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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.
Cardiovascular disease (CVD) afflicts nearly one-third of the adult population with all races and ethnicities represented in CVD prevalence. Unfortunately, a disparity exists such that the black population (BL) is disproportionately affected compared to other groups, including the white population (WH). While the underlying cause of this disparity is multifactorial, vascular dysfunction (i.e., impaired vasodilation and/or augmented vasoconstriction) is a key contributor. As has been previously observed, BL exhibit a heightened vasoconstrictor response to both pharmacological (e.g., alpha-adrenergic receptor agonists) and environmental (e.g., cold pressor test) stimuli compared to their WH counterparts. Additionally, reactive oxygen species (ROS) and the subsequent reduction in nitric oxide (NO) bioavailability may partially mediate this response.
Interestingly, the small blood vessels in the skin (cutaneous microvasculature) in BL, but otherwise healthy individuals, produce an impaired blood flow response to local heating when compared to age-, body mass index (BMI)-, and gender-matched WH. However, pre-treatment of the cutaneous microvasculature with either allopurinol or apocynin (xanthine oxidase inhibitor and NADPH oxidase inhibitor, respectively) abolishes this skin blood flow difference. These drugs inhibit possible sources of ROS, which, as mentioned, may be mediating the heightened vasoconstrictor response in BL. Accordingly, apocynin administration in previous research using an animal model ameliorates alpha-adrenergic receptor-mediated vasoconstriction, possibly due to a reduction in ROS. The role of xanthine/NADPH oxidase and the production of ROS on alpha-adrenergic receptor-mediated vasoconstriction in humans remains unknown.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control (Phenylephrine) | Active Comparator | Subjects will be administered phenylephrine at varying concentrations (10^-2 to 10^-8 M phenylephrine) at a rate of 2 microliters/minute for 10 minutes at each dose to construct a dose-response curve. |
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| Phenylephrine + Apocynin | Experimental | Subjects will be coinfused with the same phenylephrine concentrations as the control arm and apocynin (10^-4 M) at the same rate and for the same time as the control arm. |
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| Phenylephrine + Allopurinol | Experimental | Subjects will be coinfused with the same phenylephrine concentrations as the control arm and allopurinol (10^-5 M) at the same rate and for the same time as the control arm. |
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| Phenylephrine + Tempol | Experimental | Subjects will be coinfused with the same phenylephrine concentrations as the control arm and Tempol (10^-5 M) at the same rate and for the same time as the control arm. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Control (Phenylephrine) | Drug | This intervention is aimed at assessing the vascular responsiveness to phenylephrine, an alpha 1-agonist, in white and black men and women across a series of ascending dose concentrations. |
| Measure | Description | Time Frame |
|---|---|---|
| Vasoconstrictor Responsiveness to Phenylephrine using Laser Doppler Fluxmetry | Establish heightened vasoconstriction to phenylephrine stimulation in black men and women with a focus on black women. Following local infusions of phenylephrine, the changes in blood flux will be quantified using laser Doppler fluxmetry. All changes in flux will be normalized and reported as a percentage of baseline flux. | Through study completion, an average of 1 Year |
| Role of Oxidative Stress in Heightened Vasoconstriction using Laser Doppler Fluxmetry | Determine to what degree superoxide, either generally available or produced through xanthine/NADPH oxidases, contributes to heightened phenylephrine-mediated vasoconstriction. Following local coninfusions of phenylephrine with apocynin, allopurinol, or tempol, the changes in blood flux will be quantified using laser Doppler fluxmetry. All changes in flux will be normalized and reported as a percentage of baseline flux. | Through study completion, an average of 1 Year |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Science and Engineering Research and Innovation Building | Arlington | Texas | 76019 | United States |
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Each subject has one control site and three experimental sites concurrently tested within the same study using intradermal microdialysis on the dorsal forearm.
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| Phenylephrine + Apocynin | Drug | This intervention is meant to assess the impact of NADPH oxidase-derived superoxide on vasoconstrictor responses by inhibiting the enzyme NADPH oxidase. |
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| Phenylephrine + Allopurinol | Drug | This intervention is meant to assess the impact of xanthine oxidase-derived superoxide on vasoconstrictor responses by inhibiting the enzyme xanthine oxidase. |
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| Phenylephrine + Tempol | Drug | This intervention is meant to assess the impact of superoxide on vasoconstrictor responses by scavenging available superoxide. |
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| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D010656 | Phenylephrine |
| C056165 | acetovanillone |
| D000493 | Allopurinol |
| C001803 | tempol |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D000588 | Amines |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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