the deleterious effects of activation of the renin–angiotensin–aldosterone system (RAAS) with a consequent increase in circulating aldosterone. As a consequence of renal sodium retention and enhanced potassium excretion, aldosterone potentiates the occurrence of stroke, coronary artery disease, myocardial infarction and sudden cardiac death. Its contribution to the pathophysiologic origins of such salt-avid states as congestive heart failure, cirrhosis and nephrotic syndrome is well established. In recent years, aldosterone’s endocrine properties have taken on a broader perspective involving non-classic actions in non-epithelial cells found in non-classic target tissues. These actions likewise contribute to the pathophysiology of cardiac fibrosis and cardiovascular dysfunction [6,20], as well as progressive renal dysfunction [9].



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Fig. 1. The deleterious effects of aldosterone.

 
Non-classic actions of aldosterone

Recent evidence indicates that aldosterone is synthesized not only in adrenal glomerulosa, but also at other extra-adrenal sites and that it interacts with epithelial and non-epithelial tissues outside of the kidney, colon and salivary and sweat glands. Some of these interactions clearly play a role in the regulation of blood pressure and salt and volume homeostasis, both at the level of the central nervous system as well as in epithelial tissues. Others, however, can be maladaptive and can result in significant vascular lesions in target organs. In a high-salt environment, aldosterone induces a vascular inflammatory response characterized by perivascular leukocyte infiltration, vascular remodelling with fibrinoid necrosis of the media and consequent ischaemic and necrotic alterations in the affected tissues [21]. This response could ultimately result in the development of cardiac fibrosis, hypertensive nephrosclerosis or stroke. Importantly, these non-epithelial effects of systemic or local aldosterone are largely or completely abolished by administration of SABs [21]. Thus, accumulating evidence indicates that aldosterone, in the presence of a high-salt environment, plays a significant role in the pathophysiological changes that occur in target organs of hypertensive disease, including the heart, brain and kidney.

As detailed recently [22], various areas of the brain, primarily the hypothalamus, appear capable of aldosterone biosynthesis. A direct role for aldosterone in the regulation of blood pressure in the brain has been defined [22]. In addition, recent studies have identified a potential role for aldosterone in the central regulation of salt appetite [23].

The following section will briefly summarize newer observations relating to the cardiovascular effects of aldosterone.

Cardiovascular effects

Several recent reports have reviewed the adverse effects of aldosterone in the endothelial, smooth muscle and adventitial layers of the blood vessel. The innermost layer of the blood vessel is the endothelium, which produces nitric oxide (NO). Farquharson and Struthers [20] demonstrated, in an indirect manner, that aldosterone could play a major role in producing endothelial dysfunction in chronic heart failure. They reported that aldosterone blockade with spironolactone virtually doubled NO bioactivity and improved endothelial function in patients with chronic heart failure who were already being treated with angiotensin-converting enzyme (ACE) inhibitor therapy. Recently, these investigators conducted an elegant study directly demonstrating that aldosterone infusion in hypertensive patients can induce endothelial dysfunction, thereby substantiating this important effect [24]. Improving endothelial function may be highly beneficial, because endothelial dysfunction has been shown to be closely linked to cardiovascular events.

Based on this platform, one can readily marshal a compelling argument for a role of aldosterone receptor blockade in several groups of patients other than those with severe heart failure due to systolic left ventricular dysfunction, including patients with essential hypertension [6,9]. Selective aldosterone blockade has been shown to prevent the progression of left ventricular hypertrophy [25], which is recognized as predisposing to sudden cardiac death. Recent data indicate that aldosterone blocks the uptake of norepinephrine into the myocardium and that aldosterone receptor antagonists improve the uptake of norepinephrine [26], heart rate variability [27] and baroreceptor function [28]. Collectively, these findings provide a compelling theoretical platform for considering aldosterone antagonism as occupying a pivotal role in the antihypertensive regimen in order to prevent the cardiac sequelae of hypertension.

Several important clinical trials also support the protective effects of aldosterone blockade in patients with heart failure. The Randomized Aldactone Evaluation Study (RALES) [7] examined the effect of spironolactone on overall morbidity and mortality in patients with severe heart failure treated with standard therapy with an ACE inhibitor, a loop diuretic and digoxin, combined with either a non-haemodynamic dose of spironolactone (25 mg/day) or placebo. This seminal trial was discontinued early by the Data Safety Monitoring Board after a mean follow-up of 24 months, because of the dramatic benefits. Specifically, this study demonstrated that spironolactone-treated patients demonstrated a 30% reduction in the risk of death from all causes compared with the placebo group. This reduction in mortality was largely attributed to a reduction in death from progressive heart failure and sudden cardiac death. The RALES investigators attributed the beneficial actions of spironolactone to the drug’s favourable effects on myocardial and vascular fibrosis and its ability to increase myocardial uptake of norepinephrine, in addition to its anticipated ability to prevent sodium retention and potassium loss [7].

Recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [29] extended the RALES study. This landmark trial investigated whether selective aldosterone blockade with eplerenone would confer cardiovascular benefit. This large, double-blind, prospective study in patients with heart failure due to systolic dysfunction following acute myocardial infarction randomized patients to treatment with eplerenone (25–50mg/day; 3313 patients) or placebo (3319 patients) in addition to standard medical therapy. The primary endpoints were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke or ventricular arrhythmia. During a mean follow-up of 16 months, there was a 15% risk reduction for death in the eplerenone group compared with the placebo group (P = 0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes [relative risk: 0.83; 95% confidence interval (CI): 0.72–0.94; P = 0.005]. The rate of the other primary endpoint, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk: 0.87; 95% CI: 0.79–0.95; P = 0.002), as was the secondary endpoint of death from any cause or any hospitalization (relative risk: 0.92; 95% CI: 0.86–0.98; P = 0.02). Thus, EPHESUS demonstrated that eplerenone conferred dramatic benefit with respect to cardiovascular mortality and morbidity, while avoiding the sexual side-effects that have limited non-selective aldosterone blockade. Hopefully, parallel studies in patients with hypertension and progressive renal dysfunction will further extend and delineate the role of SABs as target organ protective agents.

The role of aldosterone in mediating progressive renal disease

In analogy with its effects on the cardiovascular system, aldosterone also exerts adverse effects on the kidney. I have recently reviewed the rapidly emerging evidence for aldosterone as a mediator of progressive renal disease [9]. Subsequently, several experimental and clinical studies have expanded our understanding of aldosterone and the kidney. Although the role of angiotensin II in mediating progressive renal disease has been documented extensively [3034], recent evidence also implicates aldosterone (independent of the renin–angiotensin system) as an important pathogenetic factor in progressive renal disease.

Clinical studies [34] have demonstrated a relationship between augmented levels of aldosterone and renal deterioration. Observational studies in patients with primary aldosteronism (PA) suggest a pathogenetic role for hyperaldosteronism per se in the pathogenesis of renal disease [35,36]. Originally, it was postulated that hypertensive patients with low levels of plasma renin activity have fewer cardiovascular complications than those with normal or elevated levels of plasma renin activity. However, in several recent studies, cardiovascular complications were found in 14–35% of patients with PA. Moreover, in patients with PA, the incidence and degree of proteinuria was reported to be greater than that in patients with essential hypertension [35,36].

A number of experimental models are consistent with the concept that aldosterone might play a pathogenetic role in mediating renal injury. Hyperaldosteronism and adrenal hypertrophy are common findings in the remnant kidney model, with plasma levels of aldosterone increased ~10-fold [37]. In a study by Quan et al. [38], hypertension, proteinuria and structural renal injury were less prevalent in rats that underwent subtotal nephrectomy with adrenalectomy compared with rats that had partial nephrectomy but intact adrenal glands. This occurred despite large doses of replacement glucocorticoid (aldosterone was not replaced) in the adrenalectomized rats.

In the deoxycorticosterone acetate–salt hypertensive rat model, exogenous administration of mineralocorticoids induced lesions of malignant nephrosclerosis and stroke [39]. The development of this type of lesion is likely due to the intrinsic action of mineralocorticoids, because these rats demonstrate low levels of plasma renin activity and responded poorly to ACE inhibitor therapy. Several lines of experimental evidence confirm that blockade of aldosterone, independent of renin–angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive, stroke-prone rat (SHRSP) model [40] and controls proteinuria in the subtotally nephrectomized rat model (i.e. remnant kidney) [37].

Although many studies have demonstrated a beneficial effect of ACE inhibition in retarding progressive renal disease, this intervention does not differentiate between the relative contributions of renin–angiotensin vs aldosterone. To evaluate the possible contribution of aldosterone per se, Rocha et al. [8,40] conducted a series of experiments in SHRSP that succeeded in dissociating the relative contributions of aldosterone and the renin–angiotensin system. Initially, they implanted time-release pellets of spironolactone, an aldosterone receptor antagonist, or placebo pellets in saline-drinking (1% NaCl) SHRSP ingesting a Stroke-Prone Rodent diet [40]. This model is known to induce severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy, as observed in malignant nephrosclerosis. Blood pressure and urinary protein excretion were assessed for a 3–4 week period. Results demonstrated that mineralocorticoid receptor blockade with spironolactone markedly attenuated urinary protein excretion (150 mg/day for the placebo group vs 39 mg/day for the spironolactone group; P < 0.0001). Proteinuria remained at baseline levels in the spironolactone group ~12 weeks later, although urinary protein excretion remained elevated in placebo-implanted animals (136 mg/day for the placebo group vs 39mg/day for the spironolactone group; P < 0.0001). Histological examinations revealed fewer nephrosclerotic and cerebrovascular lesions in the spironolactone group than in the placebo group (P < 0.01 and P < 0.001, respectively). Notably, systolic blood pressure did not differ between the two groups at any time during the study.

In a subsequent study, Rocha et al. [8] evaluated whether an aldosterone infusion would reverse the renal-protective effects of captopril therapy in SHRSP. The study divided SHRSP into five groups: vehicle (control), captopril (50 mg/kg/day), aldosterone infusion (40 µg/kg/day) or captopril (50 mg/kg/day) with aldosterone infusion (at 20 and 40 µg/kg/day). Animals in the control and aldosterone infusion groups experienced marked proteinuria and comparable degrees of renal injury (21% and 29%, respectively). In contrast, captopril treatment reduced endogenous aldosterone levels, prevented the development of proteinuria and prevented the development of glomerular and renal vascular lesions. However, subsequent aldosterone infusion reversed the ability of captopril to confer this protection. The aldosterone-infused, captopril-treated rats demonstrated proteinuria, renal vascular lesions and glomerular lesions despite ACE inhibitor treatment. Interestingly, systolic blood pressure in captopril-treated SHRSP receiving the aldosterone infusion was not significantly different than in SHRSP treated with captopril alone. Thus, the renal injury induced by aldosterone developed independently of blood pressure increases, suggesting a more direct tissue effect of aldosterone.

Because the above data with spironolactone may be confounded by the modest affinity of spironolactone for other steroid receptors, Rocha and colleagues performed two experiments using eplerenone, an SAB, to further evaluate the role of mineralocorticoids in renal vascular lesion development [41]. In the first experiment, the impact of eplerenone on urinary protein excretion and blood pressure was compared with a control group following infusions of aldosterone or angiotensin II. Eplerenone prevented proteinuria (15 mg/day for eplerenone vs 92 mg/day for the control group; P < 0.001) and renal lesions (2% for eplerenone vs 40% for the control group; P < 0.0005). Because blood pressure did not differ significantly between the eplerenone and control groups (226 vs 234 mmHg, respectively), we must conclude that the protective effects of eplerenone occurred independently of any confounding effects of blood pressure. In the second experiment, five groups were studied: vehicle (control), captopril, captopril followed by an aldosterone infusion, captopril followed by an angiotensin II infusion and the combination of captopril and eplerenone followed by an angiotensin II infusion. After 2 weeks, proteinuria (158, 121, 96 vs 16 mg/day, respectively; P < 0.001) and glomerular (18%, 15%, 16% vs 0%, respectively; P < 0.001) and renal vascular lesions (24%, 26%, 17% vs 0%, respectively; P < 0.001) were significantly higher in the control, captopril plus aldosterone and captopril plus angiotensin II groups vs the captopril-alone group. Thus, both the aldosterone and angiotensin II infusions reversed the renal-protective effects of captopril. However, when the captopril plus angiotensin II group was compared with the combination of captopril, eplerenone and angiotensin II, the latter combination group manifested substantially less proteinuria (96 vs 28 mg/day, respectively; P < 0.001) and significantly fewer glomerular (16% vs 4%, respectively; P < 0.001) and renal vascular lesions (17% vs 4%, respectively; P < 0.001). In contrast to the reversal of renal protection seen when angiotensin II was added to captopril treatment, the addition of eplerenone to the aforementioned regimen attenuated proteinuria and renal damage in SHRSP. Although mean systolic blood pressures were elevated after 2 weeks of treatment, there were no statistically significant differences in systolic blood pressure among the five treatment groups. These pivotal data further support a major role of aldosterone per se, independent of the renin–angiotensin system, as a mediator of renal injury in saline-drinking SHRSP.

Are the adverse effects of aldosterone produced indirectly by altering sodium and potassium?

Is induction of secondary hypokalaemia and/or hypernatraemia the mechanism by which aldosterone causes myocardial and vascular damage? Or does the injury involve a direct action of the mineralocorticoid against target cells? To address this problem, Martinez et al. [42] assessed the effects of each influence in male Wistar rats exposed to N {omega}-nitro-L-arginine methyl ester (L-NAME) and angiotensin II (a combination previously observed to cause end-organ damage [43]) as well as either a moderately high-sodium diet (1% NaCl drinking water) or a low-sodium diet; animals given 1% NaCl drinking water, but not L-NAME/angiotensin II served as controls. They compared the ability of three variables to protect against the deleterious effects of L-NAME/angiotensin II or L-NAME/angiotensin II/1% NaCl: eplerenone, a low-sodium diet and a high-potassium diet (1% KCl in food).

The fact that myocardial damage occurred in animals receiving L-NAME/angiotensin II along with a high-sodium diet, but not in animals on a low-sodium diet with or without L-NAME/angiotensin II, demonstrates that a moderately high-sodium diet and aldosterone are co-contributors to the pathophysiology. The demonstration that eplerenone, but not potassium supplementation, prevented myocardial damage by L-NAME/angiotensin II/1% NaCl suggests that aldosterone causes end-organ injury directly and not through induction of hypokalaemia and suggests that selective antagonism of aldosterone receptors accounts for the protective effect of eplerenone.

Mechanisms by which aldosterone promotes fibrosis and target organ disease

Several mechanisms may account for the ability of aldosterone to promote fibrosis and target organ dysfunction in the hypertensive patient (Table 1). These include plasminogen activator inhibitor (PAI-1) expression and consequent alterations of vascular fibrinolysis [44,45], stimulation of transforming growth factor ß1 [46] and stimulation of reactive oxygen species [47]. Another attractive mechanism incorporates the well-established ability of aldosterone to potentiate the pressor effects of angiotensin II due to upregulation of angiotensin II receptors in vascular smooth muscle cells [48]. Aldosterone has recently been hypothesized to exert a direct cellular effect to induce fibrosis and hypertrophy in vascular smooth muscle cells and myocardial cells, effects that may previously have been inaccurately attributed solely to the systemic hypertension caused by mineralocorticoids. Several studies [16,49] have linked mineralocorticoids with myocardial fibrosis through stimulation of collagen formation in myocardial cells.


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Table 1. Potential mechanisms by which aldosterone mediates fibrosis and collagen formation

 
Circulating aldosterone may mediate vascular fibrosis by the direct interaction of this steroid hormone with high-affinity, low-capacity corticoid receptors that are located in the cytosol of vascular fibroblasts. When activated, the receptor loses its heat shock protein and its monomeric form reaches the cell nucleus, where it binds to DNA with its binding region to initiate the expression of mRNA for type I collagen (or other protein) synthesis [50].

Another mechanism by which aldosterone may promote fibrosis in several target organs, including the kidney, centres on its effects on the plasminogen activator system [51]. The effect of the RAAS on the plasminogen activator system serves as one of the major endogenous defence mechanisms against intravascular thrombosis and also plays an important role in vascular and tissue remodelling. Vascular fibrinolytic balance is, to a large extent, determined by the competing effects of plasminogen activators and PAI-1, both of which are locally synthesized in the blood vessel wall, and, in particular, the vascular endothelium. Brown and colleagues [44,45] have hypothesized that a major component of the vascular toxicity brought on by activation of the RAAS is derived from the deleterious effects of angiotensin on fibrinolytic balance. There is a growing body of evidence, including data from the molecular/cellular level, experimental studies in animals and clinical studies, to support that ACE is strategically located to regulate vascular fibrinolytic balance.

Brown and colleagues [44] proposed that aldosterone contributes to the regulation of PAI-1 expression. Furthermore, recent data [44,45] indicate that plasma PAI-1 levels strongly correlate with serum aldosterone in salt-depleted healthy subjects and that aldosterone enhances the induction of PAI-1 expression in smooth muscle cells in vitro. In vivo data indicate that aldosterone activity, as assessed by serum aldosterone levels, correlates with PAI-1 antigen levels, supporting an interaction between aldosterone and the fibrinolytic system [52]. As a result, it is probable that angiotensin and aldosterone act in concert to concomitantly regulate vascular fibrinolysis and tissue remodelling. Consequently, studies should be initiated to investigate the effects of specific aldosterone antagonists on PAI-1 production and the effects of such interventions on resultant cardiovascular and renal dysfunction.

Another possible mechanism relates to the potential proinflammatory effects of angiotensin II and aldosterone. By way of background, recent studies have documented vascular inflammatory damage in the hearts of aldosterone/salt, uninephrectomized rats [53]. Rocha et al. [54] demonstrated that aldosterone plays a major role in angiotensin II-induced vascular inflammation in the heart and implicated cyclooxygenase-2 (COX-2) and osteopontin as mediators of the vascular myocardial injury.

Another mechanism by which aldosterone may promote fibrosis centres on its potential ability to increase gelatinase activity. Gelatinases, or matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, are enzymes that degrade extracellular matrix. An imbalance between myocardial MMPs and their tissue inhibitors (TIMPs) results in collagen accumulation, adverse matrix remodelling and reactive interstitial fibrosis. Indeed, altered ratios of MMP/TIMP and increased plasma levels of MMP-9 have been demonstrated in heart failure patients [55]. Moreover, it has been demonstrated that myocardial MMP activity is increased in end-stage dilated cardiomyopathy compared with normal myocardium [56]. These findings have important therapeutic implications, because the extent of extracellular matrix remodelling strongly influences how much ventricular function remains after myocardial infarction. Recently, Tanhehco et al. [57] evaluated the ability of eplerenone to modulate MMP-2 and MMP-9. In this study in dogs with experimentally induced heart failure, treatment with eplerenone significantly attenuated the rise in MMP-2 and MMP-9 compared with untreated control animals. These findings suggest an important role for aldosterone in increasing gelatinase activity and, consequently, the potential benefits of aldosterone receptor blockade to limit myocardial fibrosis and remodelling.

Dechend et al. [58] recently conducted an elegant study in rats double transgenic for the human renin and angiotensinogen genes (dTGR), to elucidate the role of aldosterone in mediating cardiac hypertrophy and renal dysfunction. They assessed the role of aldosterone, growth and transcription factors in a model of angiotensin II-induced cardiac injury following administration of eplerenone or vehicle. Untreated dTGR rats developed hypertension, cardiac hypertrophy, vasculopathy and perivascular fibrosis and the mortality was 50% at 7 weeks. Analogously treated rats that received eplerenone demonstrated reduced cardiac hypertrophy compared with untreated dTGR (P < 0.001). Blood pressure levels with eplerenone were slightly, but not significantly, lower. In contrast to untreated dTGR, eplerenone reduced albuminuria by 70% (P < 0.01). Immunohistochemical analysis revealed increased expression of the activated p65 nuclear factor {kappa}B (NF-{kappa}B) subunit in the endothelium, smooth muscle cells, infiltrated cells, glomeruli and tubuli of dTGR, which was markedly reduced by eplerenone. Eplerenone inhibited AP-1 and NF-{kappa}B DNA binding activity, which was increased in dTGR. Monocyte and lymphocyte (T4+ and T8+) infiltration, as well as dendritic cell activation and infiltration, was increased in the hearts and kidneys of dTGR and these changes were reduced by eplerenone.

Aldosterone blockade mitigates renal disease: clinical studies

Recent clinical studies have indicated that aldosterone blockade may confer an antiproteinuric effect in diabetic patients. Although the current standard of practice entails blockade of the renin–angiotensin system with either an ACE inhibitor or an angiotensin II receptor blocker (ARB), such a strategy may be fraught with difficulties for long-term therapy. Although initially ACE inhibition attenuates the release of aldosterone, over time, aldosterone rebounds from this control [59]. Such ‘rebound’ should theoretically countervail the beneficial effects on the kidney.

Recently, several studies have investigated the effectiveness of aldosterone blockade on albumin excretion. Sato et al. [60] investigated the role of aldosterone rebound in 45 patients with type 2 diabetes and early nephropathy treated with an ACE inhibitor for 40 weeks. With treatment there was a 40% reduction in average urinary albumin excretion, although urinary albumin excretion in patients with aldosterone rebound (18 patients) was significantly higher than that in patients without rebound (27 patients). Of the 18 patients with rebound, spironolactone (25 mg/day) was added to ACE inhibitor treatment in 13 patients. After a 24 week study period, urinary albumin excretion and left ventricular mass index were significantly reduced without blood pressure change. This study emphasizes that aldosterone rebound may occur in 40% of patients with type 2 diabetes with early nephropathy, despite the use of ACE inhibitors, and that aldosterone blockade can abrogate the detrimental effects on the heart and kidney.

Recently, Epstein et al. [61] extended these observations to assess the role of selective aldosterone blockade using eplerenone on protein excretion with patients with type 2 diabetes mellitus. This 24 week, double-blind study tested the hypothesis that selective aldosterone blockade with eplerenone would attenuate proteinuria in patients with type 2 diabetes equally well as the ACE inhibitor enalapril. Type 2 diabetic patients with proteinuria (urinary albumin : creatinine ratio >=100 mg/g) and mild-to-moderate hypertension (diastolic blood pressure >=95 and <110 mmHg; systolic blood pressure <180 mmHg) were randomly assigned to treatment with eplerenone 200 mg/day, enalapril 40 mg/day or combination eplerenone 200 mg/enalapril 10 mg. Doses were reached by forced titration over 4 weeks. By week 8, eplerenone significantly reduced proteinuria and by week 24, proteinuria was reduced 62% in the eplerenone monotherapy group, compared with 45% in the enalapril group (P = 0.015) and 74% in the combination therapy group (P = 0.018). Reductions in systolic and diastolic blood pressure were similar in all groups, with the exception of a larger reduction in diastolic blood pressure in the combination group as compared with the eplerenone monotherapy group. This suggests that the antiproteinuric effect of eplerenone was independent of blood pressure lowering.

In summary, these studies suggest that aldosterone blockade may constitute an effective strategy for abrogating aldosterone rebound in the course of ACE inhibitor or ARB therapy. The combination of renin–angiotensin-modulating drugs in concert with selective aldosterone blockade might constitute a rational intervention for retarding progressive renal disease. Larger randomized trials are needed to corroborate and extend these promising findings.

Limitations of non-selective aldosterone receptor blockade

Although spironolactone is an effective anti-aldosterone agent, its widespread use in humans is limited by its tendency to produce undesirable sexual side-effects. At standard doses, impotence and gynecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. These adverse effects are due to the binding of spironolactone to progesterone and androgen receptors and are a substantial cause of drug discontinuation. In a study involving 43 patients treated with long-term spironolactone for mineralocorticoid excess syndromes, 13 patients (30%) were switched to alternate therapy due to the occurrence of gynecomastia (6/20 males) and menstrual disturbances or breast pain (7/23 females) [62]. The RALES trial [7] reported a 10% incidence of gynecomastia or breast pain in its male subjects (patients in this trial received 25–50 mg/day spironolactone). This incidence was significantly higher than placebo (10% vs 1%; P < 0.001) and caused significantly more patients to discontinue treatment (2% vs 0.2%; P = 0.006).

Although troublesome, these side effects have been shown to be reversible and dose related. At doses <=50 mg/day, the incidence of gynecomastia is 6.9%, but rises to 52% as doses are increased to >150 mg/day [63]. Moreover, this adverse effect exhibits a faster onset at higher doses [64]. Other studies in women taking spironolactone for dermatological disorders reiterate the dose relationship of these sexual side-effects: that doses substantially beyond 100 mg/day are more frequently associated with menstrual disturbances and breast enlargement [65,66].

Selective aldosterone blockade

Eplerenone is the only available agent in the new class of SABs. Its chemical structure differs from the non-selective aldosterone antagonist spironolactone by replacement of the 17-{alpha} thioacetyl group with a carbomethoxy group [67]. Eplerenone has a half-life of ~3.5 h and does not appear to have an active metabolite [67]. Eplerenone is a competitive antagonist of the aldosterone receptor [67]. This agent has demonstrated effective blockade of aldosterone, and its harmful consequences, without the adverse effects characteristic of non-selective antagonists (e.g. gynecomastia, impotence and menstrual irregularities) [29,6870]. This is because eplerenone is highly selective for the mineralocorticoid receptor and exhibits little affinity for other steroid receptors [67]. Indeed, the availability of eplerenone has demonstrated a reduction in sexual side-effects and, thus, has led to an improvement in patient compliance with anti-aldosterone therapy [68]. This agent was recently approved by the US Food and Drug Administration for the treatment of hypertension and is currently under study for the treatment of heart failure.

Early clinical studies [6870] support the concept that eplerenone is effective for the treatment of hypertension without exhibiting anti-androgenic adverse effects. In patients with mild-to-moderate hypertension, eplerenone provided significant and clinically meaningful blood pressure reductions, which were sustained over the 24 h dosing period. In all studies, the incidence of adverse effects with eplerenone was similar to that of placebo, with no reports of gynecomastia. The recently reported EPHESUS study [29] confirmed this formulation, demonstrating that the incidence of gynecomastia and impotence in men and breast pain in women was identical in the eplerenone group (n = 3307) as compared with the placebo group (n = 3301).

Summary

Recent observations clearly indicate that it is no longer appropriate to consider that the endocrine or paracrine properties of aldosterone are restricted to what has been called ‘classic target cells’. These recently delineated haemodynamic and humoral actions of aldosterone have important clinical implications for the pathogenesis of both cardiovascular disease and progressive renal disease and consequently should influence future antihypertensive strategies. Although ACE inhibitors are very effective in retarding disease progression, there may be additional benefit achieved with concurrent aldosterone receptor blockade. As observed in clinical studies of congestive heart failure, including the recent EPHESUS study, as well as in animal models of renal disease, antagonism of aldosterone protects against progression of end-organ damage through both haemodynamic and direct cellular actions. With the recent advent of the SAB eplerenone, it is now feasible to conduct ‘proof of principle’ antihypertensive studies to assess whether end-organ damage, endothelial dysfunction and progressive renal disease can be more effectively prevented, without the dose-limiting side effects of non-selective aldosterone receptor blockade. Demonstration that selective aldosterone receptor blockade can retard progression of both cardiovascular and renal disease constitutes an important platform for advocating the addition of SABs to the therapeutic regimen used currently for attenuation of the cardiac, vascular and renal dysfunction of hypertension.

Conflict of interest statement. The author conducted several studies and served as a consultant to Pharmacia.

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