Date of Award

Spring 1-1-2011

Document Type


Degree Name

Doctor of Philosophy (PhD)


Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

Robert Mazzeo

Third Advisor

William C. Byrnes


Endothelial dysfunction, commonly assessed as a decline in endothelium-dependent dilation (EDD), is a clinically important predictor of future cardiovascular diseases (CVD). EDD is reduced with age and elevated systolic blood pressure (SBP), whether assessed as brachial artery flow-mediated dilation (FMDBA) or as the forearm blood flow response to acetylcholine (FBFACh). Thus, establishing the efficacy of interventions that may preserve EDD in this population is a high biomedical research priority. Dietary sodium restriction (DSR) is one potential intervention. While the influence of sodium on BP is widely documented and appreciated, high dietary sodium has other adverse effects on cardiovascular health, independent of its effect on BP. Accordingly, the purpose of these studies was to determine a) if reduced sodium intake is associated with enhanced EDD in middle-aged and older adults (MA/O) with moderately elevated SBP; b) if DSR improves EDD in this group; and c) the physiological mechanisms mediating any improvements.

In cross-sectional analyses, FMDBA was 52% higher in subjects self-reporting low sodium intake (73±6 mmol/d), without differences in endothelium-independent dilation (EID), SBP or other subject characteristics. In the entire cohort, FMDBA was inversely related to dietary sodium intake (%Δ r=-0.53, p<0.01).

In the intervention study, EDD was 71% (FMDBA) and 53% (peak FBFACh) higher following 4 weeks of low sodium (70±8 mmol/day) vs. normal sodium (153±7 mmol/day) intake (p<0.05; randomized cross-over design), whereas EID did not change. The improvements in EDD remained significant when correcting for SBP, and other subject characteristics/dietary factors did not change. Functional improvements were mediated by increased nitric oxide (NO) bioavailability (significant reduction in FBFACh with co-infusion of an endothelial nitric oxide synthase inhibitor), increased tetrahydrobiopterin (BH4) bioavailability (FMDBA no longer improved with oral BH4) and reduced oxidative stress (FMDBA and FBFACh no longer improved with ascorbic acid infusion; reduced endothelial cell nitrotyrosine abundance).

In conclusion, DSR reverses endothelial dysfunction in MA/O with moderately elevated SBP by enhancing NO and BH4 bioavailability and reducing oxidative stress. Thus, the physiological mechanisms modulating benefits of DSR are beyond BP lowering alone, and the potential impact of DSR upon CVD risk may be even greater than previously appreciated.