Excess dietary salt causes target organ damage and increases the risk for adverse cardiovascular (CV) events independent of blood pressure (BP). Recent data in salt-resistant, normotensive rodents suggest that high dietary salt enhances the excitability or gain of sympathetic circuits, exaggerates sympathetic and CV responses to various stimuli, and increases BP variability (BPV). There are limited data regarding the impact of dietary salt intake on sympathetic nerve activity (SNA) and CV function in salt-resistant humans as well as the underlying mechanisms contributing to these adverse effects. Our long-term goal is to determine how dietary salt adversely affects BP regulation and CV health. The objective of this proposal is 2-fold: (1) to comprehensively evaluate the impact of dietary salt intake on SNA and CV reactivity and BPV in normotensive humans, and (2) to identify novel mechanisms underlying these adverse neurogenic effects of dietary salt using salt-resistant rodents. Our working hypothesis is that high dietary salt elevates plasma [Na+] to activate forebrain osmoreceptors via the epithelial sodium channel (ENaC). This subsequently sensitizes neurons of the rostral ventrolateral medulla (RVLM) through a local activation of angiotensin II type 1 receptor (AT1R) and decrease in resting K+ conductance. In turn, both human subjects and animals have exaggerated SNA and BP responses to a variety of stimuli thereby leading to increased BPV and greater risk for adverse CV events. We will test this hypothesis through 4 specific aims: 1) Aim 1 will test the hypothesis that high dietary salt increases SNA and CV reactivity in normotensive adults, 2) Aim 2 will test the hypothesis that high dietary salt increases BPV in normotensive adults, 3) Aim 3 will determine the extent by which a high salt diet induces neuroplasticity and alterations in membrane properties of RVLM neurons via local activation of AT1R to exaggerate SNA reflexes and increase BPV, and 4) Aim 4 will determine the extent by which changes in plasma sodium concentration and ENaC alter RVLM neurons and exaggerate SNA reflexes and increase BPV. To address both objectives through these aims, we have established a unique multi-institutional, multi-PI collaboration that includes a human CV physiologist and an animal neurophysiologist. This combination uniquely positions the research team to readily translate findings in animal models to humans and impact CV health. The expected outcome is to definitively demonstrate that dietary salt loading increases CV reactivity and BPV through a sympathetic nervous system mechanism that originates in the brain. The proposed research is significant, as these studies will provide empirical evidence that dietary salt intake impacts neurohumoral control of the circulation in salt-resistant humans. In addition, the proposed studies in rodents will identify novel mechanisms underlying these adverse effects and thereby create a platform for new therapeutic targets. The proposed research is innovative because it will identify a novel neurogenic action of dietary salt in human CV regulation.

Public Health Relevance

Excess dietary salt increases the risk for cardiovascular events, even in people that are not hypertensive. There is some evidence that excess dietary salt exaggerates blood pressure and sympathetic nervous system responses to various perturbations and increases blood pressure variability. This proposal will examine the effects of low, medium, and high salt diets on cardiovascular reactivity and blood pressure variability. In addition, this proposal will identify novel mechanisms in the brain that contribute to these abnormal responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128388-04
Application #
9665596
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Delaware
Department
Other Health Professions
Type
Sch Allied Health Professions
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Wenner, Megan M; Paul, Erin P; Robinson, Austin T et al. (2018) Acute NaCl Loading Reveals a Higher Blood Pressure for a Given Serum Sodium Level in African American Compared to Caucasian Adults. Front Physiol 9:1354
Stocker, Sean D; Kinsman, Brian J; Sved, Alan F (2017) Recent Advances in Neurogenic Hypertension: Dietary Salt, Obesity, and Inflammation. Hypertension :
Matthews, Evan L; Brian, Michael S; Edwards, David G et al. (2017) Blood pressure responses to dietary sodium: Association with autonomic cardiovascular function in normotensive adults. Auton Neurosci 208:51-56
Kinsman, Brian J; Simmonds, Sarah S; Browning, Kirsteen N et al. (2017) Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure. Hypertension 69:163-170