Editorial Commentary Central Sympathetic Inhibition by Mineralocorticoid Receptor But Not Angiotensin II Type 1 Receptor Blockade Are Prescribed Doses Too Low?

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. -Blockers clearly benefit patients with heart failure but have less definitive effects in patients with hypertension, whereas 1-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. 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 MRendogenous 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. 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 the same central pathways. It is possible that circulating aldosterone, similar to desoxycorticosterone acetate, also acts in the lamina terminalis and via Ang II activates local MR-endogenous ouabain pathways and thereby causes persistent activation of angiotensinergic sympatho-excitatory pathways. Irrespective of the actual central pathways being activated, the most remarkable point of these studies is that the well-known renal and vascular effects of both aldosterone and Ang II are not sufficient to cause chronic hypertension if their central actions are simultaneously prevented. Evidence from human studies for a central action of circulating aldosterone arises from studies of patients with an aldosterone-producing adenoma, who were found to have elevated muscle sympathetic nerve activity (MSNA). Both MSNA and blood pressure normalized after unilateral adrenalectomy. Studies from several laboratories have demonstrated that MR-mediated activation of angiotensinergic sympatho-excitatory pathways plays a pivotal role in several experimental models of hypertension and heart failure. Direct central infusions of MR blockers or AT1 receptor blockers have been shown to prevent or reverse both the sympatho-excitation and the magnitude of hypertension or heart failure and their complications. The important next question is whether systemic treatment with MR blockers or AT1 receptor blockers is also capable of lowering the sympathetic hyperactivity of hypertension or heart failure. With respect to hypertension, this question is addressed in the well-designed study by Raheja et al reported in the present issue of Hypertension. These authors enrolled 17 stage I subjects into a randomized crossover comparison of the effect on ambulatory blood pressure and MSNA of 12 weeks of therapy with chlorthalidone (25 mg/d) alone, chlorthalidone plus spironolactone (25 mg/d), and chlorthalidone plus irbesartan (150 mg/d). In principle, systemic treatment with such drugs should achieve similar central effects, if important determinants of efficacy, such as the location of the target receptor (ie, within or outside the blood-brain barrier), the lipophilicity of the drug used, and the drug dose selected are all thoughtfully considered. For example, with respect to irbesartan, the AT1 receptor blocker selected by Raheja et al in their study of hypertensive patients, we have shown previously in Dahl S rats consuming a high-salt diet that the degree of central but not peripheral AT1 receptor blockade parallels the antihypertensive effects of its systemic administration. These findings indicate that inhibition of the brain renin-angiotensin system can contribute importantly to the therapeutic effectiveness The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology (F.H.H.L., M.R.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Division of Nephrology (M.R.), Ottawa Hospital, Ottawa, Ontario, Canada; Division of Cardiology (J.S.F.), Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada. Correspondence to Frans H.H. Leenen, Hypertension Unit, University of Ottawa Heart Institute, H3238, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada. E-mail [email protected] (Hypertension. 2012;60:00-00.) © 2012 American Heart Association, Inc.