Aldosterone: villain or protector?

During the past decade, there has been heightened interest in aldosterone as a cardiovascular risk factor, fueled by studies documenting its effects on tissues other than epithelial cells. Of particular interest is the role of aldosterone in exacerbating vascular injury. It is likely that the mechanisms mediating the vascular effects of aldosterone differ from its effects on epithelial cells, eg, the renal collecting tubule. For more than a quarter of a century, it also had been assumed that the primary mechanism of aldosterone was mediated by activation of the mineralocorticoid receptor (MR), which in turn increased transcription of MRresponsive genes. Recently, it has been documented that aldosterone can produce rapid cellular responses—MR-mediated increases in phosphorylation of transduction factors, eg, extracellular signal regulated kinase 1 and 2 (ERK1/2), protein kinase C (PKC), and endothelial nitric oxide synthase (eNOS), and changes in intracellular calcium and hydrogen ions—in addition to its traditional genomic responses. Sometimes these rapid effects are called “nongenomic.” However, it is likely that even the “rapid” actions of aldosterone can lead to genomic effects. Thus, we will use the terms “rapid” and “genomic” to contrast 2 major mechanisms of action of aldosterone. These rapid effects may be beneficial or detrimental depending on the environment in which aldosterone is acting. For example, phosphorylation of eNOS in endothelial cells leading to increased NO production and vasodilation would likely be beneficial in an environment where there is decreased perfusion to a vital organ. Activation of vasoconstriction through increases in cytosolic calcium or phosphorylation of ERK1/2 and PKC would be beneficial in hypotension secondary to injury. However, activation of these latter factors would be detrimental in a patient with congestive heart failure or hypertension. It is important to emphasize that genomic actions of aldosterone may have a similar balance of positive and negative effects as noted above for its rapid actions. For example, stimulation by aldosterone of epithelial sodium channels increases sodium absorption, which is beneficial in volume depleted individuals but not in hypertensive patients. Thus, whether aldosterone is a villain or protector depends on the balance of endogenous and exogenous factors. Support for this concept comes from both clinical and experimental studies. For example, in rodents, treatment with angiotensin II and an NO synthase inhibitor causes vascular, cardiac, and renal injury, which is prevented by blockade of the MR. However, this injury also is prevented by dietary sodium restriction suggesting that sodium restriction affects the balance of positive and negative effects induced by aldosterone.1 Mechanistically, on a liberal sodium intake, acute aldosterone administration reduces phosphorylated eNOS (a vascular protector) and increases phosphorylated ERK1/2 and PKC (vascular villains). In contrast, dietary sodium restriction increases phosphorylated eNOS and decreases phosphorylated ERK1/2 and PKC basally, and minimizes or reverses their responses to acute aldosterone administration. In vitro studies also document beneficial and adverse effects of aldosterone and further extend this concept to include variable effects depending on the cell studied. In rabbit preglomerular arterioles, aldosterone causes rapid dose-dependent vasoconstriction by activation of inositol 1,4,5-triphosphate and PKC pathways.2 However, this vasoconstriction is counterbalanced by aldosterone increasing endothelium-derived NO.2 Furthermore, in potassiuminduced vasoconstriction, only the vasodilator effects of aldosterone are apparent.3 In rat aortic rings, aldosterone rapidly attenuates phenylephrine-mediated vasoconstriction via a phosphatidylinositol 3-kinase–dependent increase in NO in endothelial cells.4 However, in endothelium-denuded ring segments, aldosterone enhances phenylephrine-mediated vasoconstriction.4 In addition to these rapid effects of aldosterone modifying vascular function, aldosterone has longterm (genomic) effects. For example, in cultured human umbilical vein endothelial cells, 16-hour exposure to aldosterone increases reactive oxygen species production and reduces vascular endothelial growth factor–induced eNOS phosphorylation. Both effects are abolished by the MR antagonist eplerenone.5 Confirmatory studies of these mechanistic hypotheses in humans have been limited. To assess mechanisms of the effects of aldosterone on the vasculature, the most extensively studied vascular bed has been the forearm. Support for a negative effect of aldosterone on this bed comes from studies reporting that chronic MR blockade in patients with congestive heart failure improves forearm blood flow response to acetylcholine and NO bioavailability.6 The 3 studies in healthy humans, however, have reported conflicting results. Farquharson et al7 demonstrated that an intravenous infusion The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Endocrinology Section, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Correspondence to Gordon H. Williams, MD, Cardiovascular Endocrinology Section, Division of Endocrinology, Diabetes and Hypertension, 221 Longwood Avenue, Boston, MA 02115. E-mail gwilliams@ partners.org (Hypertension. 2007;50:31-32.) © 2007 American Heart Association, Inc.