Local Antioxidant Therapy Vasoconstriction Effects in Different Races
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 35 |
| Updated: | 2/1/2019 |
| Start Date: | October 15, 2018 |
| End Date: | August 31, 2019 |
| Contact: | R. Matthew Brothers, PhD |
| Email: | matthew.brothers@uta.edu |
| Phone: | 8172723156 |
The Effect of Local Antioxidant Therapy 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. As has been previously observed, BL exhibit a heightened vasoconstrictor
response to both pharmacological (e.g., alpha-adrenergic receptor agonists) and environmental
(e.g., cold pressor test) stimuli compared to their WH counterparts. Additionally, reactive
oxygen species (ROS) and the subsequent reduction in nitric oxide (NO) bioavailability may
partially mediate this response. Our laboratory has recently observed (UTA IRB 2016-0268)
that the small blood vessels in the skin (cutaneous microvasculature) in BL, but otherwise
healthy individuals, produce an impaired blood flow response to local heating when compared
to age-, body mass index (BMI)-, and gender-matched WH. However, pre-treatment of the
cutaneous microvasculature with various antioxidants abolishes this skin blood flow
difference. These antioxidant drugs inhibit possible sources of ROS, which, as mentioned,
maybe mediating the heightened vasoconstrictor response in BL. However, this has not been
investigated in this population and thus remains unknown. Therefore, the purpose of this
study proposal is to test the following hypotheses: 1) BL will have a greater reduction in
cutaneous blood flow in response to local administration of Norepinephrine (alpha1-adrenergic
and alpha 2-adrenergic receptor agonist) relative to WH. 2) This greater reduction in the BL
population will be related to elevated oxidative stress and subsequent reduction in
bioavailability of the potent vasodilator Nitric oxide.
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. As has been previously observed, BL exhibit a heightened vasoconstrictor
response to both pharmacological (e.g., alpha-adrenergic receptor agonists) and environmental
(e.g., cold pressor test) stimuli compared to their WH counterparts. Additionally, reactive
oxygen species (ROS) and the subsequent reduction in nitric oxide (NO) bioavailability may
partially mediate this response. Our laboratory has recently observed (UTA IRB 2016-0268)
that the small blood vessels in the skin (cutaneous microvasculature) in BL, but otherwise
healthy individuals, produce an impaired blood flow response to local heating when compared
to age-, body mass index (BMI)-, and gender-matched WH. However, pre-treatment of the
cutaneous microvasculature with various antioxidants abolishes this skin blood flow
difference. These antioxidant drugs inhibit possible sources of ROS, which, as mentioned,
maybe mediating the heightened vasoconstrictor response in BL. However, this has not been
investigated in this population and thus remains unknown. Therefore, the purpose of this
study proposal is to test the following hypotheses: 1) BL will have a greater reduction in
cutaneous blood flow in response to local administration of Norepinephrine (alpha1-adrenergic
and alpha 2-adrenergic receptor agonist) relative to WH. 2) This greater reduction in the BL
population will be related to elevated oxidative stress and subsequent reduction in
bioavailability of the potent vasodilator Nitric oxide.
Collectively, these studies will provide novel data and insight into the impact of heightened
vasoconstrictor responses in BL on vascular function. Interested participants will be asked
to come in the fasted state (a minimum of 3 hr since the last meal) and to have refrained
from alcohol, caffeine, and physical activity for 24 hr. We will first review the
inclusion/exclusion criteria and discuss the informed consent form including an oral
explanation of the study purpose, experimental procedures and measurements, and potential
risks and benefits associated with participation. Prior to any screening/testing, all
subjects will provide written, informed consent. A medical health history questionnaire will
then be completed by the subject and subsequently reviewed by the research team to determine
eligibility. For the qualified participants, to test the aforementioned hypotheses, we will
use laser Doppler to assess the skin blood flow response to local administration of the
sympathomimetic drug-norepinephrine which is an alpha-1 and alpha-2 -adrenergic receptor
agonist. Each participant will be instrumented with four cutaneous microdialysis fibers in
the skin of the non-dominant forearm. Each of the following conditions will be randomly
assigned to an individual microdialysis site. Experimental sites will then be infused with
their respective vasoactive agents at a rate of 2 μl/min for a 30 min wash-in period. Site 1:
This site will serve as the control site and will receive lactated Ringer's (saline
solution). Site2: This site will receive 20 mM L-NAME (Nω-Nitro-L-arginine methyl ester
hydrochloride, Sigma Aldrich) to inhibit nitric oxide production by nitric oxide synthase.
This site will then be infused with no more than 10mM of norepinephrine to elicit
vasoconstriction. Site 3: This site will receive 10 mM Ascorbic Acid which serves as a
non-selective antioxidant. Ascorbic acid is commonly known as Vitamin C. This site will then
be infused with no more than 10mM of norepinephrine to elicit vasoconstriction. Site 4: This
site will receive a combination of 20mM L-NAME + 10 mM ascorbic acid. This site will then be
infused with incremental doses of 10-8M - 10-2M of norepinephrine to elicit vasoconstriction.
This dose and approach is commonly utilized in these types of studies. After the 30-min
wash-in period, 15-min of baseline data will be collected with local heaters set to
33°C(91.4°F). After 15 min of baseline data collection, the perfusate at each site will be
switched to various concentrations of norepinephrine combined with the respective vasoactive
agent for each site-incremental doses of 10-8M - 10-2M (no more than 10mM(10-2M) at a rate of
2 μl/min for a brief period (no more than 6-min each dose) to quantify the level of
vasoconstriction at each site. The order of the procedure will be as follows: 1.
Instrumentation with membranes. 2. Wash-in perfusion with vasoactive agent at respective site
(each site will receive its respective vasoactive agent simultaneously). Temperature set at
33°C(91.4°F). 3. Baseline data collection. Temperature set at 33 degree C(91.4°F). 4. Switch
to Norepinephrine + combined vasoactive agent (for each respective site) infusion.
Temperature set at 33 degree C(91.4°F). 5. Repeat step 4 for each concentration of
norepinephrine used. As commonly done in these types of studies there will not be any flushes
of Ringer's solution between doses of NE. In addition we will also measure blood flow in the
brachial artery using Doppler ultrasound during resting conditions as well as during a
standard flow mediated dilation (FMD) protocol. This includes inflating a blood pressure cuff
to suprasystolic pressures (pressure slightly above the participant's systolic blood
pressure) for 5 min and making continuous blood flow measures before and after release of the
cuff. This will be performed on the upper arm in the brachial artery. This is a standard
procedure used in numerous clinical investigations to estimate endothelial function with no
reports of injury or adverse events. Subject Participation: During the course of the study, a
subject may decide not to participate in a particular experimental measurement or procedure
and therefore, this portion of the protocol will not be completed. However, all other
measurements and procedures will be performed. This will not affect the scientific value of
the subject's participation as each experimental measurement and procedure provides important
and in most cases independent information.
vasoconstrictor responses in BL on vascular function. Interested participants will be asked
to come in the fasted state (a minimum of 3 hr since the last meal) and to have refrained
from alcohol, caffeine, and physical activity for 24 hr. We will first review the
inclusion/exclusion criteria and discuss the informed consent form including an oral
explanation of the study purpose, experimental procedures and measurements, and potential
risks and benefits associated with participation. Prior to any screening/testing, all
subjects will provide written, informed consent. A medical health history questionnaire will
then be completed by the subject and subsequently reviewed by the research team to determine
eligibility. For the qualified participants, to test the aforementioned hypotheses, we will
use laser Doppler to assess the skin blood flow response to local administration of the
sympathomimetic drug-norepinephrine which is an alpha-1 and alpha-2 -adrenergic receptor
agonist. Each participant will be instrumented with four cutaneous microdialysis fibers in
the skin of the non-dominant forearm. Each of the following conditions will be randomly
assigned to an individual microdialysis site. Experimental sites will then be infused with
their respective vasoactive agents at a rate of 2 μl/min for a 30 min wash-in period. Site 1:
This site will serve as the control site and will receive lactated Ringer's (saline
solution). Site2: This site will receive 20 mM L-NAME (Nω-Nitro-L-arginine methyl ester
hydrochloride, Sigma Aldrich) to inhibit nitric oxide production by nitric oxide synthase.
This site will then be infused with no more than 10mM of norepinephrine to elicit
vasoconstriction. Site 3: This site will receive 10 mM Ascorbic Acid which serves as a
non-selective antioxidant. Ascorbic acid is commonly known as Vitamin C. This site will then
be infused with no more than 10mM of norepinephrine to elicit vasoconstriction. Site 4: This
site will receive a combination of 20mM L-NAME + 10 mM ascorbic acid. This site will then be
infused with incremental doses of 10-8M - 10-2M of norepinephrine to elicit vasoconstriction.
This dose and approach is commonly utilized in these types of studies. After the 30-min
wash-in period, 15-min of baseline data will be collected with local heaters set to
33°C(91.4°F). After 15 min of baseline data collection, the perfusate at each site will be
switched to various concentrations of norepinephrine combined with the respective vasoactive
agent for each site-incremental doses of 10-8M - 10-2M (no more than 10mM(10-2M) at a rate of
2 μl/min for a brief period (no more than 6-min each dose) to quantify the level of
vasoconstriction at each site. The order of the procedure will be as follows: 1.
Instrumentation with membranes. 2. Wash-in perfusion with vasoactive agent at respective site
(each site will receive its respective vasoactive agent simultaneously). Temperature set at
33°C(91.4°F). 3. Baseline data collection. Temperature set at 33 degree C(91.4°F). 4. Switch
to Norepinephrine + combined vasoactive agent (for each respective site) infusion.
Temperature set at 33 degree C(91.4°F). 5. Repeat step 4 for each concentration of
norepinephrine used. As commonly done in these types of studies there will not be any flushes
of Ringer's solution between doses of NE. In addition we will also measure blood flow in the
brachial artery using Doppler ultrasound during resting conditions as well as during a
standard flow mediated dilation (FMD) protocol. This includes inflating a blood pressure cuff
to suprasystolic pressures (pressure slightly above the participant's systolic blood
pressure) for 5 min and making continuous blood flow measures before and after release of the
cuff. This will be performed on the upper arm in the brachial artery. This is a standard
procedure used in numerous clinical investigations to estimate endothelial function with no
reports of injury or adverse events. Subject Participation: During the course of the study, a
subject may decide not to participate in a particular experimental measurement or procedure
and therefore, this portion of the protocol will not be completed. However, all other
measurements and procedures will be performed. This will not affect the scientific value of
the subject's participation as each experimental measurement and procedure provides important
and in most cases independent information.
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
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