Effects of aldosterone on the vasculature.

Aldosterone is a steroid with mineralocorticoid activity produced mostly by the adrenal glomerulosa. Aldosterone may also be generated in the heart and blood vessels, although there is controversy on whether the amounts produced are physiologically relevant. The classical target of aldosterone is the distal convoluted tubule of the kidney, where it acts on cytosolic mineralocorticoid receptors (MRs) that translocate to the nucleus and via different mechanisms (serum and glucocorticoid-induced kinase-1 [SGK-1], neural precursor cell expressed developmentally downregulated 4 [nedd4], nedd4 isoform 2 [nedd4-2], K-Ras2A, and capsaicin)1 modulating the epithelial sodium channel and renal outer medullary potassium channels to induce increased reabsorption of sodium and excretion of potassium, thus regulating sodium, potassium, and body fluid balance. Over the past few years it has become increasingly evident that aldosterone exerts powerful effects on blood vessels,2 independent of actions that can be attributed to blood pressure (BP) rise mediated via regulation of salt and water balance. Some deleterious consequences of aldosterone and, accordingly, some benefits derived from MR antagonism, may be BP dependent.3 However, the aldosterone effects on which this review will concentrate are the direct, BP-independent ones, although these may, indeed, contribute together with salt and water retention to BP elevation. The reader should be cautioned, however, that many of the vascular actions of aldosterone mentioned in this article were obtained with large unphysiological doses of aldosterone, which may raise questions regarding their physiological significance. Aldosterone has been reported to be synthesized,4 MRs demonstrated,5 and the presence of the cortisol-inactivating enzyme 11-hydroxysteroid-dehydrogenase-2 identified in blood vessels.6 However, the production of aldosterone by blood vessels and the heart remains controversial (see below).7,8 In addition to its classical genomic mechanisms, aldosterone exerts effects through rapid nongenomic pathways that may also be important in hypertension.9 Some studies suggest that aldosterone influences vascular contraction, as discussed below. Furthermore, aldosterone modulates membrane receptors and signaling molecules and influences the actions of a variety of agents to sensitize the vasculature to effects of various agents that induce vasoconstriction or result in direct effects on growth and remodeling. Vascular actions of aldosterone may be exerted on different layers of the blood vessel wall: on endothelium, smooth muscle cells of the media, or on the adventitial layer, as discussed below. The first 2 will be dealt with in succession, because there is little new knowledge on the actions of aldosterone on adventitia, which could, nonetheless, be important.