The Effect of Antioxidants on Skin Blood Flow-BH4
Condition: Cardiovascular Diseases; Cardiovascular Risk Factor; Vasoconstriction
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      The goal of this study is to examine possible mechanisms of heightened vasoconstriction in
      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: 
      African Americans (AA) not only have a higher prevalence of hypertension but the severity of
      the cardiovascular complications related to this condition are greater in this population
      relative to other populations. While the underlying causes of this elevated risk are
      multifactorial, vascular dysfunction (i.e. impaired vasodilation and/or augmented
      vasoconstriction) is believed to be a key contributing factor. The investigators have
      recently observed (UTA IRB 2016-0268) that the small blood vessels in the skin (the cutaneous
      microvasculature) in AA, but otherwise healthy individuals, have an impaired blood flow
      response in the cutaneous circulation to local heating when compared to age, body mass index
      (BMI), and gender, matched Caucasians (CA). This blunted response is abolished in AA when the
      sites are pre-treated with either Allopurinol or Apocynin which block the production of
      xanthine oxidase and NADPH oxidase, respectively. In addition, Tetrahydrobiopterin (BH4) is
      critically involved in vascular function. BH4 is a cofactor involved in the conversion of
      L-Arginine into the potent vasodilator nitric oxide (NO) by the enzyme endothelial nitric
      oxide synthase (eNOS). Reduced bioavailable BH4 leads to elevated oxidative stress and thus
      impaired vascular function.

      In addition to local heating another commonly utilized research approach to assess
      microcirculatory vascular function is via local infusion of the potent vasodilator
      methacholine (Mch). Mch is an acetylcholine analog that causes endothelial dependent
      vasodilation primarily through stimulation of NO production. Much like the local heating data
      mentioned above, our laboratory (data collected while at UT Austin) has demonstrated a
      blunted response to Mch in AA relative to CA. However, the role of xanthine oxidase, NADPH
      oxidase, and BH4 in this blunted response remains unknown.
    

Intervention name(s): Control: Lacated Ringers; Apocynin; Allopurinol; BH4; NG Nitro L Arginine Methyl Ester; Sodium Nitroprusside; Acetyl-ß-methylcholine chloride
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): This site will serve as the control site; This site will be used to inhibit NADPH oxidase and subsequent production of superoxide.; This site will be use to inhibit xanthine oxidase and subsequent production of superoxide.; This site will be use to locally supplement BH4.; L-Name is a NOS inhibitor that is administered to each site to allow for the quantification of NO contribution to vasodilation. The infusion rate will be 2 µl/min; SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min; Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other intervention name(s): L-Name; SNP; Mch
Intervention MeSH terms: Allopurinol; Nitroprusside; Nitroarginine; NG-Nitroarginine Methyl Ester
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