NCT03679780

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 19 (actual)
• Sponsor: The University of Texas at Arlington · Academic / Other
• Sex: All
• Age: 18 Years – 35 Years
• Healthy volunteers: Accepted

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.

Detailed description

Cardiovascular disease (CVD) afflicts nearly one-third of the adult population with all races and ethnicities represented in CVD prevalence. Unfortunately, a disparity exists such that the black population (BL) is disproportionately affected compared to other groups, including the white population (WH). While the underlying cause of this disparity is multifactorial, vascular dysfunction (i.e., impaired vasodilation and/or augmented vasoconstriction) is a key contributor. Across a series of studies conducted in our laboratory we have consistently observed impaired microvascular function in the small blood vessels in the skin (the cutaneous microvasculature) in AA relative to age, sex, and body mass index Caucasian Americans (CA). From a research design perspective this offers the opportunity to conduct minimally invasive studies while investigating research questions in a systematic and mechanistic manner. Furthermore, the cutaneous circulation is recognized as surrogate vascular bed for assessment of mechanisms underlying systemic vascular disease and microvascular dysfunction is emerging as a critical step in the artherosclerotic process and a variety of conditions including hypertension, exercise intolerance, and insulin resistance. And, impaired cutaneous microvascular function mirrors impaired responses in other vascular beds. A primary advantage to utilizing the cutaneous circulation is that it provides an accessible vascular bed through which processes of endothelial function can be investigated, with virtually no risk, through thermal stimuli and local intra-dermal drug infusions. In terms of the AA population our group and others have documented that impaired vascular function and elevated disease risk is related, in part, to reductions in bioavailability of the potent vasodilator Nitric oxide (NO). While, this has become fairly common knowledge what remains less well defined is the mechanisms of this reduced NO bioavailability. We have recently identified a role for oxidative stress in this process. However, oxidative stress is a complex process and likely does not explain all of the observed impairment. 2 other possibilities that are attractive candidate targets for mechanistic studies are the endothelin pathway as well as bioavailability of L-Arginine. Endothelin is a hormone that has been implicated in many populations with elevated CVD risk as it is a potent vasoconstrictor which also can reduce NO bioavailability. Interestingly, there are reports of elevated endothelin circulating concentration and/or increased sensitivity and thus vasoconstriction to endothelin in AA. L-Arginine is a naturally occurring amino acid that is required for the full endogenous production of NO. In other words reduced L-Arginine bioavailability is present in many disease conditions and contributes to vascular dysfunction. In regards to AA it is reported that they have reduced natural production of L-arginine and also respond more positively to intra coronary infusion of L-arginine relative to other populations. However, to our knowledge the role of the endothelin system as well as L-arginine in microvascular dysfunction in AA has never been investigated.

Conditions

• Cardiovascular Diseases
• Cardiovascular Risk Factor
• Vasoconstriction

Interventions

Type	Name	Description
DRUG	BQ-788	This intervention is aimed at blocking endothelin type B receptors to assess racial differences during vasoconstriction. The infusion rate will be 2 µl/min
DRUG	BQ-123	This intervention is aimed at blocking endothelin type A receptors to assess racial differences during vasoconstriction. The infusion rate will be 2 µl/min
DRUG	L-Arginine	A substrate that is administered to increase endogenous nitric oxide production. The infusion rate will be 2 µl/min
DRUG	NG Nitro L Arginine Methyl Ester	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
DRUG	Sodium Nitroprusside	SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min
DRUG	Lactated Ringer's	Lactated Ringer will serve as the control site. The infusion rate will be 2 µl/min

Timeline

• Start date: 2018-10-01
• Primary completion: 2023-07-26
• Completion: 2023-07-26
• First posted: 2018-09-20
• Last updated: 2024-06-11

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study