The Effect of Antioxidants on Skin Blood Flow-BH4

• ClinicalTrials.gov Identifier: NCT03680573
• Recruitment Status: Completed
• First Posted: September 21, 2018
• Last Update Posted: September 26, 2018
• Sponsor: The University of Texas at Arlington
• Information provided by (Responsible Party): Matthew Brothers, The University of Texas at Arlington

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

United States, Texas

Engineering Research Building

Arlington, Texas, United States, 76019

Sponsors and Collaborators

The University of Texas at Arlington

More Information

• 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
• Last Update Posted: September 26, 2018
• Last Verified: September 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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