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

University of Mississippi

Status and phase: Terminated; Early Phase 1

Conditions: Racial Disparity; Vascular Function

Treatments: Drug: Sildenafil 100 mg; Dietary Supplement: Dietary Nitrates 400 mg; Dietary Supplement: L-citrulline 3 g; Drug: Bosentan 125 mg

Study type: Interventional

Funder types: Other

Identifiers

NCT04770155

2P20GM104357-08

Details and patient eligibility

About

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.

Full 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.

Enrollment: 8 patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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)

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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8 participants in 8 patient groups, including a placebo group

Beetroot juice (Aim 1a)

Active Comparator group

Description:

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).

Treatment:

Dietary Supplement: Dietary Nitrates 400 mg

Placebo (Aim 1a)

Placebo Comparator group

Description:

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).

Treatment:

Dietary Supplement: Dietary Nitrates 400 mg

L-citrulline (Aim 1b)

Active Comparator group

Description:

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.

Treatment:

Dietary Supplement: L-citrulline 3 g

Placebo (Aim 1b)

Placebo Comparator group

Description:

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

Treatment:

Dietary Supplement: L-citrulline 3 g

Sildenafil (Aim 1c)

Active Comparator group

Description:

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

Treatment:

Drug: Sildenafil 100 mg

Placebo (Aim 1c)

Placebo Comparator group

Description:

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

Treatment:

Drug: Sildenafil 100 mg

Bosentan (Aim 2)

Active Comparator group

Description:

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.

Treatment:

Drug: Bosentan 125 mg

Placebo (Aim 2)

Placebo Comparator group

Description:

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

Treatment:

Drug: Bosentan 125 mg