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.

Recent evidence suggests that the gut microbiota contributes to the pathogenesis of hypertension (HTN). The gut microbiota is a highly dynamic organ mediating numerous physiological functions, which can be influenced by external factors such as diet. In particular, a major modifiable risk factor for HTN is dietary sodium intake. Sodium consumption in the United States is significantly greater than that recommended by the federal government and organizations such as the American Heart Association. Because of the emerging connection between the gut microbiota and HTN, the interaction between dietary sodium and gut microbiota has sparked interest. High-sodium diets promote local and systemic tissue inflammation and impair intestinal anatomy compared with low sodium intake in both human and animal studies. It is biologically plausible that the gut microbiota mediates the inflammatory response, as it is in constant interaction with the immune system and is necessary for proper maturation of immune cells. Recent rodent data demonstrate that dietary sodium disrupts gut microbial homeostasis as gut microbiota composition shifts with dietary sodium manipulation. In this review, we will focus on gut microbiota activity in HTN and the influence of high dietary sodium intake with an emphasis on the immune system, bacterial metabolites, and the circadian clock.

It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer’s ( n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol ( n = 22), and 100 µM apocynin ( n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine ( n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVC_max); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVC_max; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin ( P < 0.01) and Tempol ( P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS ( P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .

The influence of dietary sodium and potassium on blood pressure (BP) has been extensively studied, however their impact on endothelial function, particularly any interactive effects, has received less attention. The purpose of this study was to determine if dietary potassium can offset the deleterious effect of high dietary sodium on endothelial function independent of BP. Thirty-three adults with salt-resistant BP (16 M and 17 F; 27 ± 1 year) completed seven days each of the following diets in a random order: a moderate potassium/low sodium diet (65 mmol potassium/50 mmol sodium; MK/LS), a moderate potassium/high sodium diet (65mmol potassium/300 mmol sodium; MK/HS) and a high potassium/high sodium (120 mmol potassium/300 mmol sodium; HK/HS). On day seven of each diet, 24-h ambulatory BP and a urine collection were performed. Brachial artery flow-mediated dilation (FMD) was measured in response to reactive hyperemia. Between diets, 24-h BP was unchanged confirming salt resistance (p > 0.05). Sodium excretion increased on both HS diets compared to MK/LS (p < 0.05) and potassium excretion was increased on the HK diet compared to MK/LS and MK/HS (p < 0.05) confirming diet compliance. FMD was lower in MK/HS (5.4 ± 0.5%) compared to MK/LS (6.7 ± 0.5%; p < 0.05) and HK/HS (6.4 ± 0.5%), while there was no difference between the MK/LS and HK/HS diets (p > 0.05). These data suggest that dietary potassium provides vascular protection against the deleterious effects of high dietary sodium by restoring conduit artery function.

Diets high in salt can lead to endothelial dysfunction, a nontraditional risk factor for cardiovascular disease (CVD). Exercise is known to reduce CVD risk; however, it remains unknown whether chronic physical activity can attenuate salt-induced endothelial dysfunction independent of blood pressure (BP) and whether these changes are due to an upregulation in endogenous antioxidants. Eight-week-old Sprague-Dawley rats were fed either a normal (NS; 0.49%)- or a high (HS; 4.0%)-salt diet and further divided into voluntary wheel running (NS-VWR, HS-VWR) and sedentary (NS, HS) groups for 6 wk. BP was measured weekly and remained unchanged within groups (P = 0.373). Endothelium-dependent relaxation (EDR) was impaired in the femoral artery of HS compared with NS (38.6 ± 4.0% vs. 65.0 ± 3.6%; P = 0.013) animals, whereas it was not different between NS and HS-VWR (73.4 ± 6.4%; P = 0.273) animals. Incubation with the antioxidants TEMPOL (P = 0.024) and apocynin (P = 0.013) improved EDR in HS animals, indicating a role for reactive oxygen species (ROS). Wheel running upregulated the antioxidant superoxide dismutase-2 (SOD-2) (P = 0.011) under HS conditions and lowered NOX4 and Gp91-phox, two subunits of NADPH oxidase. Wheel running elevated phosphorylated endothelial nitric oxide synthase (eNOS) (P = 0.014) in HS-fed rats, demonstrating a role for physical activity and eNOS activity under HS conditions. Finally, there was a reduction in EDR (P = 0.038) when femoral arteries from NS-VWR animals were incubated with TEMPOL or apocynin, suggesting there may be a critical level of ROS needed to maintain endothelial function. In summary, physical activity protected HS-fed rats from reductions in endothelial function, likely through increased SOD-2 levels and reduced oxidative stress. NEW & NOTEWORTHY Our data suggest that voluntary wheel running can prevent impairments in endothelium-dependent relaxation in the femoral artery of rats fed a high-salt diet. This appears to be independent of blood pressure and mediated through a decrease in expression of NADPH oxidases as a result of physical activity. These data suggest that increased chronic physical activity can protect the vasculature from a diet high in salt, likely through a reduction in oxidative stress.