The long-term objectives of this project are (1) to explore the mechanism(s) by which high dietary salt intake, in the absence of hypertension, can inhibit the influence of nitric oxide (NO) on microvascular tone, (2) to define the relationship between dietary salt intake, blood pressure and microvascular NO activity in """"""""salt sensitive"""""""" hypertension, and (3) to determine whether salt-dependent changes in microvascular NO activity can influence local blood flow control mechanisms in the normotensive state or in hypertension. Experiments will be conducted on Dahl salt-resistant (SR/Jr) rats fed normal (0.45%) or high (7%) salt diets, and on spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats fed low (0.02%), normal or high salt diets. The intact microvascular network of the superfused spinotrapezius muscle will be studied by in vivo microscopy, and various micropipette-based techniques will be employed to first test the hypothesis that high salt intake in normotensive rats leads to an increased generation of oxygen radicals in or near the arteriolar wall that oxidize and deactivate endothelial-derived NO. This hypothesis will be tested by evaluating the effect of oxidant-scavenging agents on the contribution of NO to endothelium-dependent arteriolar dilation in SR/Jr fed high- vs. normal-salt diets. Other experiments will evaluate the possible direct effect of NaCl on NO-dependent control of arteriolar tone, as well as the influence of endothelial-derived hyperpolarizing factor on arteriolar tone in SR/Jr fed high- vs. normal-salt diets. Next, the hypothesis that high salt intake suppresses the normal endothelium-dependent modulation of myogenic activity in normotensive rats will be tested by evaluating the effect of (a) NO synthase inhibition, (b) increased NO levels, (c) cyclooxygenase inhibition and (d) nonspecific disruption of endothelial function on arteriolar constrictor responses to increased luminal pressure in high- vs. normal-salt SR/Jr. The final hypothesis addresses the possibility that the abnormal influence of endothelial-derived contracting factors on myogenic activity in hypertensive rats is further increased when hypertension is exacerbated by high salt intake and decreased when hypertension is reduced by low salt intake, and that these effects are due to changes in the offsetting influence of NO. This hypothesis will be tested by evaluating arteriolar responses to increased luminal pressure in SHR and WKY fed low-, normal- and high-salt diets before and after (a) NO synthase inhibition, (b) increased NO levels, (c) cyclooxygenase inhibition, (d) disruption of endothelial function, (e) thromboxane A2/prostaglandin H2 receptor blockade and (f) thromboxane A2 synthesis inhibition. The proposed study should provide important insight into the influence of dietary salt on local blood flow regulation in normotensive as well as in hypertensive individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044012-08
Application #
2445197
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1990-02-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
8
Fiscal Year
1997
Total Cost
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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Nurkiewicz, Timothy R; Wu, Guoyao; Li, Peng et al. (2010) Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation 17:147-57
Boegehold, Matthew A (2010) Endothelium-dependent control of vascular tone during early postnatal and juvenile growth. Microcirculation 17:394-406
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