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

Vascular Function Clinical Trial

— UMMC_Pilot  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04770155
• Other study ID #: 2P20GM104357-08
• Status: Terminated
• Phase: Early Phase 1
• Start date: May 27, 2021
• Est. completion date: September 20, 2021

Study information

• Verified date: October 2023
• Source: University of Mississippi Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 8
• Est. completion date: September 20, 2021
• Est. primary completion date: September 20, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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)

Related Conditions & MeSH terms

• Racial Disparity
• Vascular Function

Intervention

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.
• 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.

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.
• 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.

Locations

Country	Name	City	State
United States	University of Mississippi Medical Center	Jackson	Mississippi

Sponsors (1)

Lead Sponsor	Collaborator
University of Mississippi Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.