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

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.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- Individuals who have donated more than 550 ml of blood within the past 8 weeks will
not have blood drawn from them in this protocol. However, if they remain interested in
the study, and otherwise meet the inclusion criteria, than we may still opt to proceed
with data collection.

- 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