Mechanisms of Dietary Sodium-Induced Impairments in Endothelial Function and Potential Countermeasures

Abstract

Despite decades of efforts to reduce sodium intake, excess dietary sodium remains commonplace, and contributes to increased cardiovascular morbidity and mortality independent of its effects on blood pressure. An increasing amount of research suggests that high-sodium diets lead to reduced nitric oxide-mediated endothelial function, even in the absence of a change in blood pressure. As endothelial dysfunction is an early step in the progression of cardiovascular diseases, the endothelium presents a target for interventions aimed at reducing the impact of excess dietary sodium. In this review, we briefly define endothelial function and present the literature demonstrating that excess dietary sodium results in impaired endothelial function. We then discuss the mechanisms through which sodium impairs the endothelium, including increased reactive oxygen species, decreased intrinsic antioxidant defenses, endothelial cell stiffening, and damage to the endothelial glycocalyx. Finally, we present selected research findings suggesting that aerobic exercise or increased intake of dietary potassium may counteract the deleterious vascular effects of a high-sodium diet.

Keywords: aerobic exercise; dietary sodium; endothelium oxidative stress; glycocalyx; high salt; nitric oxide; potassium.

Figure 1

Excess dietary sodium negatively (−) influences nitric oxide (NO)-mediated endothelial function via increases in oxidative stress, an increase in endothelial cell (EC) stiffness, and damage to the endothelial glycocalyx (eGC). Each of these factors results in decreased bioavailability of NO derived from endothelial nitric oxide synthase (eNOS). Evidence suggests that aerobic exercise and/or increased intake of dietary potassium positively (+) influence these factors and thus may be effective strategies to counteract the impact of excess dietary sodium.

Figure 2

In response to various physiological and pharmacological stimuli, such as shear stress and acetylcholine (ACh), the endothelium produces nitric oxide (NO) via endothelial nitric oxide synthase (eNOS) that diffuses into the vascular smooth muscle cells, where it activates soluble guanylate cyclase (sGC), which then converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), ultimately leading to vasodilation. Excess dietary sodium increases superoxide (O₂⁻) via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, while also inhibiting cytosolic superoxide dismutase (SOD-1) and mitochondrial SOD (SOD-2). NO readily reacts with O₂⁻, thus rendering it unable to diffuse into the VSM. The resulting peroxynitrite (ONOO⁻) oxidizes tetrahydrobiopterin (BH4), which leads to uncoupling of eNOS, leading to further reductions in NO and increases in O₂⁻ (not shown).

Figure 3

On the left, the healthy glycocalyx functions as a barrier between the plasma and the endothelial cell. The negatively charged glycocalyx buffers the positively charged sodium ions. On the right, increases in plasma sodium cause damage to the glycocalyx, thus increasing the access of sodium to epithelial sodium channels (ENaC) on the surface of the endothelium, leading to increased intracellular sodium concentrations. Under these conditions, the cell becomes stiffer, and the transduction of shear stress into NO release is decreased.