- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03680573
The Effect of Antioxidants on Skin Blood Flow-BH4
Study Overview
Status
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
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Texas
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Arlington, Texas, United States, 76019
- Engineering Research Building
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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:
SNP will be perfused through each site to induce maximal vasodilation.
The infusion rate will be 2 µl/min
Other Names:
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
|
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:
SNP will be perfused through each site to induce maximal vasodilation.
The infusion rate will be 2 µl/min
Other Names:
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
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:
SNP will be perfused through each site to induce maximal vasodilation.
The infusion rate will be 2 µl/min
Other Names:
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
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:
SNP will be perfused through each site to induce maximal vasodilation.
The infusion rate will be 2 µl/min
Other Names:
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Names:
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
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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
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites
- Protective Agents
- Antioxidants
- Free Radical Scavengers
- Gout Suppressants
- Nitric Oxide Donors
- Allopurinol
- Nitroprusside
- NG-Nitroarginine Methyl Ester
- Nitroarginine
Other Study ID Numbers
- 2017-0842
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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