Eplerenone Antagonizes Atherosclerosis, But What Is the Agonist?

Abstract

A recent analysis of the Framingham Heart Study implicated elevated serum aldosterone as an independent risk factor for the development of cardiovascular disease.1 Although adrenal-derived aldosterone may prove to be important in this regard, less evident is the source of aldosterone and the mechanism for mineralocorticoid receptor (MR) activation in studies such as the Randomized ALdactone Evaluation Study (RALES)2 and the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and Survival Study (EPHESUS),3 where MR blockade exerts obvious cardiovascular benefit but adrenal aldosterone levels are normal. In this issue of Hypertension , the article by Takai et al4 documents such a study and thereby adds to the discussion not only of the applicability of MR blockade in cardiovascular disease but also of the mechanisms for MR activation. The authors report that monkeys with diet-induced hypercholesterolemia treated with the selective MR antagonist eplerenone had reduced extent of atherosclerotic lesions in aorta and carotid arteries compared with placebo-treated monkeys. The results extend the beneficial influence of MR blockade to a model with similarities highly relevant to the atherogenic process in humans. Rajagopalan et al5 were the first to demonstrate that local vascular expression of MR might play a role in atherosclerosis. In this study, dietary hypercholesterolemia in rabbits was associated with increased aorta superoxide generation. Eplerenone administration to hypercholesterolemic rabbits normalized superoxide generation, decreased NADH and NADPH oxidase activity to basal levels, and nearly normalized endothelium-dependent vasorelaxation. A study by Keidar et al6 showed similar inhibition of atherosclerosis when eplerenone was administered to apolipoprotein E (apoE)-deficient mice. …