Potential Mechanisms of Low Sodium Diet–Induced Cardiac Disease

Abstract

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 −8 mol/L), and bradykinin (10 −4 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 acid: 8.97±1.39 to 4.53±1.12 μmol/min; glucose: 1.31±0.52 to 6.86±1.78 μmol/min). Western blotting indicated an increase in both p47 phox (121%) and gp91 phox (44%) as did RNA microarray analysis (433 genes changed) showed an increase in p47 phox (1.6-fold) and gp91 phox (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.