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

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

EARLY_PHASE1

Total Enrollment

8 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-05-27

Study Completion Date

2021-09-20

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Vascular Function Racial Disparity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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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).

Group Type ACTIVE_COMPARATOR

Dietary Nitrates 400 mg

Intervention Type 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.

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).

Group Type PLACEBO_COMPARATOR

Dietary Nitrates 400 mg

Intervention Type 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.

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.

Group Type ACTIVE_COMPARATOR

L-citrulline 3 g

Intervention Type 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.

Placebo (Aim 1b)

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

Group Type PLACEBO_COMPARATOR

L-citrulline 3 g

Intervention Type 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.

Sildenafil (Aim 1c)

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

Group Type ACTIVE_COMPARATOR

Sildenafil 100 mg

Intervention Type 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.

Placebo (Aim 1c)

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

Group Type PLACEBO_COMPARATOR

Sildenafil 100 mg

Intervention Type 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.

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.

Group Type ACTIVE_COMPARATOR

Bosentan 125 mg

Intervention Type DRUG

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

Placebo (Aim 2)

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

Group Type PLACEBO_COMPARATOR

Bosentan 125 mg

Intervention Type DRUG

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

Interventions

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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.

Intervention Type 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.

Intervention Type DIETARY_SUPPLEMENT

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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Beet It Sport Nitrate 400 Viagra, Revatio Tracleer

Eligibility Criteria

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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)

Minimum Eligible Age

18 Years

Maximum Eligible Age

40 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes