The Effect of Antioxidants on Skin Blood Flow During Local Heating
Condition: Cardiovascular Diseases; Cardiovascular Risk Factor; Vasodilation
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Control (Lactated Ringer's); Tempol; Apocynin; Allopurinol
Intervention type(s): Other; Drug; Drug; Drug
Intervention description(s): 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.; This intervention is meant to assess the impact of xanthine oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme xanthine oxidase.
Intervention MeSH terms: Allopurinol; Tempol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Each subject has one control site and three experimental sites concurrently tested within the same study using intradermal microdialysis on the dorsal forearm.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Racial Differences; Oxidative Stress; Obesity; Local Heating