title: Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats.
abstract: Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU-28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (AT(1)R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of AT(1)R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in AT(1)R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on AT(1)R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (AT(1)R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Kang
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D006339:Heart Rate / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D018384:Oxidative Stress / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013481:Superoxides; D000450:Aldosterone; D007703:Peptidyl-Dipeptidase A