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

NCT04770155 | Terminated Early Phase 1 Results FDA Drug

• 1 other identifier: 2P20GM104357-08
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Vascular Function; Racial Disparity

Keywords

Black; African American; White; Caucasian American; Hyperemia; Blood Flow; Conductance

Outcome Measures

Primary Outcomes (5)

• Flow-mediated Dilation

  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)

  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)

  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)

  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)

  Changes in femoral artery blood flow and conductance during 3 minutes of rhythmic knee extension exercise.

  Within 4 hours of drug/supplement administration.

Study Arms (8)

Beetroot juice (Aim 1a)

ACTIVE COMPARATOR

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

Placebo (Aim 1a)

PLACEBO COMPARATOR

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

L-citrulline (Aim 1b)

ACTIVE COMPARATOR

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

Placebo (Aim 1b)

PLACEBO COMPARATOR

Participants will receive pills containing a placebo to take twice daily for 7 days before the study visit.

Dietary Supplement: L-citrulline 3 g

Sildenafil (Aim 1c)

ACTIVE COMPARATOR

Upon arriving at the laboratory, participants will ingest a liquid mixture containing Sildenafil (100 mg), an inhibitor of phosphodiesterase 5.

Drug: Sildenafil 100 mg

Placebo (Aim 1c)

PLACEBO COMPARATOR

Upon arriving at the laboratory, participants will ingest a liquid mixture containing a placebo.

Drug: Sildenafil 100 mg

Bosentan (Aim 2)

ACTIVE COMPARATOR

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

Placebo (Aim 2)

PLACEBO COMPARATOR

Upon arriving at the laboratory, participants will ingest a liquid mixture containing a placebo.

Drug: Bosentan 125 mg

Interventions

Dietary Nitrates 400 mg DIETARY_SUPPLEMENT

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.

Also known as: Beet It Sport Nitrate 400

Beetroot juice (Aim 1a); Placebo (Aim 1a)

L-citrulline 3 g DIETARY_SUPPLEMENT

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.

L-citrulline (Aim 1b); Placebo (Aim 1b)

Sildenafil 100 mg DRUG

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.

Also known as: Viagra, Revatio

Placebo (Aim 1c); Sildenafil (Aim 1c)

Bosentan 125 mg DRUG

Bosentan blocks endothelin-1 receptors ETA and ETB, leading to a reduction in vasoconstrictor tone and a greater magnitude of vasodilator responses.

Also known as: Tracleer

Bosentan (Aim 2); Placebo (Aim 2)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• University of Mississippi Medical Center: lead

Study Sites (1)

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Related Publications (5)

• Barbosa TC, Young BE, Stephens BY, Nandadeva D, Kaur J, Keller DM, Fadel PJ. Functional sympatholysis is preserved in healthy young Black men during rhythmic handgrip exercise. Am J Physiol Regul Integr Comp Physiol. 2020 Sep 1;319(3):R323-R328. doi: 10.1152/ajpregu.00105.2020. Epub 2020 Aug 12.

  PMID: 32783690 BACKGROUND

• Barbosa TC, Kaur J, Stephens BY, Akins JD, Keller DM, Brothers RM, Fadel PJ. Attenuated forearm vascular conductance responses to rhythmic handgrip in young African-American compared with Caucasian-American men. Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1316-H1321. doi: 10.1152/ajpheart.00387.2018. Epub 2018 Aug 17.

  PMID: 30118345 BACKGROUND

• Kaur J, Barbosa TC, Nandadeva D, Young BE, Stephens BY, Brothers RM, Fadel PJ. Attenuated Rapid-Onset Vasodilation to Forearm Muscle Contraction in Black Men. Med Sci Sports Exerc. 2021 Mar 1;53(3):590-596. doi: 10.1249/MSS.0000000000002511.

  PMID: 32910095 BACKGROUND

• Young BE, Kaur J, Vranish JR, Stephens BY, Barbosa TC, Cloud JN, Wang J, Keller DM, Fadel PJ. Augmented resting beat-to-beat blood pressure variability in young, healthy, non-Hispanic black men. Exp Physiol. 2020 Jul;105(7):1102-1110. doi: 10.1113/EP088535. Epub 2020 May 27.

  PMID: 32362031 BACKGROUND

• Vranish JR, Holwerda SW, Young BE, Credeur DP, Patik JC, Barbosa TC, Keller DM, Fadel PJ. Exaggerated Vasoconstriction to Spontaneous Bursts of Muscle Sympathetic Nerve Activity in Healthy Young Black Men. Hypertension. 2018 Jan;71(1):192-198. doi: 10.1161/HYPERTENSIONAHA.117.10229. Epub 2017 Dec 4.

  PMID: 29203629 BACKGROUND

MeSH Terms

Conditions

Hyperemia

Interventions

Citrulline; Sildenafil Citrate; Bosentan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzenesulfonamides; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Pyrimidines

Limitations and Caveats

The only data collected were baseline measurements and no participants were ever given either intervention; the investigator was never able to obtain the treatments to use for the planned intervention arm of the study, resulting in its termination.

Results Point of Contact

• Title: Director of Clinical Trials
• Organization: University of Mississippi Medical Center

clinicaltrials@umc.edu

601-815-5000

Study Officials

• Thales C Barbosa, Ph.D.

  University of Mississippi Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor

Study Record Dates

• First Submitted: February 16, 2021
• First Posted: February 25, 2021
• Study Start: May 27, 2021
• Primary Completion: September 20, 2021
• Study Completion: September 20, 2021
• Last Updated: October 31, 2023
• Results First Posted: October 31, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: On Jan 1st, 2025 for one year.
• Access Criteria: By request.

Locations

US (1)