Aldosterone as a Mediator in Cardiovascular Injury

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Abstract
The renin-angiotensin-aldosterone system plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur, whereby aldosterone levels return to or exceed baseline levels. The classic effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, blood pressure reduction or fluid loss could not account for the results of the Randomized Aldactone Evaluation Study, which showed that a low dose of spironolactone in addition to conventional therapy could decrease the overall risk of mortality by 30% among patients with severe congestive heart failure. The action of aldosterone at nonepithelial sites in the brain, heart, and vasculature is consistent with the presence of mineralocorticoid receptors in these tissues. Aldosterone has a number of deleterious effects on the cardiovascular system, including myocardial necrosis and fibrosis, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release, and production of cardiac arrhythmias. Several studies have now shown vascular and target-organ protective effects of aldosterone receptor antagonism in the absence of significant blood pressure lowering, consistent with a major role for endogenous mineralocorticoids as mediators of cardiovascular injury. The advent of selective aldosterone receptor antagonists such as eplerenone should prove of great therapeutic value in the prevention of cardiovascular disease and associated end-organ damage.