The goal of this study is to examine possible mechanisms of impaired vasodilaton in obese and Black/African American men and women as possible links to the elevated prevalence of cardiovascular dysfunction and disease. The main targets in this study are sources of oxidative stress.
The integrative vascular laboratory has recently observed that the small blood vessels in the skin (the cutaneous microvasculature) in obese (BMI\>30kg/m2), but otherwise healthy individuals, require a greater amount of nitric oxide (NO) to achieve the same degree of dilation when compared to age, gender, and race matched lean (BMI\<25kg/m2) individuals (34). In addition, it is well documented that African Americans have impaired blood vessel function which likely contributes to the elevated risk for developing a variety of cardiovascular and metabolic diseases including coronary artery disease, metabolic syndrome, hypertension and stroke in this population. The cutaneous circulation is recognized as a surrogate vascular bed for assessment of mechanisms underlying systemic vascular disease (7, 20, 22). This is particularly important as microvascular dysfunction is emerging as a critical step in the atherosclerotic process and a variety of conditions including hypertension, exercise intolerance, and insulin resistance (25). Furthermore, impaired cutaneous microvascular function mirrors impaired responses in other vascular beds (7, 12, 20, 22). A primary advantage to utilizing the cutaneous circulation is that it provides an accessible vascular bed through which processes of endothelial function can be systematically and mechanistically investigated, with virtually no risk, through thermal stimuli and local intra-dermal drug infusions. Mechanisms of impaired NO bioavailability have been assessed in various at-risk and diseased populations including, healthy aging, hypertension, postural tachycardia syndrome, hypercholesteremia, and chronic kidney disease (8, 16, 19, 24, 36, 37). Using approaches and techniques similar to those proposed in this application (see below) the findings have implicated that a number of factors, including elevated oxidative stress, contribute to the reduced bioavailability and/or action of NO (8, 16, 19, 24, 36, 37) The recent findings suggest an impairment in the action of NO on the microvascular smooth muscle of obese young adults (34) as well as in college-aged otherwise healthy African Americans. Local heating is a common method to test nitric oxide-mediated vasodilation (3, 6, 31). Therefore, the investigators propose to test the following hypotheses: 1. Obesity results in impaired blood flow response to local heating and this will also be the case for African Americans. 2. Inhibition of superoxide, a common form of oxidative stress, augments the local heating response in obese individuals as well as in African Americans. 3. Inhibition of sources of superoxide, NADPH-oxidase and/or Xanthine-oxidase, augments skin blood flow local heating response in obese to that of their lean counterparts. This will also be the case for African Americans relative to their Caucasian American counterparts.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
44
This intervention is meant to serve as a control by which the experimental sites are compared to, to assess effectiveness.
This intervention is meant to assess the impact of superoxide on vasodilator responses by scavenging available superoxide.
This intervention is meant to assess the impact of NADPH oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme NADPH oxidase.
Engineering Research Building
Arlington, Texas, United States
Vasodilator Responses to Local Heating with Antioxidant Supplementation
Assess the impact of oxidative stress on impaired vasodilation to local heating. This will be elicited using intradermal microdialysis infusions of apocynin, allopurinol, or tempol, all of which are vasoactive substances. The changes in skin blood flux will be quantified using laser Doppler fluxmetry. All changes in flux will be normalized and reported as a percentage of maximal flux.
Time frame: Through study completion, an average of 1 year
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This intervention is meant to assess the impact of xanthine oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme xanthine oxidase.