Results of the Randomized
Aldactone Evaluation Study and the
Eplerenone Post-acute
Myocardial Infarction Heart Failure Efficacy and Survival Study indicate
aldosterone receptor antagonism, together with
angiotensin-converting enzyme inhibition and
loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascular-related mortality and morbidity in patients with symptomatic
heart failure. Responsible mechanisms are likely multifactoral. As a circulating
hormone,
aldosterone has well-known endocrine properties that contribute to the pathophysiology of
congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg2+ excretion at these sites is likewise enhanced by
aldosterone, whereas adrenal
aldosterone secretion is regulated by extracellular Mg2+. Other endocrine actions of
aldosterone receptor-
ligand binding include: a reduction in biologically active cytosolic-free Mg2+, with intracellular Ca2+ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of
aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by
aldosterone receptor antagonism and therefore may contribute to its salutary response in
heart failure.