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
angiotensin-converting 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,
eplerenone--the 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 of selective
aldosterone receptor antagonism in the treatment of chronic
cardiovascular disease.