Aldosterone and vascular mineralocorticoid receptors: regulators of ion channels beyond the kidney.

Abstract

Elevated levels of the steroid hormone aldosterone have been reported in populations at risk for cardiovascular disease and are associated with adverse cardiovascular events, such as myocardial infarction, stroke, and death.1–3 Clinical trials demonstrate that either inhibition of aldosterone production or antagonism of its receptor, the mineralocorticoid receptor (MR), significantly reduces cardiovascular ischemic events and mortality.4–8 Classically, aldosterone regulates blood pressure by binding to the MR in renal epithelial cells and increasing expression and activity of ion channels in the distal nephron resulting in sodium retention and blood pressure elevation.9 Accordingly, clinical trials of MR antagonists report decreases in blood pressure.4,5 However, the modest reductions in BP do not fully account for the cardioprotective effects of MR antagonism nor do renal electrolyte changes fully explain the antihypertensive effects of MR antagonists.10 For the past 2 decades, it has become clear that aldosterone and MR have extrarenal actions that may contribute to alterations in vascular function leading to the development and progression of cardiovascular disease. Exploration of the precise mechanisms by which aldosterone/MR regulates vascular function and promotes cardiovascular diseases remains a very active area of investigation and a potential avenue for novel pharmacological interventions. Because MR is a critical regulator of renal ion channels,9 and more recently has been implicated in ion channel regulation in the heart,11 we propose that MR may also regulate vascular ion channel expression and function, thereby contributing to aldosterone/MR-induced vascular dysfunction and cardiovascular disease. Vascular ion channels are critical to generation of vascular tone, vessel contraction and relaxation, and vascular stiffness (reviewed elsewhere)12–15 and contribute to vascular dysfunction associated with diseases, including atherosclerosis,16 diabetes mellitus,17–19 and hypertension.20,21 This review focuses on new …