Aldosterone receptor blockade and the role of eplerenone: evolving perspectives

Aldosterone is a major regulator of extracellular fluid volume and the major determinant of potassium metabolism [1–5]. 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 [6–9]. 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 [6,10–15]. 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 [6,7,16–19]. 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. 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 [1–3]. 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]. The deleterious effects 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. 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. 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 [30–34], 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 nephrectomy but adrenal glands. This of was not in the In the hypertensive model, administration of lesions of nephrosclerosis and stroke The development of this of is due to the action of because these rats low levels of plasma renin activity and to ACE inhibitor therapy. Several of experimental evidence that blockade of aldosterone, of renin–angiotensin proteinuria and nephrosclerosis in the and controls proteinuria in the remnant [37]. Although studies have demonstrated a beneficial effect of ACE in progressive renal disease, this not between the of renin–angiotensin aldosterone. the contribution of aldosterone per et al. conducted a of in that in the of aldosterone and the renin–angiotensin of an aldosterone receptor or placebo in a This is to induce severe hypertension and and vascular lesions of as in pressure and were for a demonstrated that mineralocorticoid receptor blockade with spironolactone for the placebo group for the spironolactone P at levels in the spironolactone group elevated in for the placebo group for the spironolactone P fewer and lesions in the spironolactone group than in the placebo group (P and P systolic blood pressure not between the groups at any during the study. In a et al. whether an aldosterone infusion would the effects of therapy in The study into aldosterone infusion or with aldosterone infusion and in the control and aldosterone infusion groups proteinuria and of renal injury and In treatment reduced aldosterone the development of proteinuria and the development of and renal vascular However, aldosterone infusion the ability of to confer this The rats demonstrated renal vascular lesions and lesions ACE inhibitor systolic blood pressure in the aldosterone infusion was not than in treated with Thus, the renal injury by aldosterone independently of blood pressure a direct effect of aldosterone. the data with spironolactone may be by the of spironolactone for other and an to further the role of in renal vascular development In the the impact of eplerenone on and blood pressure was compared with a control group following of aldosterone or angiotensin Eplerenone proteinuria for eplerenone for the control P and renal lesions for eplerenone for the control P blood pressure not between the eplerenone and control groups that the protective effects of eplerenone independently of any effects of blood In the groups were by an aldosterone by an angiotensin II infusion and the of and eplerenone by an angiotensin II proteinuria 16 P and P and renal vascular lesions P were in the aldosterone and angiotensin II groups the group. Thus, both the aldosterone and angiotensin II the effects of However, when the angiotensin II group was compared with the of eplerenone and angiotensin the group manifested less proteinuria P and fewer P and renal vascular lesions P In to the of renal when angiotensin II was to the addition of eplerenone to the regimen proteinuria and renal in Although mean systolic blood were elevated after of there were significant in systolic blood pressure the treatment These pivotal data further support a major role of aldosterone per of the renin–angiotensin system, as a mediator of renal injury in of secondary the by which aldosterone causes myocardial and vascular the injury a direct action of the mineralocorticoid target this et al. the effects of in rats to and angiotensin II to cause as well as either a or a but not II as They compared the ability of to the deleterious effects of II or a and a in The that myocardial in II with a but not in on a with or that a and aldosterone are to the The that but not potassium myocardial by that aldosterone causes injury directly and not through of and that selective antagonism of aldosterone for the protective effect of Several mechanisms may for the ability of aldosterone to fibrosis and target organ dysfunction in the hypertensive patient These inhibitor and consequent alterations of vascular of factor and of the ability of aldosterone to the effects of angiotensin II due to of angiotensin II in vascular smooth muscle cells Aldosterone has recently been to a direct effect to induce fibrosis and hypertrophy in vascular smooth muscle cells and myocardial effects that may have been attributed to the systemic hypertension by Several studies have linked with myocardial fibrosis through of collagen formation in myocardial mechanisms by which aldosterone fibrosis and collagen formation mechanisms by which aldosterone fibrosis and collagen formation aldosterone may vascular fibrosis by the direct of this with that are in the of vascular the receptor its and its the cell where it to with its binding to the of for I collagen other by which aldosterone may fibrosis in several target including the kidney, on its effects on the system The effect of the on the system as one of the major mechanisms and also plays an important role in vascular and to a by the effects of and both of which are synthesized in the blood vessel and, in the vascular and have that a major of the vascular on by activation of the is from the deleterious effects of angiotensin on There is a body of including data from the experimental studies in and clinical studies, to support that ACE is to vascular and that aldosterone to the regulation of Furthermore, recent data indicate that plasma levels with aldosterone in and that aldosterone the of in smooth muscle cells in In data indicate that aldosterone as by aldosterone with an between aldosterone and the system As a it is that angiotensin and aldosterone in to vascular and studies be to the effects of aldosterone antagonists on and the effects of such on cardiovascular and renal dysfunction. to the potential effects of angiotensin II and aldosterone. By of recent studies have documented vascular inflammatory in the of rats et al. demonstrated that aldosterone plays a major role in angiotensin vascular in the heart and and as of the vascular myocardial injury. by which aldosterone may fibrosis on its potential ability to increase activity. or such as and are that extracellular between myocardial and in collagen adverse remodelling and interstitial of and increased plasma levels of have been demonstrated in heart failure patients Moreover, it has been demonstrated that myocardial activity is increased in compared with normal myocardium These findings have important because the of extracellular remodelling ventricular function after myocardial Recently, et al. the ability of eplerenone to and In this study in with heart failure, treatment with eplerenone the in and compared with control These findings suggest an important role for aldosterone in increasing activity and, consequently, the potential of aldosterone receptor blockade to myocardial fibrosis and et al. recently conducted an elegant study in rats for the renin and to the role of aldosterone in mediating cardiac hypertrophy and renal dysfunction. They the role of aldosterone, and in a of angiotensin cardiac injury following administration of eplerenone or rats hypertension, cardiac and perivascular fibrosis and the mortality was at treated rats that eplerenone demonstrated reduced cardiac hypertrophy compared with (P pressure levels with eplerenone were but not In to eplerenone reduced by (P increased of the factor in the endothelium, smooth muscle and of which was reduced by Eplerenone and binding which was increased in and and infiltration, as well as cell activation and infiltration, was increased in the and of and these changes were reduced by Recent clinical studies have that aldosterone blockade may confer an effect in Although the standard of blockade of the renin–angiotensin system with either an ACE inhibitor or an angiotensin II receptor blocker such a may be with for therapy. Although ACE the of aldosterone, aldosterone from this control Such the beneficial effects on the kidney. Recently, several studies have investigated the of aldosterone blockade on excretion. et al. investigated the role of aldosterone in patients with and early treated with an ACE inhibitor for treatment there was a reduction in excretion, in patients with aldosterone patients) was than that in patients Of the patients with spironolactone (25 mg/day) was to ACE inhibitor treatment in a 24 study and left ventricular were reduced blood pressure This study that aldosterone may occur in of patients with with early the of ACE and that aldosterone blockade can the effects on the heart and kidney. Recently, et al. extended these observations to the role of selective aldosterone blockade eplerenone on with patients with This 24 study the that selective aldosterone blockade with eplerenone would proteinuria in patients with well as the ACE inhibitor patients with proteinuria and hypertension blood pressure and systolic blood pressure were to treatment with eplerenone or eplerenone were by By eplerenone reduced proteinuria and by proteinuria was reduced in the eplerenone compared with in the group (P = and in the therapy group (P = in systolic and blood pressure were in all with the of a reduction in blood pressure in the group as compared with the eplerenone group. This that the effect of eplerenone was of blood pressure In these studies suggest that aldosterone blockade may an for aldosterone in the of ACE inhibitor or therapy. The of in with selective aldosterone blockade might a for progressive renal disease. randomized trials are to and extend these Although spironolactone is an its widespread in is limited by its to sexual standard and can be in may These adverse effects are due to the binding of spironolactone to and and are a cause of In a study involving patients treated with spironolactone for mineralocorticoid patients were to therapy due to the occurrence of and or The RALES trial [7] reported a incidence of or in its in this trial This incidence was than placebo P and patients to treatment P = Although these effects have been shown to be and dose the incidence of is but to as are increased to Moreover, this adverse effect a at studies in spironolactone for the dose relationship of these sexual that are associated with and Eplerenone is the only in the new of Its from the non-selective aldosterone antagonist spironolactone by of the group with a group Eplerenone has a of and not appear to have an Eplerenone is a antagonist of the aldosterone receptor This has demonstrated blockade of aldosterone, and its the adverse effects of non-selective antagonists and This is because eplerenone is highly selective for the mineralocorticoid receptor and for other the of eplerenone has demonstrated a reduction in sexual side-effects and, has to an in patient with therapy This was recently by the and for the treatment of hypertension and is study for the treatment of heart failure. clinical studies support the concept that eplerenone is for the treatment of hypertension adverse effects. In patients with hypertension, eplerenone significant and blood pressure which were the 24 In all studies, the incidence of adverse effects with eplerenone was to that of with reports of The recently reported EPHESUS study [29] this demonstrating that the incidence of and in and in was in the eplerenone group = as compared with the placebo group = Recent observations clearly indicate that it is to consider that the endocrine or properties of aldosterone are to has been target These recently haemodynamic and actions of aldosterone have important clinical for the pathogenesis of both cardiovascular disease and progressive renal disease and antihypertensive Although ACE are in disease there may be benefit with aldosterone receptor blockade. As in clinical studies of congestive heart failure, including the recent EPHESUS as well as in models of renal disease, antagonism of aldosterone progression of through both haemodynamic and direct the recent of the it is to of antihypertensive studies to whether endothelial dysfunction and progressive renal disease can be the effects of non-selective aldosterone receptor blockade. that selective aldosterone receptor blockade can progression of both cardiovascular and renal disease an important platform for the addition of SABs to the regimen for of the vascular and renal dysfunction of hypertension. of interest The conducted several studies and as a to