Aldosterone antagonism

Mechanism of action Na"", K -ATPase inhibition Na /H " exchange mechanism inhibition (proximal tubule) Aldosterone antagonism Membrane effect... 

Richards AM, Nicholls MG. Aldosterone antagonism in heart failure. Lancet 1999 354(9181) 789-90. 

Aldosterone antagonism with low-dose spironolactone has been shown to reduce mortality in patients with New York Heart Association (NYHA) class III and IV heartfailure and thus should be strongly considered in these patients. Given its low cost and safety profile at the doses studied, it may be reasonable to consider in other patients with symptomatic heart failure, especially those taking potassium supplementation, in whom the aldosterone antagonist might allow dose reduction or discontinuation of the potassium supplement, and should be considered strongly in patients with severe heart failure. 

Apart from the valuable benefit of aldosterone antagonism in hypertension, MR blockade has been shown to substantially reduce both morbidity and mortality among patients with severe chronic heart failure (CHF) and post-myocardial infarction (MI) in clinical trials [17, 18]. The Randomized Aldactone Evaluation Study (RALES) has shown that 26 mg spironolactone on average per day on top of existing standard therapy [i.e. an angiotensin-converting enzyme (ACE) inhibitor, aspirin and a loop diuretic] given to patients with severe heart failure (New York Heart Association class III or IV, left ventricular ejection fraction <35%) results in 30%... 

Udelson JE, Feldman AM, Greenberg B, Pitt B, Mukherjee R, Solomon HA, Konstam MA. Randomized, double-blind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction. Circ Heart Fail 2010 3(3) 347-53. 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone at the late distal and cortical collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors ( spironolactone, eplerenone ) or... 

Drospirenone, a progestin in an oral contraceptive, also antagonizes the effects of aldosterone. 

While the angiotensins promote release of aldosterone, the atrial natriuretic hormoner aa cc inhibits release. This group of 21- to 33-residue polypeptides, secreted by cells of the atria (auricles) of the heart, also inhibits release of renin and promotes secretion of both Na+ and water. Thus, they antagonize the action of aldosterone, which promotes Na+ retention. However, there is uncertainty as to the significance of these peptides. The following metabolite of y-tocopherol (Fig. 15-24) has been isolated from urine and is proposed as a new endogenous natriuretic factor.dd... 

Spironolactone competes for the mineralocorticoid receptor and thus inhibits sodium reabsorption in the kidney (see p. 232). It can also antagonize aldosterone and testosterone synthesis. It is effective against hyperaldosteronism. The drug is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. 

The action of Xlla in reversing the electrolyte effects of aldosterone probably is directly on the distal tubular handling of sodium and potassium rather than through a specific antagonism of the hormone. ... 

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