The long-term objectives of this project are (1) to further clarify the mechanism(s) by which high dietary salt intake can eliminate microvascular nitric oxide (NO) in some vascular beds, and (2) to explore the impact of these changes on the regulation of arteriolar tone and blood flow. High salt intake leads to increased generation of reactive oxygen species in rat spinotrapezius muscle microvessels, and the salt-dependent loss of arteriolar NO activity in this vascular bed is due to the resulting oxidation of NO. Experiments will be conducted on Sprague-Dawley rats fed normal (0.45 percent) or high (0.7 percent) salt diets for 4 weeks. In-vivo microscopy will be used to study the microcirculation of the spinotrapezius muscle or intestine, and this approach will be combined with in vitro analysis to evaluate the possibility that increased microvascular oxidative stress in salt-fed rats is due to increased expression and/or activity of oxidant-generating enzymes or decreased expression and/or activity of oxidant scavenging enzymes. These hypotheses will be tested by using Western analysis and densitometry to quantify the expression of xanthine-oxidase and NAD(P)H oxidase (oxidant-generating enzymes) as well as superoxide dismutase and catalase (oxidant scavenging enzymes) in arterioles and venules from spinotrapezius muscle of rats fed the normal and high-salt diets. In each dietary group, the contributions of the oxidant-generating enzymes to microvascular oxidative stress, and the ability of the oxidant scavenging enzymes to limit this oxidative stress, will also be determined in vivo. Image analysis will be used to quantify arteriolar and venular wall oxidant activity (tetranitroblue tetrazolium reduction) in muscles exposed to selective inhibitors of the above enzymes. The link between the activity of each enzyme and microvascular NO concentration, measured with an electrode, will then be explored in each dietary group to (1) verify the link between venular wall NO and oxidative stress, and (2) assess the effects of increased venular NO production on nearby arteriolar tone. Finally, the in vivo techniques will be used to evaluate the effect of dietary salt on the oxidative state and NO of arterioles in the intestine, and the contribution of each enzyme to an increase in oxidative stress, and any subsequent impact on the ability of arteriolar NO to limit sympathetic vasoconstriction in this vascular bed. This project will provide important insight into the mechanisms by which dietary salt can alter microvascular function in normotensive individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044012-14
Application #
6638293
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
1990-02-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2006-06-30
Support Year
14
Fiscal Year
2003
Total Cost
$255,500
Indirect Cost
Name
West Virginia University
Department
Physiology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
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