Abstract 419: Central Angiotensin II Increases Circulating Endogenous Ouabain, Arterial Myocyte Na/Ca Exchanger Expression and Blood Pressure via Brain Aldosterone and Mineralocorticoid Receptors
The brain, together with altered arterial function, plays a crucial role in the pathogenesis of hypertension. We have suggested that endogenous ouabain (EO), and its actions on arterial Na+ and Ca2+ transporters, are key in some forms of hypertension; these entities may be controlled by brain mechanisms (review: Blaustein et al., Am J Physiol Heart Circ Physiol 302:H1031-49, 2012). One commonly-used hypertension model involves infusion of angiotensin II (Ang II) in rodents. When Ang II was infused (subcutaneous minipump, 400 ng/kg/min x 15 days) into 8 normal ∼35 g C57Bl/6 mice, 24 hr mean blood pressure (MBP in mm Hg, telemetry), was 119±4, vs 97±2 in 8 vehicle-infused controls, C (P <0.001). Expression of Na/Ca exchanger-1 (NCX1, immunoblots with R3F1 antibody) was increased by 171±21% (P <0.001 vs C) in the aortas of the Ang II-treated mice. To test the role of the brain in Ang II-induced hypertension, vehicle (C; n = 7) or Ang II (A; n = 8) was administered by intra-cerebroventricular infusion (Ang II, 3.6 μg/day x 12 days) in 200-250 g Wistar rats. In some rats, the Ang II infusion contained the mineralocorticoid receptor (MR) blocker, eplerenone (E, 5 μg/day x 12 days; n = 7), or the aldosterone synthase inhibitor, FAD-286 (F, 25 μg/day x 12 days; n = 8). At the end of the treatment, the following MBPs were recorded (mm Hg, telemetry): C: 101±2; A: 123±4 (P <0.05 vs C, E & F); E: 108±2; F: 112±2 (P <0.05 vs C). Upon euthanasia, blood, pituitary and adrenal samples were taken for EO radioimmunoassay (RIA), and aortas were harvested for NCX1 immunoblotting. The following results were obtained: 1) Plasma EO (nM): C, 0.34±0.07; A, 0.58±0.08 (P <0.05 vs C; P <0.01 vs F); E, 0.37±0.08; F, 0.30±0.05. The plasma EO increase in A was confirmed by off-line liquid chromatography-RIA on pooled samples. 2) NCX1 expression (normalized to C = 1.0±0.2): A, 2.6±0.3 (P <0.01 vs C; P <0.05 vs E); E, 0.9±0.3; F, 1.3±0.2. 3) Adrenal and pituitary EO were not changed. These results provide the first evidence that circulating EO levels and arterial NCX expression are regulated by the brain Ang II-aldosterone-MR system. Thus, in addition to regulating BP by direct, neurally-mediated vasoconstriction, the brain also influences BP by modulating ion transport pathways involved in arterial Na+ and Ca2+ homeostasis.
- © 2012 by American Heart Association, Inc.