Introduction 1 1 2 1 Fig. 1 1 2 1 1 2 1  2003 2003 1994 1998 1 2 2004 2000 2000 2002 2002 1999 2003 1999 2003 1995 2001 1998 1997 Aldosterone synthesis at cardiac tissue sites? CYP11B2 1998 1997 1995 1997 2003 1998 2004 2001 2004 2003 1994 1997 2001 2005 2004 1998 2006 2 1994 1997 2001 2005 2000 2006 2005 2004 Fig. 2 2006  Activation of cardiac mineralocorticoid receptors by aldosterone? + 2000 1995 1992 2005 2004 1992 d 1987 1994 3 2000 3 1994 Fig. 3 top bottom 1987 2005 1994  2006 2005b 2004 2006 2005b 3 2002 2003 2000 2005b 2006 2006 Genomic versus non-genomic effects + 2002 2003 2004 2005 2004 2003 2005a 1995 2005a 2005 2005a + 2003 2001 3 2+ + + 2004b 2005a 2003 2002 2004 1997 + + + + + + 2004 2005 2004 Effects of aldosterone in the cardiovascular system 2005 2005 1995 Endothelial dysfunction 2005 2004 2004 2004 Oxidative stress, inflammation, fibrosis and atherosclerosis 2005 2003 2002 2002 2005 2004 2004 2002 1994 2005 2005 2006 Cardiac inotropy and coronary flow 2005a 1996 2002 2002 2005a 2002 2005a 4 2005b 2005b 4 2002 2004b 2005a 2004 2003 + + 2004 2000 Fig. 4 Left panel Right panel 2005b  2005b 2005 2004 3 + + + + 2005 2003 2004 2003 2003 Arrhythmias 1999 2003 2005 2001 2001 2005a 2006 5 2006 2004 2005b 2006 2006 2005 2005a 2006 Fig. 5 left panel middle panel right panel A S E A + E).  2005a 2006 P  Cardiac hypertrophy 1997 CYP11B2 2004a 1998 1998 1999 2004 2004 2005c 2005 CYP11B2 CYP11B1 2005 2005 CYP11B1 2005 2005 Interaction with angiotensin II 2005 2002 2005 2004 2004 1 2005a 1987 1996 2005 Clinical perspective: why are MR antagonists cardioprotective? The beneficial effects of MR antagonists in heart failure cannot be explained on the basis of their renal and/or blood pressure-lowering effects. Most likely they relate, at least in part, to blockade of a wide range of MR-mediated effects in the heart, including endothelial dysfunction, a decrease in cardiac inotropy and coronary flow, and the induction of fibrosis, hypertrophy, oxidative stress and arrhythmias. Some of these effects occur via or in synergy with Ang II. Given the virtual absence of aldosterone production in the heart, and in view of the low cardiac levels of the cortisol-inactivating enzyme 11β-HSD2, it is unlikely that, under all conditions, aldosterone is the endogenous agonist of cardiac MR. Thus, some of the MR-mediated effects in the heart may be due to MR activation by glucocorticoids, particularly when ROS levels are high. The aldosterone levels in the failing human heart, but not those in the healthy heart, are high enough to be of functional importance. Whether some of the above (acute, ‘non-genomic’) in vitro effects of aldosterone are mediated via a non-MR-mediated mechanism remains to be proven, in particular because no (membrane receptor) candidate has been identified so far that induces these effects. If true, however, aldosterone synthase inhibitors might be expected to exert beneficial effects on top of MR blockade.