Vascular Dysfunction in Black Individuals: Roles of Nitric Oxide and Endothelin-1 (UMMC_Pilot)

October 6, 2023 updated by: Thales Coelho Barbosa, University of Mississippi Medical Center

The research aims of this proposal are:

  • Specific Aim 1: To test whether an increase in nitric oxide signaling can increase vasodilator responses in young Black individuals.
  • Specific Aim 2: To test whether a decrease in endothelin-1 signaling can increase vasodilator responses in young Black individuals.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Studies will be conducted in the Clinical Research and Trials Unit at the University of Mississippi Medical Center. All study visits will follow the same procedures, except for the drug or supplement being administered.

For Aim 1, double-blind, randomized, placebo-controlled crossover designs will examine the effects of increasing nitric oxide and cyclic guanosine monophosphate bioavailability on vascular function of young Black and White individuals. Three sets of two visits will be performed:

  • Aim 1a: At the beginning of each visit, participants will ingest either a nitrate-rich beetroot juice or a nitrate-depleted beetroot juice (serving as placebo) in their liquid commercial form, which has a distinct color and flavor. The nitrates will be absorbed and reduced in the plasma to nitrite and nitric oxide, increasing endothelium-independent nitric oxide bioavailability.
  • Aim 1b: Participants will receive a 7-day supplement of L-citrulline or placebo before each study visit, with a washout period of 7 days between visits. The activity of the endothelial nitric oxide synthase converts L-arginine into nitric oxide and L-citrulline, which is normally recycled back into L-arginine. Unlike L-arginine, oral ingestion of L-citrulline is not catabolized in the gut, nor is it extracted from systemic circulation through hepatic first-pass metabolism. Thus, ingested L-citrulline becomes available in large quantities in the plasma for enzymatic conversion into L-arginine, increasing endothelium-dependent nitric oxide bioavailability.
  • Aim 1c: At the beginning of each visit, participants will ingest a liquid mixture prepared by Investigational Drug Services at the University of Mississippi Medical Center containing Sildenafil or placebo. Sildenafil inhibits phosphodiesterase 5, an enzyme that degrades cyclic guanosine monophosphate in the vascular smooth muscle cells inactivating the nitric oxide-mediated signal; thus, Sildenafil will prolong the availability of cyclic guanosine monophosphate, enhancing the nitric oxide-mediated intracellular cascade.

For Aim 2, a double-blind, randomized, placebo-controlled crossover design will examine the role of endothelin-1 on the vascular function of young Black and White individuals. Two visits will be performed, with a minimum of 7 days between them.

• Aim 2: At the beginning of each visit, participants will ingest a liquid mixture prepared by Investigational Drug Services at the University of Mississippi Medical Center containing Bosentan or placebo. Bosentan blocks ETA and ETB receptors, leading to a reduction in vasoconstrictor tone and a greater magnitude of vasodilator responses.

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • University of Mississippi Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 36 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Self-identification of their race and the race of their biological parents as being only Black (i.e., African American) or only White (i.e., Caucasian American)
  • Born and raised in the United States

Exclusion Criteria:

  • Mixed races
  • Any chronic or ongoing disease
  • Prescribed pharmacological treatment
  • Smoking or tobacco use
  • Obesity (body mass index > 30 kg / m2)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Beetroot juice (Aim 1a)
Upon arriving at the laboratory, participants will ingest 140 ml of beetroot juice containing a high (~12.8 mmol) concentration of nitrates (James White Drinks, Suffolk, UK).
Dietary supplement: Dietary Nitrates 400 mg
The nitrates in the beetroot juice will be absorbed and reduced in the plasma to nitrite and nitric oxide, increasing endothelium-independent nitric oxide bioavailability.
Other Names:
  • Beet It Sport Nitrate 400
Placebo Comparator: Placebo (Aim 1a)
Upon arriving at the laboratory, participants will ingest 140 ml of beetroot juice containing a low concentration (~0.0055 mmol) of nitrates (James White Drinks, Suffolk, UK).
Dietary supplement: Dietary Nitrates 400 mg
The nitrates in the beetroot juice will be absorbed and reduced in the plasma to nitrite and nitric oxide, increasing endothelium-independent nitric oxide bioavailability.
Other Names:
  • Beet It Sport Nitrate 400
Active Comparator: L-citrulline (Aim 1b)
Participants will receive pills containing 3 g of L-citrulline (Superior Labs, Park City, UT) to take twice daily for 7 days before the study visit.
Dietary supplement: L-citrulline 3 g
Ingested L-citrulline becomes available in large quantities in the plasma for enzymatic conversion into L-arginine. The activity of the endothelial nitric oxide synthase converts L-arginine into nitric oxide, increasing endothelium-dependent nitric oxide bioavailability.
Placebo Comparator: Placebo (Aim 1b)
Participants will receive pills containing a placebo to take twice daily for 7 days before the study visit.
Dietary supplement: L-citrulline 3 g
Ingested L-citrulline becomes available in large quantities in the plasma for enzymatic conversion into L-arginine. The activity of the endothelial nitric oxide synthase converts L-arginine into nitric oxide, increasing endothelium-dependent nitric oxide bioavailability.
Active Comparator: Sildenafil (Aim 1c)
Upon arriving at the laboratory, participants will ingest a liquid mixture containing Sildenafil (100 mg), an inhibitor of phosphodiesterase 5.
Drug: Sildenafil 100 mg
Sildenafil inhibits phosphodiesterase 5, an enzyme that degrades cyclic guanosine monophosphate in the vascular smooth muscle cells inactivating the nitric oxide-mediated signal; thus, Sildenafil will prolong the availability of cyclic guanosine monophosphate, enhancing the nitric oxide-mediated intracellular cascade.
Other Names:
  • Viagra, Revatio
Placebo Comparator: Placebo (Aim 1c)
Upon arriving at the laboratory, participants will ingest a liquid mixture containing a placebo.
Drug: Sildenafil 100 mg
Sildenafil inhibits phosphodiesterase 5, an enzyme that degrades cyclic guanosine monophosphate in the vascular smooth muscle cells inactivating the nitric oxide-mediated signal; thus, Sildenafil will prolong the availability of cyclic guanosine monophosphate, enhancing the nitric oxide-mediated intracellular cascade.
Other Names:
  • Viagra, Revatio
Active Comparator: Bosentan (Aim 2)
Upon arriving at the laboratory, participants will ingest a liquid mixture containing Bosentan (125 mg), a non-selective blocker of endothelin-1 receptors ETA and ETB.
Drug: Bosentan 125 mg
Bosentan blocks endothelin-1 receptors ETA and ETB, leading to a reduction in vasoconstrictor tone and a greater magnitude of vasodilator responses.
Other Names:
  • Tracleer
Placebo Comparator: Placebo (Aim 2)
Upon arriving at the laboratory, participants will ingest a liquid mixture containing a placebo.
Drug: Bosentan 125 mg
Bosentan blocks endothelin-1 receptors ETA and ETB, leading to a reduction in vasoconstrictor tone and a greater magnitude of vasodilator responses.
Other Names:
  • Tracleer

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Flow-mediated Dilation
Time Frame: Within 4 hours of drug/supplement administration.
The percent change in arterial diameter normalized to arterial shear rate during reperfusion after 5 minutes of circulatory occlusion.
Within 4 hours of drug/supplement administration.
Reactive Hyperemia (Cuff Release)
Time Frame: Within 4 hours of drug/supplement administration.
Blood velocity area-under-the-curve from the beginning of reperfusion to return to resting values.
Within 4 hours of drug/supplement administration.
Muscle Hyperemia (Passive Leg Movement)
Time Frame: Within 4 hours of drug/supplement administration.
Peak and the area-under-the-curve of the change in femoral artery blood flow during 1 minute of passive leg movement.
Within 4 hours of drug/supplement administration.
Muscle Hyperemia (Rhythmic Handgrip Exercise)
Time Frame: Baseline measurements with no drug/supplement administration before or after.
Changes in brachial artery blood flow and conductance during single handgrip contractions at 3 intensities.
Baseline measurements with no drug/supplement administration before or after.
Muscle Hyperemia (Rhythmic Knee Extension Exercise)
Time Frame: Within 4 hours of drug/supplement administration.
Changes in femoral artery blood flow and conductance during 3 minutes of rhythmic knee extension exercise.
Within 4 hours of drug/supplement administration.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Mississippi Medical Center

Investigators

  • Principal Investigator: Thales C Barbosa, Ph.D., University of Mississippi Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 27, 2021

Primary Completion (Actual)

September 20, 2021

Study Completion (Actual)

September 20, 2021

Study Registration Dates

First Submitted

February 16, 2021

First Submitted That Met QC Criteria

February 22, 2021

First Posted (Actual)

February 25, 2021

Study Record Updates

Last Update Posted (Actual)

October 31, 2023

Last Update Submitted That Met QC Criteria

October 6, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2P20GM104357-08 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Doppler ultrasound videos, analog-digital recordings, participants' characteristics, and randomization codes will be available in an unidentified format.

IPD Sharing Time Frame

On Jan 1st, 2025 for one year.

IPD Sharing Access Criteria

By request.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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