Aldosterone affects blood flow and vascular tone regulated by endothelium-derived NO: therapeutic implications

Abstract

Aldosterone, in doses inappropriate to the salt status, plays an important role in the development of cardiovascular injury, including endothelial dysfunction, independent of its hypertensive effects. Acute non-genomic effects of aldosterone acting on mineralocorticoid receptors are inconsistent in healthy humans: vasoconstriction or forearm blood flow decrease via endothelial dysfunction, vasodilatation mediated by increased NO actions, or no effects. However, in studies with experimental animals, aldosterone mostly enhances vasodilatation mediated by endothelium-derived NO. Chronic exposure to aldosterone, which induces genomic responses, results in impairments of endothelial function through decreased NO synthesis and action in healthy individuals, experimental animals and isolated endothelial cells. Chronic aldosterone reduces NO release from isolated human endothelial cells only when extracellular sodium is raised. Oxidative stress is involved in the impairment of endothelial function by promoting NO degradation. Aldosterone liberates endothelin-1 (ET-1) from endothelial cells, which elicits ET(A) receptor-mediated vasoconstriction by inhibiting endothelial NO synthesis and action and through its own direct vasoconstrictor action. Ca(2+) flux through T-type Ca(2+) channels activates aldosterone synthesis and thus enhances unwanted effects of aldosterone on the endothelium. Mineralocorticoid receptor inhibitors, ET(A) receptor antagonists and T-type Ca(2) + channel blockers appear to diminish the pathophysiological participation of aldosterone in cardiovascular disease and exert beneficial actions on bioavailability of endothelium-derived NO, particularly in resistant hypertension and aldosteronism.

Figure 1

Schematic presentation of information pathways via NO liberated from endothelial cells to vascular smooth muscle cells. Superoxide generation via NAD(P)H oxidase is also included in the right part of the figure. Possible sites of action of aldosterone (ALD) and ET on eNOS and superoxide generation are shown in the figure. R in the square on the endothelial membrane, drug receptor or mechanoreceptor; pool, Ca²⁺ storage site; CV, caveolin-1; CaM, calmodulin; Akt, serine/threonine protein kinase Akt; eNOS*, activated eNOS; L-Arg., L-arginine; L-Citru., L-citrulline; O₂^–, superoxide anion; L-NA, N^G-nitro-L-arginine; SOD, superoxide dismutase; sGC, soluble guanylyl cyclase; cGMP, cyclic GMP; ODQ, 1H[1,2,4] oxadiazolo[4,3-a]quinoxalin-o1-one.

Figure 2

Information pathways via ET-1 liberated from endothelial cells to vascular smooth muscle cells. Possible site of action of ALD on ET-1 synthesis is shown in the figure. ET_A receptor; pool, Ca²⁺ storage site; [Ca²⁺]i, intracellular Ca²⁺ concentration.