The Effect of Antioxidants on Skin Blood Flow-BH4

September 24, 2018 updated by: Matthew Brothers, The University of Texas at Arlington
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

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Texas
      • Arlington, Texas, United States, 76019
        • Engineering Research Building

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Individuals (ages 18-35, both genders) will be recruited from the greater Arlington area to participate in the study.
  • Must self-report both parents as either African American or Caucasian American.

Exclusion Criteria:

  • Individuals who have donated more than 550 ml of blood within the past 8 weeks will not have blood drawn from them in this protocol. However, if they remain interested in the study, and otherwise meet the inclusion criteria, than we may still opt to proceed with data collection.
  • Individuals with cardiovascular, neurological, and/or metabolic illnesses will be excluded from participating as well as individuals with a history of various diseases of the microvasculature including Reynaud's disease, cold-induced urticaria, cryoglobulinemia, etc.
  • Subjects currently taking any prescription medications and individuals with a body mass index about 30 kg/m2) will be excluded.
  • Pregnant subjects and children (i.e. younger than 18) will not be recruited for the study. Eligible females will be scheduled for days 2-7 of their menstrual cycle to account for hormonal effects on blood flow. A regular menstrual cycle is required to identify and schedule the study for the low hormone period, therefore females who lack a regular cycle will be excluded from the study. Females currently taking birth control are eligible, as long as they can be scheduled during a low-hormone "placebo" week. If their hormone do not contain a placebo week than these individuals will not be eligible for data collection. Females who are breast-feeding will also be eligible as there are no systemic or lasting effects of the proposed vasoactive agents.
  • Given that smoking can affect the peripheral vasculature, current smokers and individuals who regularly smoked (>1 pack per two weeks) within the prior 2 years will be excluded

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control- Lactated Ringers
This site will serve as the control site and will receive lactated Ringer's (saline solution) at an infusion rate of 2 µl/min.
This site will serve as the control site
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
Other Names:
  • L-Name
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Names:
  • SNP
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
  • Mch
Experimental: Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone)
This site will receive 100 µM apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone) at an infusion rate of 2 µl/min.
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
Other Names:
  • L-Name
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Names:
  • SNP
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
  • Mch
This site will be used to inhibit NADPH oxidase and subsequent production of superoxide.
Experimental: Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one)
This site will receive 10 µM allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one)at an infusion rate of 2 µl/min.
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
Other Names:
  • L-Name
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Names:
  • SNP
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
  • Mch
This site will be use to inhibit xanthine oxidase and subsequent production of superoxide.
Experimental: BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride)
This site will receive 10 mM (6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride (BH4) at an infusion rate of 2 µl/min.
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
Other Names:
  • L-Name
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Names:
  • SNP
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
  • Mch
This site will be use to locally supplement BH4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Flow Response to the Administration of Methacholine (Mch) before and after Infusions of Vasoactive Drugs using Intradermal Microdialysis and Laser Doppler Fluxmetry
Time Frame: Through study completion, an average of 1 Year
To establish impaired blood flow response to local administration of Mch in African American relative to Caucasians. Mch will be administered using intradermal microdialysis in separate doses while the skin blood flux response will be determined using laser Doppler fluxmetry. All changes in flux will be normalized and reported as a percentage of maximal flux. The role of oxidative stress and low nitric oxide synthase cofactors will be assessed using infusions of apocynin/allopurinol and tetrahydrobiopterin (BH4), respectively. These infusions will be given after the first infusion of Mch and before the second infusion of Mch to determine how Mch responsiveness changes with these vasoactive drugs.
Through study completion, an average of 1 Year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 8, 2018

Primary Completion (Actual)

May 5, 2018

Study Completion (Actual)

May 5, 2018

Study Registration Dates

First Submitted

September 17, 2018

First Submitted That Met QC Criteria

September 19, 2018

First Posted (Actual)

September 21, 2018

Study Record Updates

Last Update Posted (Actual)

September 26, 2018

Last Update Submitted That Met QC Criteria

September 24, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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