Aldosterone as a Mediator in Cardiovascular Injury

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.

Human Endothelium: Target for Aldosterone

“…6 In any case, induction of sodium channels causes cells to electrically depolarize because of increased sodium influx. Although sodium is pumped out of the cell by the Na ϩ /K ϩ ATPase, located in the basolateral membrane, Cl Ϫ accumulates in the cell because of electrochemical driving forces set by the altered cell membrane potential.…”

“…4,5 Because of the fact that aldosterone acts on cardiomyocytes, cardiac fibroblasts, and endothelial cells, this hormone plays a major role in the development of heart failure, myocardial fibrosis, and endothelial dysfunction. 6 Moreover, there is much interest in the possibility of the use of aldosterone receptor blockade in patients to diminish pathological effects that can be produced by this hormone. 7 A study applying atomic force microscopy (AFM) on living aortic endothelial cells showed transient cell swelling that occurred over minutes and that was prevented by a high dose of amiloride known to inhibit plasma membrane Na ϩ /H ϩ exchange.…”

Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go–Related Gene Channels

“…In fact, aldosterone causes sodium retention, myocardial fibrosis, and potassium and magnesium depletion; potentiates the effects of catecholamines; blunts the baroreflex response; and induces ventricular arrhythmias. 4 SP is extensively metabolized in humans, and Ϸ79% of the SP oral dose is converted to canrenone, its major biologically active metabolite. 5 Canrenone undergoes hydrolysis of its ␥-lactone ring to canrenoic acid (CA), which is water soluble.…”

BNP-Mediated Vasodilatation for Dialysis-Dependent Patient with Acute Heart Failure Syndrome in the Emergency Department

“…[6,7] Current medical Represents difference of value immediately prior to infusion and immediately after discontinuing infusion. A negative value repre sents a reduction in the measurement.…”

“…[6][7][8] B-type natriuretic peptide (BNP) is one of the neurohormal peptides affected by AHFS. This hormone is released by myocytes as a result of myocardial stretch resulting from volume overload, increased pressure, or ventricular dilation.…”