Local Antioxidant Therapy Vasoconstriction Effects in Different Races

NCT03684213 | Completed Phase 1 FDA Drug

• 1 other identifier: 2018-0647
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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. Our laboratory has recently observed (UTA IRB 2016-0268) that 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 various antioxidants abolishes this skin blood flow difference. These antioxidant drugs inhibit possible sources of ROS, which, as mentioned, maybe mediating the heightened vasoconstrictor response in BL. However, this has not been investigated in this population and thus remains unknown. Therefore, the purpose of this study proposal is to test the following hypotheses: 1) BL will have a greater reduction in cutaneous blood flow in response to local administration of Norepinephrine (alpha1-adrenergic and alpha 2-adrenergic receptor agonist) relative to WH. 2) This greater reduction in the BL population will be related to elevated oxidative stress and subsequent reduction in bioavailability of the potent vasodilator Nitric oxide.

Conditions

Cardiovascular Diseases; Cardiovascular Risk Factor; Vasoconstriction

Keywords

Racial Differences; Oxidative Stress; Antioxidant; Microvasculature

Outcome Measures

Primary Outcomes (2)

• Vasoconstrictor Responsiveness to Norepinephrine using Laser Doppler Fluxmetry

  Establish heightened vasoconstriction to norepinephrine stimulation in black men and women with a focus on black women. Following the local infusion of norepinephrine, 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 global oxidative stress and differences in endothelial nitric oxide play a role in heightened vasoconstriction. Following the local infusion of norepinephrine combined with either Ascorbic Acid, L-NAME, or L-NAME with Ascorbic Acid, 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

Study Arms (4)

Control (Norepinephrine)

ACTIVE COMPARATOR

Subjects will be administered norepinephrine 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.

Drug: Control (Norepinephrine)

Norepinephrine + Ascorbic Acid

EXPERIMENTAL

Subjects will be coinfused with the same norepinephrine concentrations as the control arm and ascorbic acid (Vitamin C; 10 mM) at the same rate and for the same time as the control arm.

Drug: Norepinephrine + Ascorbic Acid

Norepinephrine + L-NAME

EXPERIMENTAL

Subjects will be coinfused with the same norepinephrine concentrations as the control arm and L-NAME (Nω-Nitro-L-arginine methyl ester hydrochloride; 20 mM) at the same rate and for the same time as the control arm.

Drug: Norepinephrine + L-NAME

Norepinephrine + L-NAME + Ascorbic Acid

EXPERIMENTAL

Subjects will be coinfused with the same norepinephrine concentrations as the control arm and combined L-NAME (Nω-Nitro-L-arginine methyl ester hydrochloride; 20 mM) and ascorbic acid (Vitamin C; 10 mM) at the same rate and for the same time as the control arm.

Drug: Norepinephrine + L-NAME + Ascorbic Acid

Interventions

Control (Norepinephrine) DRUG

This intervention is aimed at assessing the vascular responsiveness to norepinephrine, an alpha 1-agonist, in white and black men and women across a series of ascending dose concentrations.

Control (Norepinephrine)

Norepinephrine + Ascorbic Acid DRUG

This intervention is meant to globally assess the impact of oxidative stress on vasoconstrictor responses by scavenging numerous oxidative molecules.

Norepinephrine + Ascorbic Acid

Norepinephrine + L-NAME DRUG

This intervention is meant to assess the impact of endothelium-derived nitric oxide on vasoconstrictor responses by inhibiting production of this source of nitric oxide.

Norepinephrine + L-NAME

Norepinephrine + L-NAME + Ascorbic Acid DRUG

This intervention is meant to assess the combined impact of scavenging oxidative stress and inhibiting endothelium-derived nitric oxide on vasoconstrictor responses.

Norepinephrine + L-NAME + Ascorbic Acid

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Texas at Arlington: lead

Study Sites (1)

Science and Engineering Research and Innovation Building

Arlington, Texas, 76019, United States

Location

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

Norepinephrine; Ascorbic Acid; NG-Nitroarginine Methyl Ester

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor / Associate Chair for Graduate Programs in Exercise Science and Kinesiology Director of the Integrative Vascular Physiology Laboratory

Model Details: Each subject has one control site and three experimental sites concurrently tested within the same study using intradermal microdialysis on the dorsal forearm.

Study Record Dates

• First Submitted: September 17, 2018
• First Posted: September 25, 2018
• Study Start: October 15, 2018
• Primary Completion: May 15, 2024
• Study Completion: June 8, 2024
• Last Updated: June 11, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)