The Effect of Endothelin and L-Arginine on Racial Differences in Vasoconstriction

NCT03679780 | Completed Phase 1 FDA Drug

• 1 other identifier: 2018-0648
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of the study is to examine the possible mechanisms of impaired cutaneous microvascular function through local heating along with administration of vasoconstrictors.

Conditions

Cardiovascular Diseases; Cardiovascular Risk Factor; Vasoconstriction

Keywords

Racial Differences; Oxidative Stress

Outcome Measures

Primary Outcomes (1)

• Vasodilatory Response to Endothelin Receptor-A/B Blockers and L-Arginine following local heating as assessed by Intradermal Microdialysis and Laser Doppler Fluxmetry

  Determine to what extent overactivation of Endothelin Receptor Type A/B or L-Arginine deficiencies have on vasodilatory capacity by delivering specific Endothelin receptor agonists or supplemental L-Arginine via intradermal microdialysis. Vasodilation will be elicited by local heating and changes in skin blood flux will be assessed via laser Doppler fluxmetry. All changes in skin blood flux will be normalized and reported as a percentage of maximal flux.

  Through study completion, an average of 1 Year

Study Arms (4)

Control

ACTIVE COMPARATOR

This site will serve as the control site and will receive lactated Ringer's (saline solution) (2 µl/min) throughout the entire duration of the protocol. This site will additionally receive 20mM L-NAME and 28mM SNP to inhibit nitric oxide (NO) production and elicit vasodilation, respectively, to assess NO contribution and maximal vasodilation.

Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside; Drug: Lactated Ringer's

Inhibitor of Endothelin Type B Receptor

EXPERIMENTAL

This site will receive 300 nM BQ-788, an inhibitor of the endothelin type B receptors. This site will additionally receive 20mM L-NAME and 28mM SNP to inhibit nitric oxide (NO) production and elicit vasodilation, respectively, to assess NO contribution and maximal vasodilation.

Drug: BQ-788; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside

Inhibition of Endothelin Type A Receptor

EXPERIMENTAL

This site will receive 500 nM aBQ-123, an inhibitor of endothelin type A receptors. This site will additionally receive 20mM L-NAME and 28mM SNP to inhibit nitric oxide (NO) production and elicit vasodilation, respectively, to assess NO contribution and maximal vasodilation.

Drug: BQ-123; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside

L-Arginine

EXPERIMENTAL

This site will receive 10 mM L-Arginine to supplement the substrate for endothelial nitric oxide synthase. This site will additionally receive 20mM L-NAME and 28mM SNP to inhibit nitric oxide (NO) production and elicit vasodilation, respectively, to assess NO contribution and maximal vasodilation.

Drug: L-Arginine; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside

Interventions

BQ-788 DRUG

This intervention is aimed at blocking endothelin type B receptors to assess racial differences during vasoconstriction. The infusion rate will be 2 µl/min

Inhibitor of Endothelin Type B Receptor

BQ-123 DRUG

This intervention is aimed at blocking endothelin type A receptors to assess racial differences during vasoconstriction. The infusion rate will be 2 µl/min

Inhibition of Endothelin Type A Receptor

L-Arginine DRUG

A substrate that is administered to increase endogenous nitric oxide production. The infusion rate will be 2 µl/min

L-Arginine

NG Nitro L Arginine Methyl Ester DRUG

L-Name is a NOS inhibitor that is administered to each site to allow for the quantification of NO contribution to vasodilation. The infusion rate will be 2 µl/min

Also known as: L-Name

Control; Inhibition of Endothelin Type A Receptor; Inhibitor of Endothelin Type B Receptor; L-Arginine

Sodium Nitroprusside DRUG

SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min

Also known as: SNP

Control; Inhibition of Endothelin Type A Receptor; Inhibitor of Endothelin Type B Receptor; L-Arginine

Lactated Ringer's DRUG

Lactated Ringer will serve as the control site. The infusion rate will be 2 µl/min

Control

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Individuals (ages 18-35, both genders) will be recruited from the greater Arlington area to participate in the study.
• Must self-report both parents as either African American or Caucasian American.

You may not qualify if:

• Individuals with cardiovascular, neurological, and/or metabolic illnesses will be excluded from participating as well as individuals with a history of various diseases of the microvasculature including Reynaud's disease, cold-induced urticaria, cryoglobulinemia, etc.
• Subjects currently taking any prescription medications and individuals with a body mass index about 30 kg/m2) will be excluded.
• Pregnant subjects and children (i.e. younger than 18) will not be recruited for the study. Eligible females will be scheduled for days 2-7 of their menstrual cycle to account for hormonal effects on blood flow. A regular menstrual cycle is required to identify and schedule the study for the low hormone period, therefore females who lack a regular cycle will be excluded from the study. Females currently taking birth control are eligible, as long as they can be scheduled during a low-hormone "placebo" week. If their hormone do not contain a placebo week than these individuals will not be eligible for data collection. Females who are breast-feeding will also be eligible as there are no systemic or lasting effects of the proposed vasoactive agents.
• Given that smoking can affect the peripheral vasculature, current smokers and individuals who regularly smoked (\>1 pack per two weeks) within the prior 2 years will be excluded

Sponsors & Collaborators

• The University of Texas at Arlington: lead

Study Sites (1)

Science and Engineering Research and Innovation Building

Arlington, Texas, 76019, United States

Location

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

BQ 788; cyclo(Trp-Asp-Pro-Val-Leu); Arginine; NG-Nitroarginine Methyl Ester; Nitroprusside; Ringer's Lactate

Intervention Hierarchy (Ancestors)

Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Each subject has one control site and three experimental sites concurrently tested within the same study using intradermal microdialysis on the dorsal forearm.

Study Record Dates

• First Submitted: September 17, 2018
• First Posted: September 20, 2018
• Study Start: October 1, 2018
• Primary Completion: July 26, 2023
• Study Completion: July 26, 2023
• Last Updated: June 11, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)