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The Effect of Antioxidants on Skin Blood Flow-BH4

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03680573
Recruitment Status : Completed
First Posted : September 21, 2018
Last Update Posted : September 26, 2018
Sponsor:
Information provided by (Responsible Party):
Matthew Brothers, The University of Texas at Arlington

Brief 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

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Cardiovascular Risk Factor Vasoconstriction Drug: Control: Lacated Ringers Drug: Apocynin Drug: Allopurinol Drug: BH4 Drug: NG Nitro L Arginine Methyl Ester Drug: Sodium Nitroprusside Drug: Acetyl-ß-methylcholine chloride Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
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
Official Title: The Effect of Antioxidants on Skin Blood Flow-BH4
Actual Study Start Date : January 8, 2018
Actual Primary Completion Date : May 5, 2018
Actual Study Completion Date : May 5, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antioxidants

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.
Drug: Control: Lacated Ringers
This site will serve as the control site

Drug: NG Nitro L Arginine Methyl Ester
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 Name: L-Name

Drug: Sodium Nitroprusside
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Name: SNP

Drug: Acetyl-ß-methylcholine chloride
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Name: 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.
Drug: Apocynin
This site will be used to inhibit NADPH oxidase and subsequent production of superoxide.

Drug: NG Nitro L Arginine Methyl Ester
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 Name: L-Name

Drug: Sodium Nitroprusside
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Name: SNP

Drug: Acetyl-ß-methylcholine chloride
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Name: Mch

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.
Drug: Allopurinol
This site will be use to inhibit xanthine oxidase and subsequent production of superoxide.

Drug: NG Nitro L Arginine Methyl Ester
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 Name: L-Name

Drug: Sodium Nitroprusside
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Name: SNP

Drug: Acetyl-ß-methylcholine chloride
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Name: Mch

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.
Drug: BH4
This site will be use to locally supplement BH4.

Drug: NG Nitro L Arginine Methyl Ester
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 Name: L-Name

Drug: Sodium Nitroprusside
SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
Other Name: SNP

Drug: Acetyl-ß-methylcholine chloride
Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.
Other Name: Mch




Primary Outcome Measures :
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03680573


Locations
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United States, Texas
Engineering Research Building
Arlington, Texas, United States, 76019
Sponsors and Collaborators
The University of Texas at Arlington
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Responsible Party: Matthew Brothers, Associate Professor, The University of Texas at Arlington
ClinicalTrials.gov Identifier: NCT03680573    
Other Study ID Numbers: 2017-0842
First Posted: September 21, 2018    Key Record Dates
Last Update Posted: September 26, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Matthew Brothers, The University of Texas at Arlington:
Racial Differences
Oxidative Stress
Additional relevant MeSH terms:
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Cardiovascular Diseases
Allopurinol
Nitroprusside
Nitroarginine
NG-Nitroarginine Methyl Ester
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents
Nitric Oxide Donors