title: Actions of circulating angiotensin II and aldosterone in the brain contributing to hypertension.
abstract: In the past 1-2 decades, it has become apparent that the brain renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the regulation of blood pressure (BP) by the circulating RAAS. In the brain, angiotensinergic sympatho-excitatory pathways do not contribute to acute, second-to-second regulation but play a major role in the more chronic regulation of the setpoint for sympathetic tone and BP. Increases in plasma angiotensin II (Ang II) or aldosterone and in cerebrospinal fluid [Na(+)] can directly activate these pathways and chronically further activate/maintain enhanced activity by a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels, and endogenous ouabain. Blockade of any step in this slow pathway prevents Ang II-, aldosterone-, or salt and renal injury-induced forms of hypertension. It appears that the renal and arterial actions of circulating aldosterone and Ang II act as amplifiers but are not sufficient to cause chronic hypertension if their central actions are prevented, except perhaps at high concentrations. From a clinical perspective, oral treatment with an angiotensin type 1 (AT1)-receptor blocker at high doses can cause central AT1-receptor blockade and, in humans, lower sympathetic nerve activity. Low doses of the MR blocker spironolactone appear sufficient to cause central MR blockade and a decrease in sympathetic nerve activity. Integrating the brain actions of the circulating RAAS with its direct renal and arterial actions provides a better framework to understand the role of the circulating RAAS in the pathophysiology of hypertension and heart failure and to direct therapeutic strategies.
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. fleenen@ottawaheart.ca.
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D001923:Brain Chemistry; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D018377:Neurotransmitter Agents; D012084:Renin-Angiotensin System
chemical_list: D018377:Neurotransmitter Agents; D000804:Angiotensin II; D000450:Aldosterone
keywords: aldosterone; angiotensin II; blood pressure; brain; hypertension; sympathetic activity.