Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade

Abstract

See related article, pp 319–325 Chronic sympathetic hyperactivity, characteristic of the majority of patients with hypertension or heart failure, can contribute to cardiovascular morbidity and mortality via a number of actions. Pharmacological strategies to prevent these adverse effects have had variable success. β-Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas α1-blockers or centrally acting agents have shown mixed results, and all of these classes can cause bothersome adverse effects. Device-based approaches, such as baroreflex activation therapy and renal denervation, have been shown to lower sympathetic activity in patients with hypertension, but beneficial actions on cardiovascular outcomes have yet to be demonstrated. So, where do the central nervous system (CNS) actions of angiotensin II (Ang II), aldosterone, and, hence, Ang II type 1 (AT1) receptor and mineralocorticoid receptor (MR) blockers fit in? Experimental studies have demonstrated that both circulating Ang II and aldosterone act within the CNS to cause sympatho-excitation and raise blood pressure.1,2 Ang II stimulates AT1 receptors in nuclei of the lamina terminalis and thereby activates mainly angiotensinergic pathways to the paraventricular nucleus (PVN) and rostral ventrolateral medulla. Circulating Ang II, in addition, activates an MR-endogenous ouabain pathway. This slowly acting, neuromodulatory pathway appears responsible for most of the persistent neuronal activation in, for example, the PVN, and the progressive hypertension induced by circulating Ang II. Studies using central infusions of an aldosterone synthase inhibitor suggest that the CNS MR activation by Ang II largely depends on locally produced aldosterone rather than circulation-derived aldosterone.1 However, the progressive hypertension caused by a chronic increase in circulating aldosterone can also be prevented by specific CNS blockade of either MR or AT1 receptors,2 suggesting that both circulating aldosterone and Ang II may activate …