Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)

Abstract

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensinconverting enzyme (ACE) inhibitors and angiotensin type 1 (AT 1 ) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels -a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenonethe first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) -is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding 185

Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension

“…Because aldosterone was recently shown to increase the abundance of the Na-Cl cotransporter (NCC) (17), an increase in NCC could be one potential compensatory change in response to the chronic blockade of AR that sustained Na ϩ reabsorption. A bolus dosage of epl given by oral gavage in rats was shown to reverse the effects of aldosterone on urinary Na ϩ /K ϩ ratio suggesting that AR antagonism is effective in acutely antagonizing the renal actions of aldosterone on electrolyte transport (6). Similarly, the present study identified an acute natriuresis associated with an initial period of negative renal Na ϩ balance at the onset of epl treatment.…”

“…Inappropriately elevated circulating aldosterone concentrations may induce a number of pathophysiological consequences including sodium retention, hypertension, and fibrosis. Mineralocorticoid receptor (MR) antagonism has been shown to ameliorate cardiovascular and renal injury in several hypertensive models (6,7,19,26). Chronic MR antagonism should in theory increase urinary Na ϩ excretion and thus reduce blood pressure; however, in previous studies chronic treatment with MR antagonists did not acutely (23) nor chronically (10,21,23) alter urinary Na ϩ excretion suggesting that alternative renal mechanisms are invoked to compensate for the chronic blockade of the MR.…”

“…Animals were allowed to acclimate to the cages for 3 days before the initiation of data collection. Blood pressure measurements were taken weekly on days 6,13,20, and 27 by tail-cuff plethysmography.…”

“…Chronic MR antagonism should in theory increase urinary Na ϩ excretion and thus reduce blood pressure; however, in previous studies chronic treatment with MR antagonists did not acutely (23) nor chronically (10,21,23) alter urinary Na ϩ excretion suggesting that alternative renal mechanisms are invoked to compensate for the chronic blockade of the MR. In adrenalectomized rats, the specific aldosterone receptor (AR) antagonist, eplerenone (epl), acutely (Ͻ24 h) reversed the renal actions of aldosterone in a dose-dependent manner by increasing mean urinary Na ϩ :K ϩ ratio by as much as 57% (6). However, in rats on a normal Na ϩ -K ϩ diet, chronic (5 wk) MR antagonism with spironolactone (20 mg/day) did not alter serum concentrations nor urinary excretion of either Na ϩ or K ϩ despite an increase in plasma aldosterone by 2.5-fold (10) indicating that alternative mechanisms may be elicited to regulate electrolyte balance during conditions of chronic MR blockade.…”

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats

“…In G3, the rats received 100 mg/kg/day of SAB starting from week 12 by gavage. The dose of SAB in the current study was almost comparable to that used in clinical practice (26). The animals were allowed free access to food and water throughout the acclimation and experimental protocols.…”