Abstract
See related article, pp 1033–1040 Clinically, mineralocorticoid receptor (MR) antagonists are widely prescribed for the treatment of hypertension and heart failure because of their diuretic action in aldosterone-sensitive distal nephron. Clinical trials of MR antagonism in patients with various degrees of heart failure severity have also demonstrated a pronounced reduction of cardiovascular mortality in MR antagonist–treated patients.1 The underlying mechanisms of these cardiovascular benefits are still debated and are probably diverse. Potential beneficial effects of MR antagonism on extracellular matrix remodeling, arrhythmia susceptibility, coronary flow reserve, cardiovascular inflammation, and vascular function have all been suggested. Indeed, the vasculature has been recently highlighted as a primary target of aldosterone and MR antagonists. MR is expressed in human vascular endothelial cells (ECs) and smooth muscle cells as is the 11β-HSD2 enzyme that allows for selective aldosterone versus cortisol activation of MR. The effects of MR activation on vascular reactivity in healthy humans remains controversial because of conflicting results from clinical studies with many demonstrating a constrictive response and some showing vascular relaxation.2 Discrepancies may be due to differences in the vascular health of study participants as well as differences in study design. However, when patients with underlying cardiovascular diseases are studied, the data are consistent with MR activation promoting increased systemic vascular resistance and reduced forearm blood flow and MR antagonism improving endothelium-dependent vasodilatation, independent of changes in blood pressure. The aggregate of data supports that, in healthy vessels, acute MR activation may evoke endothelium-dependent, NO-mediated vasodilatation, whereas, in the presence of endothelial dysfunction, vascular injury, or high vascular oxidative stress (as in patients with cardiovascular risk factors or heart …
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