The Effect of Antioxidants on Skin Blood Flow During Local Heating

NCT ID: NCT03680638

Last Updated: 2018-09-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-07
• Study Completion Date: 2017-10-09

Brief Summary

The goal of this study is to examine possible mechanisms of impaired vasodilaton in obese and 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

The integrative vascular laboratory has recently observed that the small blood vessels in the skin (the cutaneous microvasculature) in obese (BMI>30kg/m2), but otherwise healthy individuals, require a greater amount of nitric oxide (NO) to achieve the same degree of dilation when compared to age, gender, and race matched lean (BMI<25kg/m2) individuals (34). In addition, it is well documented that African Americans have impaired blood vessel function which likely contributes to the elevated risk for developing a variety of cardiovascular and metabolic diseases including coronary artery disease, metabolic syndrome, hypertension and stroke in this population. The cutaneous circulation is recognized as a surrogate vascular bed for assessment of mechanisms underlying systemic vascular disease (7, 20, 22). This is particularly important as microvascular dysfunction is emerging as a critical step in the atherosclerotic process and a variety of conditions including hypertension, exercise intolerance, and insulin resistance (25). Furthermore, impaired cutaneous microvascular function mirrors impaired responses in other vascular beds (7, 12, 20, 22). A primary advantage to utilizing the cutaneous circulation is that it provides an accessible vascular bed through which processes of endothelial function can be systematically and mechanistically investigated, with virtually no risk, through thermal stimuli and local intra-dermal drug infusions. Mechanisms of impaired NO bioavailability have been assessed in various at-risk and diseased populations including, healthy aging, hypertension, postural tachycardia syndrome, hypercholesteremia, and chronic kidney disease (8, 16, 19, 24, 36, 37). Using approaches and techniques similar to those proposed in this application (see below) the findings have implicated that a number of factors, including elevated oxidative stress, contribute to the reduced bioavailability and/or action of NO (8, 16, 19, 24, 36, 37)

The recent findings suggest an impairment in the action of NO on the microvascular smooth muscle of obese young adults (34) as well as in college-aged otherwise healthy African Americans. Local heating is a common method to test nitric oxide-mediated vasodilation (3, 6, 31). Therefore, the investigators propose to test the following hypotheses:

1. Obesity results in impaired blood flow response to local heating and this will also be the case for African Americans.

2. Inhibition of superoxide, a common form of oxidative stress, augments the local heating response in obese individuals as well as in African Americans.

3. Inhibition of sources of superoxide, NADPH-oxidase and/or Xanthine-oxidase, augments skin blood flow local heating response in obese to that of their lean counterparts. This will also be the case for African Americans relative to their Caucasian American counterparts.

Conditions

Cardiovascular Diseases; Cardiovascular Risk Factor; Vasodilation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Control (Lactated Ringer's)

This site will only be infused with Lactated Ringer's during the local heating stimulus. After the local heating stimulus, this site will be infused with L-NAME (Nω-nitro-L-arginine methylester; 20mM) to inhibit nitric oxide synthase and with SNP (sodium nitroprusside; 28mM) to elicit vasodilation. This will help establish nitric oxide contribution to vasodilation and establish maximal vasodilation for data normalization, respectively.

Group Type: SHAM_COMPARATOR

Control (Lactated Ringer's)

Intervention Type: OTHER

This intervention is meant to serve as a control by which the experimental sites are compared to, to assess effectiveness.

Tempol

This site will only be infused with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; 10µM) during the local heating stimulus. After the local heating stimulus, this site will be infused with L-NAME (Nω-nitro-L-arginine methylester; 20mM) to inhibit nitric oxide synthase and with SNP (sodium nitroprusside; 28mM) to elicit vasodilation. This will help establish nitric oxide contribution to vasodilation and establish maximal vasodilation for data normalization, respectively.

Group Type: EXPERIMENTAL

Tempol

Intervention Type: DRUG

This intervention is meant to assess the impact of superoxide on vasodilator responses by scavenging available superoxide.

Apocynin

This site will only be infused with apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone; 100µM) during the local heating stimulus. After the local heating stimulus, this site will be infused with L-NAME (Nω-nitro-L-arginine methylester; 20mM) to inhibit nitric oxide synthase and with SNP (sodium nitroprusside; 28mM) to elicit vasodilation. This will help establish nitric oxide contribution to vasodilation and establish maximal vasodilation for data normalization, respectively.

Group Type: EXPERIMENTAL

Apocynin

Intervention Type: DRUG

This intervention is meant to assess the impact of NADPH oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme NADPH oxidase.

Allopurinol

This site will only be infused with tempol (1H-pyrazolo\[3,4-d\]pyrimidin-4(2H)-one; 10µM) during the local heating stimulus. After the local heating stimulus, this site will be infused with L-NAME (Nω-nitro-L-arginine methylester; 20mM) to inhibit nitric oxide synthase and with SNP (sodium nitroprusside; 28mM) to elicit vasodilation. This will help establish nitric oxide contribution to vasodilation and establish maximal vasodilation for data normalization, respectively.

Group Type: EXPERIMENTAL

Allopurinol

Intervention Type: DRUG

This intervention is meant to assess the impact of xanthine oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme xanthine oxidase.

Interventions

Control (Lactated Ringer's)

This intervention is meant to serve as a control by which the experimental sites are compared to, to assess effectiveness.

Intervention Type: OTHER

Tempol

This intervention is meant to assess the impact of superoxide on vasodilator responses by scavenging available superoxide.

Intervention Type: DRUG

Apocynin

This intervention is meant to assess the impact of NADPH oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme NADPH oxidase.

Intervention Type: DRUG

Allopurinol

This intervention is meant to assess the impact of xanthine oxidase-derived superoxide on vasodilator responses by inhibiting the enzyme xanthine oxidase.

Intervention Type: DRUG

Eligibility 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.

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The University of Texas at Arlington

OTHER

Sponsor Role: lead

Responsible Party

Matthew Brothers

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Engineering Research Building

Arlington, Texas, United States

Countries

United States

Other Identifiers

2016-0268

Identifier Type: -

Identifier Source: org_study_id