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Randomized Controlled Trial
. 2013 Jan 22;61(3):335-43.
doi: 10.1016/j.jacc.2012.09.010. Epub 2012 Nov 7.

Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure

Kristen L Jablonski  1 , Matthew L Racine, Candace J Geolfos, Phillip E Gates, Michel Chonchol, Matthew B McQueen, Douglas R Seals
Affiliations
Randomized Controlled Trial

Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure

Kristen L Jablonski et al. J Am Coll Cardiol. .

Abstract

Objectives: This study sought to determine the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP) (130-159 mm Hg) and the associated physiological mechanisms.

Background: Vascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown.

Methods: Seventeen subjects (11 men and 6 women; mean age, 62 ± 7 years) completed a, randomized crossover study of 4 weeks of both low (DSR) and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH(4)) bioavailability, and oxidative stress-associated mechanisms were assessed following each condition.

Results: Urinary sodium excretion was reduced by ≈ 50% (to 70 ± 30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMD(BA)]) and resistance (forearm blood flow responses to acetylcholine [FBF(ACh)]) artery EDD were 68% and 42% (peak FBF(ACh)) higher following DSR (p < 0.005). Low sodium markedly enhanced NO-mediated EDD (greater ΔFBF(ACh) with endothelial NO synthase inhibition) without changing endothelial NO synthase expression/activation (Ser 1177 phosphorylation), restored BH(4) bioactivity (less ΔFMD(BA) with acute BH(4)), abolished tonic superoxide suppression of EDD (less ΔFMD(BA) and ΔFBF(ACh) with ascorbic acid infusion), and increased circulating superoxide dismutase activity (all p < 0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged.

Conclusions: DSR largely reversed both macro- and microvascular endothelial dysfunction by enhancing NO and BH(4) bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces "vascular protection" beyond that attributable to its BP-lowering effects.

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Figures

Figure 1
Figure 1. 24-hour Urinary Sodium and Potassium Excretion
24-hour urinary excretion of sodium (left) and potassium (right) at baseline (B), weeks 1–5 of the normal sodium condition (N1–N5) and weeks 1–5 of the low sodium condition (L1–L5). Values are mean ± S.E.; * P<0.001; † P<0.005 vs. baseline or normal sodium of same week (repeated measures ANOVA with post-hoc Bonferonni corrected comparisons; n=17).
Figure 2
Figure 2. Brachial Artery Flow-Mediated Dilation
Mean group (A) and individual subject (B) brachial artery FMD %Δ during normal sodium [NS] vs. low sodium [LS] condition. Values are mean ± S.E.; *P<0.001 vs. NS (linear mixed-effects models (see supplement for details); n=16/17). Note, all seventeen subjects are shown in (B), but due to similarities some subjects overlap and may not be individually distinguishable.
Figure 3
Figure 3. Forearm Blood Flow to Acetylcholine
Forearm blood flow [FBF] (A) and vascular conductance [VC] (B) response to acetylcholine [ACh] during normal sodium [NS] vs. low sodium [LS]. Individual subject FBFAch (area under the curve, AUC) (C). Values are mean ± S.E.; * P<0.005; † p<0.05 LS vs. NS (linear mixed-effects model; n=12/13).
Figure 4
Figure 4. Contribution of eNOS to EDD
Dose-response for forearm blood flow [FBF] (A) and forearm vascular conductance [FVC] (B) to acetylcholine [ACh] + NG monomethyl-L-arginine [L-NMMA] during normal sodium [NS] and low sodium [LS]; area under the curve [AUC] values (C–D). Total endothelial nitric oxide synthase [eNOS] protein (E) and eNOS phosphorylated at Ser 1177 [PeNOS] (F) in subjects’ endothelial cells relative to human umbilical vein endothelial cell [HUVEC] control; representative images shown below. Values are mean ± S.E.; * P<0.001; † P<0.05 (drug x sodium condition interaction; linear mixed-effects model; n=12/13).
Figure 5
Figure 5. Contributions of Oxidative Stress and BH4 Bioavailability to EDD
Brachial artery FMD %Δ during normal sodium [NS] vs. low sodium [LS] ± co-administration of ascorbic acid [Vit C] and/or tetrahydrobiopterin [BH4] (A). Circulating superoxide dismutase [SOD] activity (B). Forearm blood flow (C) and vascular conductance (D) response to acetylcholine [ACh] ± Vit C. Values are mean ± S.E.; * p<0.001; † p<0.005; ‡ p<0.05 (drug x sodium condition interaction or main effect of sodium condition; linear mixed-effects model; n=12–17).
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References

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