Potential Mechanisms of Low Sodium Diet–Induced Cardiac Disease: Superoxide-NO in the Heart

• Published in: Circulation research 2010-02, Vol.106 (3), p.593-600
• Main Authors: Suematsu, Nobuhiro, Ojaimi, Caroline, Recchia, Fabio A, Wang, Zipping, Skayian, Yester, Xu, Xiaobin, Zhang, Suhua, Kaminski, Pawel M, Sun, Dong, Wolin, Michael S, Kaley, Gabor, Hintze, Thomas H
• Format: Article
• Language: English
• Subjects: Acetophenones - administration & dosage; Acetophenones - therapeutic use; Angiotensin II - blood; Animals; Ascorbic Acid - administration & dosage; Ascorbic Acid - therapeutic use; Biological and medical sciences; Coronary Vessels - metabolism; Diet, Sodium-Restricted - adverse effects; Dogs; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Glucose - metabolism; Hemodynamics; Infusions, Intravenous; Lactates - metabolism; Male; Myocardium - metabolism; NADPH Oxidases - biosynthesis; NADPH Oxidases - genetics; Nitric Oxide - deficiency; Nitric Oxide - metabolism; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Oxygen Consumption; Renin-Angiotensin System - physiology; Superoxides - metabolism; Vasodilation - drug effects; Vasodilation - physiology; Veratrine - pharmacology; Vertebrates: cardiovascular system; Weight Loss
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.208397

RATIONALE:Patients on a low salt (LS) diet have increased mortality. OBJECTIVE:To determine whether reduction in NO bioactivity may contribute to the LS-induced cardiac dysfunction and mortality. METHODS AND RESULTS:Adult male mongrel dogs were placed on LS (0.05% sodium chloride) for 2 weeks. Body weight (25.4±0.4 to 23.6±0.4 kg), left ventricular systolic pressure (137.0±3.4 to 124.0±6.7 mm Hg), and mean aortic pressure (111±3.1 to 98±4.3 mm Hg) decreased. Plasma angiotensin II concentration increased (4.4±0.7 to 14.8±3.7 pg/mL). Veratrine-induced (5 μg/kg) NO-mediated vasodilation was inhibited by 44% in LS; however, the simultaneous intravenous infusion of ascorbic acid or apocynin acutely and completely reversed this inhibition. In LS heart tissues, lucigenin chemiluminescence was increased 2.3-fold to angiotensin II (10 mol/L), and bradykinin (10 mol/L) induced reduction of myocardial oxygen consumption in vitro was decreased (40±1.3% to 16±6.3%) and completely restored by coincubation with tiron, tempol or apocynin. Switching of substrate uptake from free fatty acid to glucose by the heart was observed (free fatty acid8.97±1.39 to 4.53±1.12 μmol/min; glucose1.31±0.52 to 6.86±1.78 μmol/min). Western blotting indicated an increase in both p47 (121%) and gp91 (44%) as did RNA microarray analysis (433 genes changed) showed an increase in p47 (1.6-fold) and gp91 (2.0 fold) in the LS heart tissue. CONCLUSIONS:LS diet induces the activation of the renin–angiotensin system, which increases oxidative stress via the NADPH oxidase and attenuates NO bioavailability in the heart.