Why are mineralocorticoid receptor antagonists cardioprotective?
Two clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effect could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, and it has therefore been proposed that aldosterone, the endogenous MR agonist, also acts extrarenally, in particular in the heart. Indeed, MR are present in cardiac tissue, and possibly aldosterone synthesis occurs in the heart. This review critically addresses the following questions: (1) is aldosterone synthesized at cardiac tissue sites, (2) what agonist stimulates cardiac MR normally, and (3) what effects are mediated by aldosterone/MR in the heart that could explain the beneficial effects of MR blockade in heart failure? Conclusions are that most, if not all, of cardiac aldosterone originates in the circulation (i.e., is of adrenal origin), and that glucocorticoids, in addition to aldosterone, may serve as the endogenous agonist of cardiac MR. MR-mediated effects in the heart include effects on endothelial function, cardiac fibrosis and hypertrophy, oxidative stress, cardiac inotropy, coronary flow, and arrhythmias. Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade.
Chai
Wenxia
W
Department of Pharmacology, Room EE1418b, Erasmus MC, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
Danser
A H Jan
AH
D000450:Aldosterone / Q000096:biosynthesis / Q000502:physiology; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000378:metabolism / Q000503:physiopathology; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016678:Genome / Q000502:physiology; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2