Aldosterone receptor blockade and the role of eplerenone: evolving perspectives.

Aldosterone is a major regulator of extracellular fluid volume and the major determinant of potassiummetabolism [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 nongenomic 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.