Clinical trial NCT03371823
Conditions: Cardiovascular Diseases Hypertension
Keywords: Hypertension Endothelin-1 receptor
Sponsor: University of Delaware
Start date: 2017-09-01; Completion date: 2019-12-31
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the role of ET-1 in mediating vasoconstrictor tone in hypertensive postmenopausal women (PMW) alone and in combination with a commonly prescribed Angiotensin II (ANG II) antagonist. The long term goal is to understand the mechanisms contributing to hypertension (HTN) in PMW. This study is the first step in reaching our goal.

Detailed description:
Cardiovascular disease (CVD) is the leading cause of death in women, and mortality from CVD is higher in PMW compared to age-matched men. PMW are at a greater risk for developing HTN, a major risk factor for CVD. They are also more likely to have uncontrolled or resistant HTN despite medication.

ANG II is a common therapeutic target for the treatment HTN. ANG II blockade is highly effective in normalizing blood pressure (BP) in hypertensive male rats, but does not reduce BP to the same degree in hypertensive post menopausal female rats. Endothelin-1 (ET-1) receptor antagonists reduce BP in hypertensive postmenopausal female rats, but have no effect on males. Thus the mechanisms contributing to HTN in female rats and likely women, particularly after menopause, are complex, multifactorial and not completely understood.

After menopause, the vasoconstrictor effects of both ANG II and ET-1 are amplified in animal models. As such, these two predominant pathways may contribute to the high incidence of HTN in PMW. ET-1 is a potent vasoconstrictor produced and released by endothelial cells that binds to two receptor subtypes, ET-A and ET-B. While both receptors are located on vascular smooth muscle (VSM) and mediate vasoconstriction, ET-B receptors are also located on the endothelium and mediate vasodilation via nitric oxide.

Importantly, the production of ET-1 and expression of ET-A and B receptors can be modulated by hormones such as estradiol and ANG II. Estradiol attenuates ET-1 production, and reduces ET-1 mediated vasoconstriction via an ET-B receptor mechanism in vitro. Thus, decline in estradiol after menopause may enhance vasoconstrictor tone via ET-1 and lead to HTN. ET-1 also potentiates the vasoconstrictor effects of ANG II since the vasoconstrictor and hypertensive effects of ANG II are ameliorated by ET-1 receptor blockade. Additionally, ANG II stimulates the synthesis of ET-1 and upregulates ET-A and ET-B receptor expression on VSM. The ANG II receptor antagonist Losartan reduces ET-A and ET-B receptor expression and attenuates the constrictor effects of ET-1 in a diabetic rat model. Therefore, ET-1 is an important independent factor contributing to HTN in PMW, but therapeutic agents targeting both ANG II and ET-1 may have greater efficacy given their interactions.

The investigators propose a comprehensive assessment of vascular function by measuring blood flow responses in the cutaneous circulation during perfusion of ET-1 receptor antagonists via microdialysis, combined with measures of intracellular protein and receptor expression of endothelial cells and skin punch biopsies collected from normotensive and hypertensive PMW. Investigators central hypothesis is that hypertensive PMW have greater ET-1 mediated vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on endothelial cells and up-regulation of both ET-A and ET-B receptors on VSM leading to increased vasoconstriction and HTN. Investigators further hypothesize that ANG II exacerbates the increase in ET-1, and ET-A and ET-B receptor expression contributing to exaggerated constriction with HTN in PMW.

Arms: arm 1: Normotensive PMW will complete an experimental visit to assess vascular function. All women will wear an ambulatory BP monitor during the 24 hours preceding the experimental visit to confirm BP classification. Large blood vessel function will be assessed using two non-invasive techniques: 1. Flow Mediated Dilation (FMD) 2. Pulse Wave Analysis and Pulse Wave Velocity. ET-1 mediated vasoconstrictor tone is assessed by measuring the cutaneous blood flow during microdialysis perfusions of ET-A and ET-B receptor antagonist. ET-1 production, ET-A and ET-B receptor expression is assessed from antecubital vein endothelial cells and skin punch biopsy samples. arm 2: Hypertensive women will be tested at baseline and then administered Losartan 50 mg once a day at night for 14 days. Vascular function is measured at baseline and again after 2 weeks of losartan. All women will wear an ambulatory BP monitor during the 24 hours preceding the experimental visits to confirm BP classification. Large blood vessel function will be assessed using two non-invasive techniques: 1. Flow Mediated Dilation (FMD) 2. Pulse Wave Analysis and Pulse Wave Velocity. ET-1 mediated vasoconstrictor tone is assessed by measuring the cutaneous blood flow during microdialysis perfusions of ET-A and ET-B receptor antagonist. ET-1 production, ET-A and ET-B receptor expression is assessed from antecubital vein endothelial cells and skin punch biopsy samples.
Interventions: intervention 1: Normotensive intervention 2: Hypertensives
Intervention descriptions: intervention 1: FMD is a measure of endothelial function by assessing the degree to which vessel dilates in response to increased flow. Pulse Wave Analysis and Pulse Wave Velocity assesses arterial stiffness and wave reflection in all women. Laser Doppler flowmetry is used in combination with cutaneous microdialysis as a minimally invasive technique to examine mechanisms of vascular function. ET-B and ET-A receptor antagonists will be perfused via intradermal microdialysis fibers while measuring cutaneous blood flow. ET-1 production and ET-B receptor expression in endothelial cells collected from an antecubital vein will also be assessed. Immunohistochemistry will be performed on skin punch biopsy samples to assess for protein expression of ET-A and ET-B receptors. intervention 2: ANG II increases the synthesis of ET-1 and alters ET-A/B receptor expression, thus affecting ET-1 bioavailability. Losartan is an ANG II receptor antagonist which attenuates ET-1 production. Losartan 50 mg daily is administered for 14 days to hypertensive women. FMD is used to measure endothelial function. Pulse Wave Analysis and Pulse Wave Velocity assesses arterial stiffness and wave reflection. Laser Doppler flowmetry with cutaneous microdialysis is used to examine vascular function when ET-A and ET-B receptor antagonists is perfused via intradermal microdialysis fibers. ET-1 production and ET-B receptor expression in endothelial cells collected from an antecubital vein will be assessed. Skin punch biopsy samples will be used to assess for protein expression of ET-A and ET-B receptors.

Protocol documents:
Prot_SAP_003.pdf: 
Vascular Dysfunction in Hypertensive Postmenopausal Women 
 
Registered Clinical Trial # NCT03371823 
 
IRB Protocol Approved February 13, 2019 


 
HUMAN SUBJECTS PROTOCOL  
University of Delaware 
 
Protocol Title: Losartan and ET-1 mediated constriction in postmenopausal women with high blood 
pressure 
 
 
 
  
 
Principal Investigator   
 
 
Name:  Megan M. Wenner, PhD 
 
Department/Center:  KAAP 
 
Contact Phone Number:  302.831.7343 
 
Email Address:  mwenner@udel.edu 
 
Advisor (if student PI):  
 
Name: 
 
Contact Phone Number: 
 
Email Address:  
 
Other Investigators:  Michael Stillabower, MD.  
 
 
 
 
Investigator Assurance: 
 
By submitting this protocol, I acknowledge that this project will be conducted in strict accordance 
with the procedures described. I will not make any modifications to this protocol without prior 
approval by the IRB. Should any unanticipated problems involving risk to subjects occur during this 
project, including breaches of guaranteed confidentiality or departures from any procedures 
specified in approved study documents, I will report such events to the Chair, Institutional Review 
Board immediately.   
 
 
 
1.  Is this project externally funded? X YES  □ NO 
 
If so, please list the funding source:  COBRE (NIH) 
 
 
2. Research Site(s) 
 
X University of Delaware 
□ Other (please list external study sites) 
 
 
Is UD the study lead?  X YES □ NO (If no, list the institution that is serving as the study 
lead) 
 
 
 
 
 
 


 
 
 
4.  Special Populations 
Does this project involve any of the following: 
 
Research on Children?   No 
 
Research with Prisoners?  No 
 
If yes, complete the Prisoners in Research Form and upload to IRBNet as supporting documentation 
 
Research with Pregnant Women?  No 
 
Research with any other vulnerable population (e.g. cognitively impaired, economically 
disadvantaged, etc.)? please describe 
 
No 
 
 
5.  RESEARCH ABSTRACT  Please provide a brief description in LAY language (understandable to 
an 8th grade student) of the aims of this project. 
 
Hypertension is major health problem for postmenopausal women. Hypertension is more likely to be 
uncontrolled in women, despite medication use. Medications to block the angiotensin II pathway are 
commonly used to treat hypertension. However, recent data in animals suggest that multiple 
pathways are involved in blood pressure control in females. Specifically, blocking the angiotensin II 
pathway along with the endothelin-1 pathway resulted in a larger drop in blood pressure in these 
animals compared to single drug therapy. These blood pressure lowering effects observed in the 
female animals may be related to the interactions between angiotensin II and endothelin-1. Both 
angiotensin II and endothelin-1 are potent vasoconstrictors that can cause an increase in blood 
pressure, and these substances interact to cause additive effects on constricting blood vessels. The 
aims of this study are to examine how angiotensin II and endothelin-1 interact to regulate blood 
vessel function in hypertensive postmenopausal women. To do this, we will recruit women with 
elevated blood pressure not taking blood pressure medications, and test their blood vessel function 
on 2 separate visits: 1) baseline, and 2) after 14-days of losartan (an angiotensin II receptor blocker). 
Blood vessel function will be assessed using a technique called microdialysis, which involves placing 
tiny sterile plastic tubes (microdialysis probes) in the surface layer of the skin on the forearm, and 
blood flow will be measured using a small disk with a laser. We will also recruit normotensive women 
to complete 2 visits to assess blood vessel function pre/post 14 days as a control (no losartan 
administration). 
 
6.  PROCEDURES  Describe all procedures involving human subjects for this protocol.  Include 
copies of all surveys and research measures. 
 
We will recruit postmenopausal women with high BP (>130 and/or 80 mmHg) and normotensive 
postmenopausal women (ages 50-70 years).  Women with high BP will complete 5 visits 
(screening/orientation, VO2max test, Blood Vessel Assessment 1, Blood draw to check electrolytes and kidney 
function, and Blood Vessel Assessment 2), and normotensive women will complete 4 visits 
(screening/orientation, VO2max test, Blood Vessel Assessment 1, and Blood Vessel Assessment 2). 
 
Procedures in Women with high BP (5 visits): 


 
Visit 1: Screening/orientation: The first visit is about 1 hour long and includes  
1). Completion of informed consent, medical history, and menstrual cycle history 
2). Measures of height and weight,  
3). Measures of resting blood pressure and 12-lead electrocardiogram 
4). Blood Draw 
 
Participants will be fasted from food, caffeine, and alcohol (12 hours) and exercise (24 hours). Informed consent 
will be obtained by Megan Wenner, study PI, Joshua Hobson, Lab/Study Coordinator, or doctoral student trained by 
Dr. Wenner. Subjects will also be familiarized with the laboratory and experimental procedures. The blood draw and 
electrocardiogram will be done by a trained healthcare professional at the Nurse Managed Primary Care Center 
(NMPCC).  Blood will be analyzed for cholesterol, electrolytes, kidney and liver function, c-reactive protein, and 
blood glucose (sugar). All screening results will be reviewed by a Nurse Practitioner at the NMPCC. In the event 
that the test results are abnormal, the NMPCC will refer the subject to their physician for follow-up and they will not 
be able to participate in the research study. Participants will be provided a HIPAA authorization form that includes 
permission for sharing of patient protected health information with the research team. Women will also be given a 
24 hour ambulatory blood pressure monitor, and instruction on how to wear and operate the monitor. They will don 
the monitor at the completion of Visit 1. The blood pressure monitor measures BP every 20 minutes during the day, 
and every 30 minutes at night. Women will return the monitor the next day. When they return the monitor, we will 
ask that they be seated for 5-10 minutes, and we will take 3 resting blood pressure measures using an automated 
brachial blood pressure cuff. At the end of this visit we will give participants a standard blood pressure monitor to 
take home (Omron). This device is often used for adults to monitor blood pressure at home. The device takes 3 
blood pressures and reports the average of these readings on the device. Women will be instructed to take seated 
resting blood pressures at home 3 times each week for 2 weeks. Blood pressures should be taken in the morning, at 
lunchtime, and again in the evening. Instructions will be provided along with a log to record the readings and time of 
day. Participants will return the BP monitor and log when they return to the lab prior to Visit 2. 
 
Two to three days prior to Visit 2, women will be given a 24 hour ambulatory blood pressure monitor, and 
instruction on how to wear and operate the monitor. They will don the monitor the day before Visit 2. The blood 
pressure monitor measures BP every 20 minutes during the day, and every 30 minutes at night. Women will return 
the monitor the third visit.  
 
Visit 2: Blood Vessel Assessment 1:  The second visit lasts approximately 5 hours.  Measurements will be 
conducted in the Cardiovascular Core Lab at STAR Health Sciences Complex.  Subjects will be asked not to drink 
alcohol and caffeine for 12 hours, food for 4 hours, and refrain from exercise for 24 hours prior to this visit.  
Subjects will be asked to wear a short-sleeved shirt.  If they do not bring one, we will provide one for them.  
 
Endothelial Function: An 18 gauge catheter will be placed in an antecubital vein by a registered nurse or nurse 
practitioner. We will collect blood samples for the measurement of electrolytes, serum creatinine, estradiol, 
progesterone, testosterone, follicle stimulating hormone, angiotensin II, aldosterone, renin, norepinephrine, and 
endothelin-1 (90 mL). The blood samples will be stored in a freezer in the Physiology Core Lab until the time of 
analysis. After the samples are analyzed they will be destroyed at UD. The tubes will be labeled with subject 
numbers; no names will appear on the tubes. In addition we will collect some cells from the wall of the vein. Two 
sterile J-wires are inserted through the IV catheter and gently moved back and forth inside the vessel. One wire is 
used at a time. The wires are then transferred to a 50mL conical tube with endothelial dissociation buffer. The cells 
are rinsed and recovered by centrifugation. The cells are then fixed to coverslips, and stored in the freezer to be 
stained and analyzed for protein expression of ET-1 and ET-B receptors in batches at a later date.  Large blood 
vessel function will then be assessed using two non-invasive techniques. First, a pressure probe is placed over the 
radial artery to record pressure waveforms. Then, the pressure probe will be placed over the carotid and femoral 
arteries to record pressure waveforms. A cloth tape will measure the distance between the carotid and femoral sites. 
Second, an ultrasound will be used to image the brachial artery. A small blood pressure cuff is placed just distal to 
the olecranon process. This cuff will be inflated for 5 minutes. Images of the brachial artery are collected 
continuously before, during, and for 3 minutes after cuff deflation. Changes in brachial artery diameter are used as 
an index of endothelial function. 


 
Microdialysis placement:  Four microdialysis fibers (Bioanalytical Systems) with a membrane length of 10mm and a 
20-kDa cutoff will be inserted on the dorsal side of the forearm.  Microdialysis fibers will be placed by Megan 
Wenner, PhD or doctoral student trained by Dr. Wenner. Under sterile conditions the fibers are placed in the 
intradermal space with a 23-gauge needle used as a guide cannula.  Ice is used on the site locally to numb the skin, 
reduce blood flow, and minimize release of vasoactive substances.  The entrance and exit site on the skin are 
separated by at least 2 cm.  The guide cannula is inserted horizontally in the dermis and the microdialysis fiber is fed 
through the guide cannula.  The needle is removed, and the fiber left in place at a depth of ≈ 2-5 mm.  After 
placement, the fiber is perfused with lactated Ringers at a rate of 2 µl/min using a syringe pump (Bioanalytical 
Systems, Inc.) for 90 minutes.  This recovery period (after fiber insertion) is required to allow local skin blood flow 
(SkBF) to return to baseline before data measurements can be made. During the recovery period, the subject will be 
instrumented for the measurement of heart rate (ECG) and blood pressure. 
 
ET-1 receptor antagonists:  ET-A and ET-B receptor antagonists (BQ-123 and BQ-788, respectively, Sigma) will be 
perfused via intradermal microdialysis fibers while measuring skin blood flow (SkBF) at rest and during local 
heating.  The antagonists will be dissolved in lactated Ringers solution and filtered using syringe microfilters 
(Whatman Puradisc 13 mm Syringe Filters, Florham Park, NJ). Following recovery from the microdialysis fiber 
placement, we will measure resting SkBF using laser Doppler flowmetry (LDF) for 15 min at all sites with the local 
heating devices off.  Laser Doppler probes (MoorLAB, Temperature Monitor SH02, Moor Instruments, Devon, UK) 
which both measure and control local skin temperature, will be placed on the surface of the skin on the dorsal 
forearm over the microdialysis site.  The laser Doppler probes will be maintained at 33°C during baseline and ET 
receptor antagonist infusion.  Microdialysis fibers will then be perfused at 5.0 μl/min for 45 minutes with the 
following drugs: the first fiber will be perfused with lactated Ringers; the second fiber will be perfused with 500 nM 
of the ET-A receptor antagonist (BQ-123) 1; the third fiber will be perfused with 300 nM of ET-B receptor 
antagonist (BQ-788) 1; the fourth fiber will be perfused with combined ET-A and ET-B receptor subtype antagonists 
(i.e. BQ-123 and BQ-788; 500 and 300  nM respectively).  After perfusing the blocking agents, all four local heating 
devices will be raised until the skin temperature under the LDF probes reaches a stable temperature of 42°C 2.  The 
SkBF response will be measured at each microdialysis site until a stable plateau is reached after heating.  The 
microdialysis perfusions of antagonists will continue throughout the local heating response to maintain ET-A and 
ET-B receptor inhibition.  Each series of perfusions will be followed by a perfusion of sodium nitroprusside (SNP, 
28 mM) through the microdialysis fiber combined with local heating to 43°C to determine maximal SkBF. 
Cutaneous vascular conductance (CVC) will be calculated as mean SkBF/mean arterial pressure.  We will collect 
blood samples for the measurement of estradiol, progesterone, testosterone, and endothelin-1at the end of the 
recovery period just prior to beginning the perfusions, and again prior to maximal heating. 
 
Perfusion of the ET-A and ET-B receptor antagonists, BQ-123 and BQ-788, either in arteries or skin vessels in 
humans, is an acceptable and safe experimental technique.  Included is a list of the published research studies 
utilizing this technique: 
• 
1Wenner MM et al. Endothelin B receptor contribution to peripheral microvascular function in women with 
polycystic ovary syndrome. JPHYS 2011. 
• 
Kellogg DL et al. Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular 
tone in humans. J Appl Phys 2001. 
• 
Stauffer BL et al. Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older 
adults. Am J Physiol Regul Integr Comp Physiol. 2010. 
 
Losartan administration: At the completion of visit 3, women with high BP will be given 7 days of losartan 
(50mg), and be instructed to take the study medication once per day (at nighttime before bed). Losartan is a 
medication given to treat hypertension. Losartan administration will be overseen by Dr. Michael Stillabower.  
 
Visit 3: Blood draw. This visit will occur one week after starting losartan. This visit will last ~20 minutes. 
Participants will report to the Physiology Core Laboratory at the STAR Health Sciences complex. Participants will 
be seated, and 10mL of blood will be drawn from a vein. Serum electrolytes and creatinine will be assessed to 
ensure using losartan in not having adverse effects on kidney function or electrolytes. If serum potassium is >5.2 
mmol/L or creatinine is >50% over baseline values, the PI will contact the study physician Dr. Stillabower, and he 
will determine if the medication will be discontinued and the participant be removed from the study. Elevated levels 


typically resolve on their own upon cessation of drug therapy. Rarely, acute renal injury or cardiac arrhythmia’s may 
develop. Additional medical follow-up may be instructed by Dr. Stillabower, determined on a case-by-case basis 
(depending on individual responses to the medication), either to the emergency room or to the PCP. They will also 
be weighed. Women will be given another 7 days of losartan (50mg) and instructed to take the medication once per 
day (at nighttime before bed). Women will also be given a 24 hour ambulatory blood pressure monitor, and 
instruction on how to wear and operate the monitor. They will don the monitor the day before Visit 4 The blood 
pressure monitor measures BP every 20 minutes during the day, and every 30 minutes at night. Women will return 
the monitor the fourth visit.  
 
Visit 4: Blood Vessel Assessment 2:  The fifth visit is will occur 14 days after beginning losartan.  This visit is 
approximately 5 hours long, and is identical to Visit 2 (Blood Vessel Assessment 1).  
 
Visit 5: VO2max Testing. This visit will last ~1 hour. Participants will be fasted from alcohol and caffeine for 12 
hours, food for 4 hours, and exercise for 24 hours prior to testing. Exercise tests will be conducted in the stress 
testing laboratory in the NMPCC and overseen by a Certified Exercise Physiologist and Nurse Practicioner after 
clearance from the study physician, Dr. Stillabower. A resting 12-lead ECG and blood pressure will be taken in the 
supine and standing position. If resting BP is >200/110 mmHg, the test will not be performed. A standard ramp 
treadmill protocol will be used, consisting of 1.5-minute stages where the speed and grade is increased 
incrementally. Expired gases will be collected and analyzed using the Parvo Medics Metabolic Cart. Exercise BP, 
HR, and ECG will be taken throughout, along with ratings of perceived exertion. This is a symptom-limited 
metabolic stress test; test termination criteria are based on ACSM guidelines (RER >1.10, plateau in HR or VO2 
despite increased workload), and absolute indications for test termination such as chest pain, ECG abnormalities or 
arrhythmias, BP >250/115 mmHg, or participants request to stop. Dr. Stillabower will review the exercise test 
results. The NMPCC will send the test results to be read and interpreted by their cardiologist, Dr. Goldenberg. In the 
event of a positive test or if additional follow up is needed, the NMPCC will contact the participant’s primary care 
doctor. 
 
 
Procedures in Normotensive Women (4 visits): 
Visit 1: Screening/orientation: The first visit is about 1 hour long and includes  
1). Completion of informed consent, medical history, and menstrual cycle history 
2). Measures of height and weight,  
3). Measures of resting blood pressure and 12-lead electrocardiogram 
4). Blood Draw 
Participants will be fasted from food, caffeine, and alcohol (12 hours) and exercise (24 hours). Informed consent 
will be obtained by Megan Wenner, study PI, or doctoral student trained by Dr. Wenner. Subjects will also be 
familiarized with the laboratory and experimental procedures. The blood draw and electrocardiogram will be done 
by a trained healthcare professional at the Nurse Managed Primary Care Center (NMPCC).  Blood will be analyzed 
for cholesterol, c-reactive protein, electrolytes, kidney and liver function, and blood glucose (sugar). All screening 
results will be reviewed by a Nurse Practitioner at the NMPCC. In the event that the test results are abnormal, the 
NMPCC will refer the subject to their physician for follow-up and they will not be able to participate in the research 
study. Participants will be provided a HIPAA authorization form that includes permission for sharing of patient 
protected health information with the research team. Women will also be given a 24 hour ambulatory blood pressure 
monitor, and instruction on how to wear and operate the monitor. They will don the monitor at the completion of 
Visit 1. The blood pressure monitor measures BP every 20 minutes during the day, and every 30 minutes at night. 
Women will return the monitor the next day. When they return the monitor, we will ask that they be seated for 5-10 
minutes, and we will take 3 resting blood pressure measures using an automated brachial blood pressure cuff. At the 
end of this visit we will give participants a standard blood pressure monitor to take home (Omron). This device is 
often used for adults to monitor blood pressure at home. The device takes 3 blood pressures and reports the average 
of these readings on the device. Women will be instructed to take seated resting blood pressures at home 3 times 
each week for 2 weeks. Blood pressures should be taken in the morning, at lunchtime, and again in the evening. 
Instructions will be provided along with a log to record the readings and time of day. Participants will return the BP 
monitor and log when they return to the lab prior to Visit 2. 
 


Two to three days prior to Visit 2, women will be given a 24 hour ambulatory blood pressure monitor, and 
instruction on how to wear and operate the monitor. They will don the monitor the day before Visit 2. The blood 
pressure monitor measures BP every 20 minutes during the day, and every 30 minutes at night. Women will return 
the monitor the third visit. 
 
Visit 2: Blood Vessel Assessment 1:  The second visit lasts approximately 5 hours.  Measurements will be 
conducted in the Cardiovascular Core Lab at STAR Health Sciences Complex.  Subjects will be asked not to drink 
alcohol and caffeine for 12 hours, food for 4 hours, and refrain from exercise for 24 hours prior to this visit.  
Subjects will be asked to wear a short-sleeved shirt.  If they do not bring one, we will provide one for them.   
 
Endothelial Function: An 18 gauge catheter will be placed in an antecubital vein by a registered nurse or nurse 
practitioner. We will collect blood samples for the measurement of electrolytes, serum creatinine, estradiol, 
progesterone, testosterone, follicle stimulating hormone, angiotensin II, aldosterone, renin, norepinephrine, and 
endothelin-1 (90 mL). The blood samples will be stored in a freezer in the Physiology Core Lab until the time of 
analysis. After the samples are analyzed they will be destroyed at UD. The tubes will be labeled with subject 
numbers; no names will appear on the tubes. In addition we will collect some cells from the wall of the vein. Two 
sterile J-wires are inserted through the IV catheter and gently moved back and forth inside the vessel. One wire is 
used at a time. The wires are then transferred to a 50mL conical tube with endothelial dissociation buffer. The cells 
are rinsed and recovered by centrifugation. The cells are then fixed to coverslips, and stored in the freezer to be 
stained and analyzed for protein expression of ET-1 and ET-B receptors in batches at a later date.  Large blood 
vessel function will then be assessed using two non-invasive techniques. First, a pressure probe is placed over the 
radial artery to record pressure waveforms. Then, the pressure probe will be placed over the carotid and femoral 
arteries to record pressure waveforms. A cloth tape will measure the distance between the carotid and femoral sites. 
Second, an ultrasound will be used to image the brachial artery. A small blood pressure cuff is placed just distal to 
the olecranon process. This cuff will be inflated for 5 minutes. Images of the brachial artery are collected 
continuously before, during, and for 3 minutes after cuff deflation. Changes in brachial artery diameter are used as 
an index of endothelial function. 
 
Microdialysis placement:  Four microdialysis fibers (Bioanalytical Systems) with a membrane length of 10mm and a 
20-kDa cutoff will be inserted on the dorsal side of the forearm.  Microdialysis fibers will be placed by Megan 
Wenner, PhD, or doctoral student trained by Dr. Wenner.  Under sterile conditions the fibers are placed in the 
intradermal space with a 23-gauge needle used as a guide cannula.  Ice is used on the site locally to numb the skin, 
reduce blood flow, and minimize release of vasoactive substances.  The entrance and exit site on the skin are 
separated by at least 2 cm.  The guide cannula is inserted horizontally in the dermis and the microdialysis fiber is fed 
through the guide cannula.  The needle is removed, and the fiber left in place at a depth of ≈ 2-5 mm.  After 
placement, the fiber is perfused with lactated Ringers at a rate of 2 µl/min using a syringe pump (Bioanalytical 
Systems, Inc.) for 90 minutes.  This recovery period (after fiber insertion) is required to allow local skin blood flow 
(SkBF) to return to baseline before data measurements can be made. During the recovery period, the subject will be 
instrumented for the measurement of heart rate (ECG) and blood pressure. 
 
ET-1 receptor antagonists:  ET-A and ET-B receptor antagonists (BQ-123 and BQ-788, respectively, Sigma) will be 
perfused via intradermal microdialysis fibers while measuring skin blood flow (SkBF) at rest and during local 
heating.  The antagonists will be dissolved in lactated Ringers solution and filtered using syringe microfilters 
(Whatman Puradisc 13 mm Syringe Filters, Florham Park, NJ). Following recovery from the microdialysis fiber 
placement, we will measure resting SkBF using laser Doppler flowmetry (LDF) for 15 min at all sites with the local 
heating devices off.  Laser Doppler probes (MoorLAB, Temperature Monitor SH02, Moor Instruments, Devon, UK) 
which both measure and control local skin temperature, will be placed on the surface of the skin on the dorsal 
forearm over the microdialysis site.  The laser Doppler probes will be maintained at 33°C during baseline and ET 
receptor antagonist infusion.  Microdialysis fibers will then be perfused at 5.0 μl/min for 45 minutes with the 
following drugs: the first fiber will be perfused with lactated Ringers; the second fiber will be perfused with 500 nM 
of the ET-A receptor antagonist (BQ-123) 1; the third fiber will be perfused with 300 nM of ET-B receptor 
antagonist (BQ-788) 1; the fourth fiber will be perfused with combined ET-A and ET-B receptor subtype antagonists 
(i.e. BQ-123 and BQ-788; 500 and 300  nM respectively).  After perfusing the blocking agents, all four local heating 
devices will be raised until the skin temperature under the LDF probes reaches a stable temperature of 42°C 2.  The 
SkBF response will be measured at each microdialysis site until a stable plateau is reached after heating.  The 


microdialysis perfusions of antagonists will continue throughout the local heating response to maintain ET-A and 
ET-B receptor inhibition.  Each series of perfusions will be followed by a perfusion of sodium nitroprusside (SNP, 
28 mM) through the microdialysis fiber combined with local heating to 43°C to determine maximal SkBF. 
Cutaneous vascular conductance (CVC) will be calculated as mean SkBF/mean arterial pressure.  We will collect 
blood samples for the measurement of estradiol, progesterone, testosterone, and endothelin-1at the end of the 
recovery period just prior to beginning the perfusions, and again prior to maximal heating. 
 
Perfusion of the ET-A and ET-B receptor antagonists, BQ-123 and BQ-788, either in arteries or skin vessels in 
humans, is an acceptable and safe experimental technique.  Included is a list of the published research studies 
utilizing this technique: 
• 
1Wenner MM et al. Endothelin B receptor contribution to peripheral microvascular function in women with 
polycystic ovary syndrome. JPHYS 2011. 
• 
Kellogg DL et al. Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular 
tone in humans. J Appl Phys 2001. 
• 
Stauffer BL et al. Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older 
adults. Am J Physiol Regul Integr Comp Physiol. 2010. 
 
At the completion of Visit 2, women will be given a 24 hour ambulatory blood pressure monitor, and instruction on 
how to wear and operate the monitor. They will don the monitor the day before Visit 3. The blood pressure monitor 
measures BP every 20 minutes during the day, and every 30 minutes at night. Women will return the monitor the 
third visit.  
 
 
Visit 3: Blood Vessel Assessment 2:  The fourth visit is will occur 14 days after Visit 2.  This visit is approximately 
5 hours long, and is identical to Visit 2 (Blood Vessel Assessment 1).  
 
Visit 4: VO2max Testing. This visit will last ~1 hour. Participants will be fasted from alcohol and caffeine for 12 
hours, food for 4 hours, and exercise for 24 hours prior to testing. Exercise tests will be conducted in the stress 
testing laboratory in the NMPCC and overseen by a Certified Exercise Physiologist and Nurse Practitioner. A 
resting 12-lead ECG and blood pressure will be taken in the supine and standing position. If resting BP is >200/110 
mmHg, the test will not be performed. A standard ramp treadmill protocol will be used, consisting of 1.5-minute 
stages where the speed and grade is increased incrementally. Expired gases will be collected and analyzed using the 
Parvo Medics Metabolic Cart. Exercise BP, HR, and ECG will be taken throughout, along with ratings of perceived 
exertion. This is a symptom-limited metabolic stress test; test termination criteria are based on ACSM guidelines 
(RER >1.10, plateau in HR or VO2 despite increased workload), and absolute indications for test termination such 
as chest pain, ECG abnormalities or arrhythmias, BP >250/115 mmHg, or participants request to stop. The NMPCC 
will send the test results to be read and interpreted by their cardiologist, Dr. Goldenberg. In the event of a positive 
test or if additional follow up is needed, the NMPCC will contact the participant’s primary care doctor. 
 
 
7.  STUDY POPULATION AND RECRUITMENT 
Describe who and how many subjects will be invited to participate. Include age, gender and other 
pertinent information.   
 
Normotensive and postmenopausal women and women with high BP (ages 50-70 years) will be recruited. A total of 
60 women will be recruited (30 normotensive and 30 high BP).  Subjects will be recruited from campus and local 
community- posting flyers and advertisement in local newspapers, in physicians’ offices, community centers or 
events, through professional societies, or online (UD classifieds, website). In addition, we will conduct blood 
pressure screenings in the community. 
 
 
Attach all recruitment fliers, letters, or other recruitment materials to be used. If verbal recruitment 
will be used, please attach a script. 
 


Recruitment flyers are attached. 
 
 
Describe what exclusionary criteria, if any will be applied. 
 
Women will be excluded from the study if they have a history of any heart disease, kidney or liver disease, history 
of blood clots, pulmonary embolism, deep vein thrombosis, stroke, cancer, diabetes, or any other chronic disease. 
Women will also be excluded from the study if they use tobacco products (including cigarettes and chewing 
tobacco), are using hormone therapy, are pregnant, or if their body mass index is greater than 35. Women will be 
excluded if resting blood pressure is greater than 180/100 mmHg, or less than 100/60 mmHg at the initial screening. 
 
 
Describe what (if any) conditions will result in PI termination of subject participation. 
 
We are assessing serum electrolytes, creatinine and blood pressure at baseline and after 1 week of losartan 
administration. If serum electrolytes (potassium >5.2 mmol/L), creatinine levels (>50% over baseline values) rise 
too high, or blood pressure (less than 100/60 mmHg) drops too low, the study physician Dr. Stillabower will be 
contacted to determine if the subject will be instructed to stop taking the medication and will be excluded from the 
study. 
 
8.  RISKS AND BENEFITS 
List all potential physical, psychological, social, financial or legal risks to subjects (risks listed here 
should be included on the consent form). 
 
There are no known risks associated with obtaining height, weight, resting electrocardiogram, and resting blood 
pressure. The 24-hour blood pressure monitor may interrupt sleep in some participants.  
 
Microdialysis: Subjects will probably experience some pain and bruising like that from a blood draw. However, we 
will use ice to numb the skin during insertion of the fibers. Also, the small needle size (23 gauge) reduces pain 
during placement of the fibers. Subjects will probably not have pain after the fiber is in place but may feel a little 
pain when the fiber is removed from the skin. Similar to a blood draw subjects may become lightheaded or faint. 
Mild pressure with sterile gauze would be applied to stop any slight bleeding that may occur. Infection is possible. 
Sterile techniques and supplies are used to minimize risk. We will apply a sterile bandage after the experiment. 
 
Substances infused through microdialysis fibers: The amount of substance that enters the skin is very small. 
However, there is a chance of having an adverse reaction to the substances. This reaction could produce redness, 
itching, rash, and/or swelling. Although unlikely, it is possible that a more serious reaction could also cause fever, 
breathing problems, changes in heart rate, convulsions, and/or collapse. If a serious reaction should occur, 
emergency medical help will be summoned right away. 
 
Lactated Ringer’s solution: This fluid contains salt, potassium, lactate, and chloride. The acid content is similar to 
the body’s fluids. A bad reaction to this fluid is highly unlikely. 
 
BQ-123, BQ-788, and SNP: Only minute amounts of these substances enter the nickel-sized area of skin around the 
tubing.  Dr. Wenner has previously used BQ-123, BQ-788, and SNP infusions in the skin without adverse 
reactions1,2. Additionally, these drugs have been used in the skin by other researchers without adverse reactions3. 
 
Laser Doppler: Lasers can damage the eye if pointed into the eye for a prolonged period of time. We will not turn 
the laser on until it is taped to the skin surface and will turn it off before removing it. 
 
Local Heating: We measure the temperature of the skin under the holders. The skin will feel very warm but will not 
hurt. The heating will make the skin under the holders red similar to taking a hot bath. The redness will not last more 
than several hours. Some people may be more sensitive to the heating than others. If a subject’s arm feels too hot, 
we will reduce or stop the heating. 


 
Losartan:  Losartan is a drug commonly used to treat high blood pressure. Common side effects may include cold or 
flu symptoms (stuffy/runny nose, sneezing, sore throat, fever), dry cough, muscle cramps, pain in the legs or back, 
stomach pain, nausea, or diarrhea, headache, hypotension, dizziness or light-headed, hyperkalemia, tired feeling, 
trouble concentrating, or sleep problems (insomnia). Other side effects may include pain or burning when urinating, 
wheezing or chest pain, rapid heart rate, increased thirst, loss of appetite, swelling, weight gain, urinating less than 
usual or not at all, confusion, or mood changes. Women will be given a list of potential side effects with instructions 
to either call 911 (severe allergic reaction) or call the study investigators.   
 
Exercise Test: The risks of performing an exercise test are low. As summarized in the American College of Sports 
Medicine Guidelines for Exercise Testing and Prescription (10th ED, 2018)4, there are ~6 cardiac events per 10,000 
tests. All participants (normotensives and hypertensives) are initially screened by the NMPCC to ensure they are 
otherwise healthy and not high risk (i.e., no known disease, no signs or symptoms of disease). The study physician, 
Dr. Stillabower, will determine whether hypertensive participants are able to complete the exercise test based on 
their blood pressure and screening results since hypertension is a CVD risk factor. 
 
 
In your opinion, are risks listed above minimal* or more than minimal? If more than minimal, please 
justify why risks are reasonable in relation to anticipated direct or future benefits. 
(*Minimal risk means the probability and magnitude of harm or discomfort anticipated in the research are not greater 
than those ordinarily encountered in daily life or during the performance of routine physical or psychological 
examinations or tests) 
 
More than minimal, however the risks associated with the study are low. Data collected from this study will help to 
understand the mechanisms contributing to hypertension in women. 
 
What steps will be taken to minimize risks? 
 
The risk of infection during blood draws, endothelial cell collection, and microdialysis fiber placement is minimized 
by using sterile materials and technique throughout the protocol. Subject discomfort due to microdialysis fiber 
placement is minimized by the application of ice to the area for 10 minutes prior to fiber insertion.  Losartan is a 
drug commonly used to treat patients with high blood pressure. Using losartan may cause an electrolyte imbalance, 
and rarely kidney failure. Women will be instructed not to drink alcohol while taking losartan, and also to avoid 
potassium supplements or salt substitutes, and NSAIDs. We will assess electrolytes and creatinine levels in all 
women taking losartan on day 7 of administration. If serum potassium is >5.2 mmol/L or creatinine is >50% over 
baseline, the study physician will be contacted to advise the participant to discontinue the study medication and 
determine whether they should discontinue the study. The study physician will determine if additional medical 
follow-up is needed (ER, PCP). Women will keep in close contact with study investigators. A list of potential side 
effects of using losartan will be given to women, with instructions to either call 911 (if signs of an allergic reaction 
occur such as hives, difficulty breathing, swelling of the face, lips, tongue, or throat), or to call the study 
investigators. The participant will be given contact information to reach the study investigator and Nurse Managed 
Primary Care Center if questions or concerns arise during the study protocol. The study investigator can reach Dr. 
Stillabower, who can then call the participant if needed. 
A clinical exercise physiologist and nurse practitioner will directly supervise the exercise test, and follow set 
guidelines published by the American College of Sports Medicine for stopping the test. The NMPCC will send the 
test results to be read and interpreted by their cardiologist, Dr. Goldenberg. In the event of a positive test or if 
additional follow up is needed, the NMPCC will contact the participant’s primary care doctor. 
 
 
Describe any potential direct benefits to participants. 
There may be no direct benefit to subjects for participating in this research study however they will be provided the 
results of screening blood work and VO2max test when they complete the study. The results will be interpreted and 
provided to the participants PCP if additional follow-up is needed. 
 


Describe any potential future benefits to this class of participants, others, or society. 
This study may provide new information regarding the mechanisms contributing to hypertension in women. 
 
If there is a Data Monitoring Committee (DMC) in place for this project, please describe when and 
how often it meets. 
 
N/A 
 
9.  COMPENSATION 
Will participants be compensated for participation? 
Yes 
 
If so, please include details. 
Women with high BP:  Subjects completing all aspects of the study will receive $275.00. If a participant is excluded 
due to elevated blood levels (visit 3), they will receive $100.00. Participants that do not complete visit 5 (exercise 
test) will receive $225.00. They will receive the compensation at the end of the study in the form of a check. 
Normotensive women – hormone intervention:  Subjects completing all aspects of the study will receive $200.00.  
They will receive the compensation at the end of the study in the form of a check. Participants that do not complete 
visit 4 (exercise test) will receive $150.00. 
 
 
 
10.  DATA 
Will subjects be anonymous to the researcher? 
Information obtained from this study will be kept strictly confidential. Participants are not anonymous to the 
researcher, and will not be individually identified except by a participant number known only to the investigators.   
 
 
If subjects are identifiable, will their identities be kept confidential? (If yes, please specify how) 
Informed consents and medical history questionnaires will be kept in a separate locked filing cabinet from any data 
with participant numbers. A list of names and participant numbers will be encrypted and kept on a password 
protected computer. The list will be kept for 5 years after study completion; the list will be deleted and digital media 
scrubbed.  Information obtained in the medical history form is used only by the Nurse Managed Health Center at the 
University of Delaware, and electronic records are stored in a secure HIPAA compliant database.  
How will data be stored and kept secure (specify data storage plans for both paper and electronic 
files. For guidance see http://www.udel.edu/research/preparing/datastorage.html )    
Information obtained from this study will be kept strictly confidential. Subjects will not be individually identified, 
except by subject number, known only to the investigators. All data stored as paper files or digitally will be kept 
indefinitely. The paper files are stored in a locked cabinet. A list of names and participant numbers will be kept on a 
password-protected computer.  All data will be stored in a locked cabinet or password protected computer 
indefinitely.  All data will be encrypted. The data will be stored and archived for potential use in other, future 
studies. Information obtained in the medical history form is used only by the Nurse Managed Health Center at the 
University of Delaware, and electronic records are stored in a secure HIPAA compliant database. In the event of any 
publication or presentation resulting from the research, no personally identifiable information will be revealed. 
 
How long will data be stored? 
All data will be stored in a locked cabinet or password protected computer indefinitely.  All data will be encrypted. 
 
 
Will data be destroyed?  □ YES   X NO (if yes, please specify how the data will be destroyed)  


 
 
Will the data be shared with anyone outside of the research team?  □ YES   X NO (if yes, please 
list the person(s), organization(s) and/or institution(s) and specify plans for secure data transfer) 
 
 
How will data be analyzed and reported?  
Cutaneous vascular conductance (CVC) will be calculated as mean SkBF/mean arterial pressure.     
While the results of this research will be published, neither participant name nor identity will be revealed. 
 
 
11. CONFIDENTIALITY 
Will participants be audiotaped, photographed or videotaped during this study? 
No 
 
How will subject identity be protected? 
Information obtained from this study will be kept strictly confidential. Subjects will not be individually identified, 
except by subject number, known only to the investigators. All data stored as paper files or digitally will be kept 
indefinitely. The paper files are stored in a locked cabinet. While the results of the research may be published, 
subjects’ names and identities will not be revealed. 
 
 
Is there a Certificate of Confidentiality in place for this project?  (If so, please provide a copy). 
No 
 
 
12. CONFLICT OF INTEREST 
(For information on disclosure reporting see: http://www.udel.edu/research/preparing/conflict.html ) 
 
Do you have a current conflict of interest disclosure form on file through UD Web forms? 
YES 
 
Does this project involve a potential conflict of interest*?   NO 
 
* As defined in the University of Delaware's Policies and Procedures ,a potential conflict of interest (COI) occurs when 
there is a divergence between an individual's private interests and his or her professional obligations, such that an 
independent observer might reasonably question whether the individual's professional judgment, commitment, 
actions, or decisions could be influenced by considerations of personal gain, financial or otherwise. 
 
 
 
If yes, please describe the nature of the interest: 
 
 
 
13.  CONSENT and ASSENT 
 
_X___ Consent forms will be used and are attached for review (see Consent Template under Forms 
and Templates in IRBNet) 
 
 
____ Additionally, child assent forms will be used and are attached. 
 


 
____ Waiver of Documentation of Consent (attach a consent script/information sheet with the 
signature block removed). 
 
 
____ Waiver of Consent (Justify request for waiver) 
 
 
 
14.  Other IRB Approval 
Has this protocol been submitted to any other IRBs?  NO 
 
 
If so, please list along with protocol title, number, and expiration date. 
 
 
 
15.  Supporting Documentation 
Please list all additional documents uploaded to IRBNet in support of this application. 
 
 
 
 
 
 
 
 
 
REFERENCES: 
 
1. 
Wenner MM, Taylor HS, Stachenfeld NS. Endothelin B receptor contribution to peripheral microvascular 
function in women with polycystic ovary syndrome. J Physiol. Oct 1 2011;589(Pt 19):4671-4679. 
2. 
Wenner MM, Taylor HS, Stachenfeld NS. Progesterone enhances adrenergic control of skin blood flow in 
women with high but not low orthostatic tolerance. J Physiol. Dec 20 2011;589(4):975-986. 
3. 
Kellogg DL, Jr., Liu Y, Pergola PE. Selected contribution: Gender differences in the endothelin-B receptor 
contribution to basal cutaneous vascular tone in humans. J Appl Physiol. Nov 2001;91(5):2407-2411; 
discussion 2389-2490. 
4. 
ACSM's Guidelines for Exercise Testing and Prescription, 10th Ed. 2018. Philadelphia, PA: Wolters 
Kluwer. 
 
 
 
 
 
Rev. 10/2012 


Statistical Plan 
 
Sample size estimates were calculated for our main outcome variables in Specific Aim 1 based on 
previously published data in normotensive and pre-hypertensive adults utilizing arterial infusions of the 
ET-1 receptor antagonist. A three level 2x2 General Linear Mixed Model will be used to compare 
normotensive and hypertensive PMW on the outcomes. The hierarchical structure is needed as sites are 
nested within measurements, which are nested within individuals. The model assumptions of linearity and 
normality, will be evaluated using Box-Cox and Shapiro-Wilk tests, respectively. Outliers and influential 
cases will be screened for and removed. The covariance structure will be chosen using nested model 
comparisons. Violations of the assumptions will be remedied using transformations suggested by the 
Box-Cox test. Post-hoc comparisons will have the Bonferroni adjustment applied. The alpha is set at 0.05 
for each analysis, and will be adjusted by the number of primary dependent variables to control for 
multiple comparisons. In order to find a large effect (pη2 = 0.50), a sample of size of 38 women is required 
to achieve a power greater than 0.8. In order to account for screen failures, subject attrition and potential 
microdialysis fiber failure, we will recruit 60 women (30 normotensive and 30 hypertensive).  
 
A Mixed Design ANOVA will be used to evaluate if losartan administration alters endothelial ET-1 
protein expression ETB receptor expression on endothelial cells, along with ETA and ETB receptor 
expression on vascular smooth muscle cells in hypertensive PMW compared to that of normotensive 
PMW. Since values are expressed as ratios, if the assumptions of the Mixed Design ANOVA are not 
satisfied a Generalized Linear Mixed Model will be used. In order to find a moderately small effect (pη2 = 
.09), a sample of size of 38 is required to achieve a power greater than 0.8. The model also assumes of 
linearity, sphericity, and normality, which will be evaluated using Box-Cox, Mauchly’s, and Shapiro-Wilk 
tests, respectively. Outliers and influential cases will be screened for and removed. Post-hoc comparisons 
will have the Bonferroni adjustment applied. The alpha is set at 0.05 for each analysis, and will be 
adjusted by the number of primary dependent variables to control for multiple comparisons. Although we 
are planning on matching our groups based on age, body composition, VO2max, and time since 
menopause, these may be potential covariates will be compared between groups using t-tests for 
continuous data and tests for 
 tests for categorical data. If a covariate is significantly different between 
groups it will be included in the analysis.  
 

ICF_002.pdf: 
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Page 1 of 10 
 
 
 
     Participant’s Initials _________ 
INFORMED CONSENT TO PARTICIPATE IN RESEARCH 
Title of Project: Losartan and ET-1 mediated constriction in postmenopausal women with high blood 
pressure 
Principal Investigator(s): Megan M. Wenner, PhD, and Michael Stillabower, MD 
You are being invited to participate in a research study. This consent form tells you about the study 
including its purpose, what you will be asked to do if you decide to take part, and the risks and benefits of 
being in the study. Please read the information below and ask us any questions you may have before you 
decide whether or not you want to participate.  
WHAT IS THE PURPOSE OF THIS STUDY? 
The purpose of this study is to understand what causes blood vessels to constrict or get smaller in women 
with high blood pressure. Women with high blood pressure have an increased risk for cardiovascular 
disease. One early indicator of cardiovascular disease is decreased blood vessel function. The inner lining of 
the blood vessels (called the endothelium), releases substances to help control blood vessel function.  One of 
these substances is endothelin-1 (ET-1). Certain hormones that our bodies produce can influence the release 
of ET-1 like the hormone angiotensin II (ANG II), which is a common therapeutic target for high blood 
pressure. In this study we will determine if blocking both ET-1 and ANG II are more effective in reducing 
constriction compared to single therapy or control conditions. To do this we will measure blood flow in the 
very small blood vessels in your skin on your forearm while blocking the ET-1 receptors using a technique 
called microdialysis. This technique involves placing tiny sterile plastic tubes (microdialysis fibers) in the 
surface layer of your skin. The largest part of the tubing is about 6 times the diameter of human hair. During 
the experiment we will add substances to the fluid in the tubing, such as endothelin-receptor-A blocker (BQ-
123), endothelin-receptor-B blocker (BQ-788), a mixture of both endothelin-receptors A and B blocker, and 
sodium nitroprusside (SNP). This will be done at baseline and again after 14 days.  
You will be one of approximately 30 participants in this study (compared to 30 participants with high blood 
pressure).  
WHY ARE YOU BEING ASKED TO PARTICIPATE? 
You are being asked to participate because you are a postmenopausal woman between 50-70 years of age 
without high blood pressure (self-report). 
You will not be allowed to participate in the study if you:  
 
Have a history of heart disease, stroke, cancer, diabetes, kidney or liver disease, blood clots 
 
Use tobacco products (including cigarettes and chewing tobacco)  
 
Have a body mass index is greater than 35 
 
Use hormone replacement therapy, or are pregnant  


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     Participant’s Initials _________ 
 
All medications you are taking at the time of this study will be evaluated by the investigators 
 
on an individual basis, to confirm you are eligible to participate.   
 
WHAT WILL YOU BE ASKED TO DO?    
Full participation in this study will require 4 visits for a total of approximately 11 hours. These visits will be 
held at the Nurse Managed Primary Care Center (Visits 1&2) and the Physiology Core Lab (Visits 3&4). 
Both of these facilities are located at 540 S. College Avenue (STAR Health Sciences Complex) in Newark, 
DE.  
Visit 1: Participant Screening (1 visit to the Nurse Managed Primary Care Center; 1 hour in length) 
 This visit will take place in the morning (between 7:30 and 8:30am). You will be asked to not eat food, 
alcohol, and caffeine for 12 hours and to not exercise for 24 hours. This is a screening visit where:  
1). You will complete a medical history and menstrual history questionnaire 
2). Your height and weight will be measured  
3). Resting blood pressure and a resting electrocardiogram (ECG: a test to record        electrical 
activity of the heart) will be measured. 
4). A blood sample will be collected by inserting a needle into an arm vein (approximately 3 
tablespoons of blood will be removed). The blood sample will be used to measure liver and 
kidney function, electrolytes such as sodium, cholesterol, red blood cells, glucose (blood 
sugar), and C-reactive protein.  
The results from the screening, as well as the medical history form, will be reviewed by a nurse practitioner 
to determine if you qualify for the study. The investigators will discuss the results of these tests with you, 
and will make copies of the results available to you. In the event that one of the test results is abnormal, you 
will be referred to your personal physician for a follow-up exam and will not be able to participate in the 
research study. The results of your screening visit will be provided to you.  
At the end of this visit, you will be given a 24-hour blood pressure monitor, and review instructions on how 
to wear the monitor. You will wear the monitor during the 24 hours after visit 1. The monitor measures 
blood pressure every 20 minutes during the day and every 30 minutes at night. You will return the monitor 
to the Physiology Core Lab the next day, at which time we will take your blood pressure again (3 
measurements) with a standard automated cuff on your upper arm. You will be seated for ~5-10 minutes. At 
the end of this visit we will give you a blood pressure monitor to take home. You will be asked to take your 
blood pressure 3 days each week for the following 2 weeks. On each day you take your blood pressure, you 
will do so at 3 separate times: morning, noon, and evening. You should be seated for the readings. The 
device is worn on the upper arm and will take 3 measures and provide a reading which is the average of the 
three readings. You will be asked to write this number down in the space provided on the record log sheet. 
We will give you instructions and show you how to use the monitor. You will return the monitor at your 
next visit along with the record log.  


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     Participant’s Initials _________ 
 
2-3 days before Visit 2, you will come to the lab to pick up a 24-hour blood pressure monitor, and review 
instructions on how to wear the monitor. You will wear the monitor during the 24 hours before visit 2. 
 
Visit 2: Blood Vessel Function Assessment (Physiology Core Lab; 4.5 hours in length) 
This visit will occur within 2 weeks of Visit 1. You will be asked not to drink alcohol and caffeine for 12 
hours, food for at least 4 hours, and refrain from exercise for 24 hours prior to this visit. You will be asked to 
bring or wear a short sleeve shirt and shorts. During this visit the following will occur: 
 You will have 3 self-adhesive electrodes placed on your chest to monitor heart rate, and a blood 
pressure cuff around the upper arm and finger to measure blood pressure. 
 A catheter (i.e., a small needle encased in a flexible tube that is inserted into a vein) will be placed 
into a vein in your arm. The catheter in the vein will permit us to take a blood sample; approximately 
6 tablespoons / 90 mL of blood will be drawn in total.  The blood sample will be used to analyze 
hormones (estradiol, progesterone, follicle stimulating hormone, angiotensin II, aldosterone, renin, 
norepinephrine, and testosterone), a protein involved in regulating blood vessel function (endothelin-
1), and cellular markers of blood vessel dysfunction. Blood samples will be stored in the freezer until 
the time of sample processing. Once processing is complete the samples 
will be destroyed.  
 We will collect some cells from the wall of the vein.  To do this, we will 
pass a very thin j-shaped wire through the intravenous catheter (see 
photo at right) and gently move it back and forth so it scrapes against 
the side of the vein wall. When this wire is moved against the vein wall, 
it will pick up some “endothelial” cells.  We will then make 
measurements of different proteins in these cells that we collect.  
 Next we will assess large blood vessel function using two separate non-invasive techniques. First we 
will place blood pressure cuffs around your arm and thigh and take measurements. Then we will record 
the pulse in your neck (carotid artery) by placing a pressure probe on the skin over the artery. The 
pressure probe looks like a pen. A cloth tape measure will be used to measure the distance between your 
neck and thigh. Second, a small blood pressure cuff will be placed on your forearm close to your elbow.  
We will use an ultrasound to take pictures of the blood vessel in your upper arm (brachial artery). The 
cuff will then be inflated for 5 minutes; the sensation felt will be similar to having fallen asleep on your 
arm (slight numbness). We will deflate the cuff and continue to take ultrasound pictures for 2 minutes. 
 Next we will then prepare your arm for the microdialysis procedure. We will place a tight band around 
your upper arm to see your veins clearly. We will make 4 pairs of pen marks on your arm 
approximately 1 inch apart and away from veins to identify where the microdialysis tubing will be 
placed. We will then clean your arm with an orange-colored betadine fluid and alcohol. We will place 


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     Participant’s Initials _________ 
an ice bag on your arm for 10 minutes to numb your 
skin. Then we will insert a thin needle into your 
skin at each entry mark. The needle’s tip travels 
between the layers of skin for 2 cm and leaves your 
skin at the matching exit mark (See Figure 1). The 
microdialysis tubing is threaded through the 
needle, and then we will remove the needle leaving 
the tubing in your skin. You will have 4 sets of 
tubing in your skin. Any redness of your skin 
typically subsides in about 60 minutes.  
 After the tubing is placed, we will tape a thin probe (Laser Doppler) and its holder over each area 
where the tubing is located. This probe uses a weak laser light to measure blood flowing in the small 
vessels in your skin. We can also control the temperature of the holders. The temperature will start at 
91.4˚F. Then we will start a salt like solution (Lactated Ringer’s solution) to flow (perfuse) through 
the tubing in your skin (60-90 min). Lactated Ringer’s solution is a salt like solution containing 
sodium, chloride, potassium, calcium, and lactate.  
 When the redness on your arm is gone, the experiment begins. We will make resting measures for 
~20 minutes. Then we will add the test substances to the plain fluid running through the tubing for 
45 minutes: 
  
 
-Tubing site 1 will receive salt like solution (Lactated Ringer) 
  
 
-Tubing site 2 will receive salt like solution + ET-A receptor blockade (BQ-123) 
 
 
-Tubing site 3 will receive salt like solution + ET-B receptor blockade (BQ-788) 
 
 
-Tubing site 4 will receive salt like solution + BQ-123 + BQ-788 
 After 45 minutes we will increase the temperature of the local heaters to 104˚F and heat the small 
area of your skin. We maintain this temperature for about 40 minutes. When the skin blood flow 
becomes stable again, we will stop the flow of test substances through the tubing. Lastly, the salt like 
solution + SNP will flow through all of the tubing and we heat the skin to 108˚F for 30-45 minutes. 
This creates the greatest amount of blood flow possible. 
 The trial then ends. We will remove the tubing from your arm and clean all the places on your arm 
where the tubing was with alcohol. We place a sterile bandage over the sites where the tubing was in 
your skin. We will check your heart rate and blood pressure again before you leave. 
 At the completion of this visit, you will be given a 24-hour blood pressure monitor, and review 
instructions on how to wear the monitor. You will wear the monitor during the 24 hours preceding 
visit 3. 
 
 
Visit 3: Blood Vessel Function Assessment (Physiology Core Lab; 4.5 hours in length) 
This visit will occur 2 weeks after Visit 2, and will be approximately 4.5 hours in length. You will be asked 
not to drink alcohol and caffeine for 12 hours, food for at least 4 hours, and refrain from exercise for 24 
hours prior to this visit. This visit will be identical to visit 2. 
 


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     Participant’s Initials _________ 
 
Visit 4: Exercise Test (VO2max test; Nurse Managed Primary Care Center, 1 hour in length) 
 You will be asked to not eat food for 4 hours, alcohol or caffeine for 12 hours, and to not exercise 
for 24 hours prior to this visit. You will be asked to bring or wear comfortable clothing and athletic 
shoes (sneakers) to walk on the treadmill.  
 We will place 10 electrodes on your torso to monitor your heart at rest and throughout the test. We 
will also measure your blood pressure at rest and throughout the test. If your resting BP is >200/110 
mmHg we will not proceed with the test. You will wear a small mask over your nose and mouth so 
that we can measure the oxygen and carbon dioxide you breathe at rest and throughout the test.  
 You will begin the test with a warm up by walking on the treadmill. Then, every 1.5 minutes the 
speed and grade (incline) of the treadmill will increase. We will ask you to rate how hard you are 
working by using a number scale (Borg scale) that we will explain to you before the start of the test. 
The test will last ~8-10 minutes.  
 We may stop the test at any time because of signs of fatigue or changes in your heart rate, 
electrocardiogram, or blood pressure, or symptoms you may experience (for example, chest pain, 
dizziness). You may also stop the test because of feelings of fatigue or any other discomfort.  
 We will continue to measure your heart rate and blood pressure for at least 5 minutes after the end of 
the test, while you will complete a ‘cool down’ period (walking slowing on the treadmill with no 
incline). We will continue to measure your heart rate and blood pressure for an additional 5-10 
minutes after you are off the treadmill. The results of the test will be reviewed with the study 
physician. In addition, the NMPCC will send the test results to be read and interpreted by their 
cardiologist, Dr. Goldenberg. In the event of a positive test or if additional follow up is needed, the 
NMPCC will contact your primary care doctor. 
 
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
 There are no known risks associated with obtaining your height, weight, resting electrocardiogram, or 
resting blood pressure. You may have pain and/or bruising at the site where blood is taken, and there 
is a small risk of infection (this will be minimized by using sterile, single-use catheters).  Signs of 
infection include pain, swelling, and redness.  If these signs occur, you should contact the study 
investigators. Fainting sometimes occurs during or shortly after blood is drawn. There are minimal 
risks associated with the assessment of blood vessel function. You may feel some pressure or minor 
discomfort from the probes. You may feel minor discomfort when the blood pressure cuff is inflated, 
and may feel numbness and tingling in your arm and hand (similar to if your arm fell asleep). The 24-
hour blood pressure monitor may wake you up during your sleep. 
 There may also be risks associated with obtaining endothelial cells from your vein. The risks 
associated with endothelial cell collection are similar to those of an intravenous catheter and include 
pain, inflammation of the vein, infection and blood clots, although the risks of blood clots and infection 


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may be slightly greater (compared to intravenous placement alone) due to increased manipulation of 
the blood vessel. There is a low likelihood that the j-shaped wire could get stuck in the vein and/or be 
damaged; if this were to happen the nurse will assess the situation and call 911 if needed. If you require 
additional medical treatment, you will be responsible for the cost. 
 Microdialysis fiber placement into the skin may produce some short-term pain or discomfort. Risks 
associated with insertion of the microdialysis fiber include irritation to the skin, and rarely, infection.  
You will probably experience some pain and bruising like that from a blood draw. However, we use 
ice to numb your skin during insertion of the tubing. Also, the small needle reduces pain during 
placement of the tubing. You will probably not have pain after the tubing is in place. You may feel a 
little pain when the tubing is removed from your skin. You may become lightheaded or faint. Mild 
pressure with sterile gauze stops any slight bleeding that may occur. Infection is possible. Sterile 
techniques and supplies like those used in a hospital keep the risk minimal. We apply a sterile bandage 
after the experiment and tell you how to take care of the site. 
 The amount of drug that enters the skin is very small. However, there is a chance of you having a bad 
reaction to the substances. This reaction could produce redness, itching, rash, and/or swelling. 
Although unlikely, it is possible that a worse reaction could also cause fever, breathing problems, 
changes in heart rate, convulsions, and/or collapse. If a bad reaction should occur, medical help will 
be summoned right away. We have no knowledge of any adverse events associated with these 
substances utilized during this technique. 
 Lactated Ringer’s solution: The fluid is similar to natural fluids in your skin. This fluid contains salt, 
potassium, lactate, and chloride. The acid content is like that of your body’s fluids. A bad reaction to 
this fluid is highly unlikely. 
 ET-A receptor blockade (BQ-123), ET-B receptor blockade (BQ-788) and sodium nitroprusside 
(SNP): Only minute amounts of these substances enter the nickel-sized area of skin around the tubing. 
Other researchers have used these substances in human skin and there have been no reports of bad 
reactions. 
 Laser Doppler: The laser Doppler will not damage the skin. Lasers can damage the eye if pointed into 
the eye for a prolonged period of time. We will not turn the laser on until it is taped to the skin surface 
and will turn it off before removing it.  
 Local Heating: We measure the temperature of your skin under the holders. The skin will feel very 
warm but will not hurt. The heating will make the skin of your arm under the holders red like when 
you take a hot bath. The redness will not last more than several hours. Some people may be more 
sensitive to the heating than others. If your arm feels too hot, you will tell us, and we will reduce or 
stop the heating. 
 Exercise Test: The risks of performing an exercise test are low. As summarized in the American 
College of Sports Medicine Guidelines for Exercise Testing and Prescription (10th ED, 2018), there 
are ~6 cardiac events per 10,000 tests. 
 What steps will be taken to minimize risks? 


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- The risk of infection during blood draws, endothelial cell collection, and microdialysis fiber 
placement is minimized by using sterile materials and technique throughout the protocol. Discomfort due 
to microdialysis fiber placement is minimized by the application of ice to the area for 10 minutes prior to 
fiber insertion. A clinical exercise physiologist and nurse practitioner will directly supervise the exercise 
test, and follow set guidelines published by the American College of Sports Medicine for stopping the 
test. 
 
WHAT IF YOU ARE INJURED DURING YOUR PARTICIPATION IN THE STUDY?  
If you are injured during research procedures, you will be offered first aid at no cost to you. If you need 
additional medical treatment, the cost of this treatment will be your responsibility or that of your third-party 
payer (for example, your health insurance). By signing this document, you are not waiving any rights that you 
may have if injury was the result of negligence of the university or its investigators.  
 
WHAT ARE THE POTENTIAL BENEFITS? 
You may not benefit directly from taking part in this research. However, the knowledge gained from this 
study may contribute to our understanding of blood pressure control in adults (particularly women). The data 
collected at the screening session will be provided to you upon completion of the study. 
 
NEW INFORMATION THAT COULD AFFECT YOUR PARTICIPATION:  
During the course of this study, we may learn new information that could be important to you. This may 
include information that could cause you to change your mind about participating in the study. We will 
notify you as soon as possible if any new information becomes available.  
HOW WILL CONFIDENTIALITY BE MAINTAINED? WHO MAY KNOW THAT YOU 
PARTICIPATED IN THIS RESEARCH? 
 Information obtained from this study will be kept strictly confidential. Subjects will not be individually 
identified, except by subject number, known only to the investigators. All data stored as paper files or 
digitally will be kept indefinitely. The paper files are stored in a locked cabinet. A list of names and 
participant numbers will be kept on a password-protected computer and will be encrypted. The list 
will be kept for 5 years after study completion; the list will be deleted and digital media scrubbed.  All 
de-identified data will be stored in a locked cabinet or encrypted password protected computer 
indefinitely.  All data will be encrypted. The data will be stored and archived for potential use in other, 
future studies. 
 Information obtained in the medical history form is used only by the Nurse Managed Health Center 
at the University of Delaware, and electronic records are stored in a secure HIPAA compliant 
database. Information obtained from the medical history in participants who are not allowed to 


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participate will be stored in a locked cabinet or encrypted password protected computer indefinitely 
(HIPAA compliant database at the Nurse Managed Health Center). 
 In the event of any publication or presentation resulting from the research, no personally identifiable 
information will be revealed. 
 The confidentiality of your records will be protected to the extent permitted by law. Your research 
records may be viewed by the University of Delaware Institutional Review Board, which is a 
committee formally designated to approve, monitor, and review biomedical and behavioral research 
involving humans. This research is being funded by the National Institutes of Health (NIH); thereby 
they have the right to view the research data. 
 A description of this clinical trial will be made available on http://www.ClinicalTrials.gov as required 
by U.S.Law. This website will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site any time. 
 
 
HIPAA AUTHORIZATION  
State and federal privacy laws protect your PHI. These laws say that, in most cases, your health care 
provider can release your PHI for the purpose of conducting research only if you give permission by signing 
an Authorization. 
If you agree to participate in the research study, the research team will need to collect and use your PHI. To 
allow your health care provider to share your PHI with the research team, your approval is required. Signing 
this Authorization is completely voluntary. However, if you do not sign this Authorization, then you may not 
participate in the research study. 
 
 
 
Who May Disclose and Who may Use and/or Receive my PHI?  
 
By signing this document, you are hereby permitting the Nurse Managed Primary Care Center at the 
University of Delaware to disclose the PHI described in this Authorization to the research team involved in 
this project; the study sponsor and its employees; the Institutional Review Board (IRB) and other regulatory 
agencies responsible for overseeing research.  
Once your PHI is shared with these persons, you understand that the PHI may no longer be protected by 
federal or state privacy laws.  
 
What PHI Will Be Disclosed and Used, and for What Purpose? 
 
The following PHI may be disclosed to, collected by, used by and shared with those listed above for the 
following purpose 
to 
determine 
your 
eligibility for this 
study: 
Medical 
history/treatment; 
Laboratory/diagnostic tests; EKG/EEG report.  


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This Authorization will expire at the conclusion of the research study. You may cancel this Authorization at 
any time before, during, or after your participation in this study by giving a written request with your signature 
on it to the Principal Investigator at mwenner@udel.edu. If you cancel this Authorization, your PHI obtained 
before that date may still be used for this research study. 
 
I hereby authorize the disclosure and use of my Personal Health Information.  
 
_______________________________________       
            ______________ 
Signature of Patient or Authorized Representative  
 
Date 
 
Printed Name of Person Signing: ___________________________________ 
 
Relationship to Patient: ___________________________________________ 
 
WILL THERE BE ANY COSTS TO YOU FOR PARTICIPATING IN THIS RESEARCH? 
 There are no costs associated with participating in the study. 
 
WILL YOU RECEIVE ANY COMPENSATION FOR PARTICIPATION?                                   
 You will receive $200.00 for completion of all aspects of the study.  You will receive compensation 
at completion of the study in the form of a check. If you only complete 3 visits, you will receive 
$150.00.  
 
DO YOU HAVE TO TAKE PART IN THIS STUDY? 
Taking part in this research study is entirely voluntary. You do not have to participate in this research. If 
you choose to take part, you have the right to stop at any time. If you decide not to participate or if you 
decide to stop taking part in the research at a later date, there will be no penalty or loss of benefits to which 
you are otherwise entitled. Your decision to stop participation, or not to participate, will not influence 
current or future relationships with the University of Delaware. 
 
WHO SHOULD YOU CALL IF YOU HAVE QUESTIONS OR CONCERNS? 
If you have any questions about this study, please contact the Principal Investigator, Megan M. Wenner, 
PhD, Assistant Professor, Department of Kinesiology and Applied Physiology (302-831-7343). 


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If you have any questions or concerns about your rights as a research participant, you may contact the 
University of Delaware Institutional Review Board at hsrb-research@udel.edu or (302) 831-2137. 
 
 
Your signature on this form means that: 1) you are at least 18 years old; 2) you have read and 
understand the information given in this form; 3) you have asked any questions you have about the 
research and those questions have been answered to your satisfaction; 4) you accept the terms in the 
form and volunteer to participate in the study. You will be given a copy of this form to keep.  
 
_____________________________  
 
________________________ 
 
_________ 
Printed Name of Participant  
 
 
Signature of Participant                              
Date                           
 
 
______________________________ 
 
________________________                    
_________ 
Person Obtaining Consent  
 
 
   
Person Obtaining Consent 
 
             Date 
     (PRINTED NAME) 
 
                         (SIGNATURE) 
 
 
 
 
 
 
 
OPTIONAL CONSENT TO BE CONTACTED FOR FUTURE STUDIES:  
 
Do we have your permission to contact you regarding participation in future studies?  Please write your 
initials next to your preferred choice.  
 
________ YES 
 
 
________ NO 
 
 


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INFORMED CONSENT TO PARTICIPATE IN RESEARCH 
Title of Project: Losartan and ET-1 mediated constriction in postmenopausal women with high blood 
pressure 
Principal Investigator(s): Megan M. Wenner, PhD, and Michael Stillabower, MD 
You are being invited to participate in a research study. This consent form tells you about the study 
including its purpose, what you will be asked to do if you decide to take part, and the risks and benefits of 
being in the study. Please read the information below and ask us any questions you may have before you 
decide whether or not you want to participate.  
WHAT IS THE PURPOSE OF THIS STUDY? 
The purpose of this study is to understand what causes blood vessels to constrict or get smaller in women 
with high blood pressure. Women with high blood pressure have an increased risk for cardiovascular 
disease. One early indicator of cardiovascular disease is decreased blood vessel function. The inner lining of 
the blood vessels (called the endothelium), releases substances to help control blood vessel function.  One of 
these substances is endothelin-1 (ET-1). Certain hormones that our bodies produce can influence the release 
of ET-1 like the hormone angiotensin II (ANG II), which is a common therapeutic target for high blood 
pressure. In this study we will determine if blocking both ET-1 and ANG II are more effective in reducing 
constriction compared to single therapy or control conditions. To do this we will measure blood flow in the 
very small blood vessels in your skin on your forearm while blocking the ET-1 receptors using a technique 
called microdialysis. This technique involves placing tiny sterile plastic tubes (microdialysis fibers) in the 
surface layer of your skin. The largest part of the tubing is about 6 times the diameter of human hair. During 
the experiment we will add substances to the fluid in the tubing, such as endothelin-receptor-A blocker (BQ-
123), endothelin-receptor-B blocker (BQ-788), a mixture of both endothelin-receptors A and B blocker, and 
sodium nitroprusside (SNP). This will be done at baseline and again after 14 days of taking the blood 
pressure lowering drug called losartan.  
You will be one of approximately 30 participants in this study (compared to 30 participants without high 
blood pressure).  
WHY ARE YOU BEING ASKED TO PARTICIPATE? 
You are being asked to participate because you are a postmenopausal woman between 50-70 years of age 
with high blood pressure (self report). 
You will not be able to participate in the study if you: 
 
Have a history of heart disease, stroke, cancer, diabetes, kidney or liver disease, blood clots 
 
Use tobacco products (including cigarettes and chewing tobacco)  
 
Have a body mass index greater than 35  


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 
Use hormone replacement therapy, or are pregnant  
 
Are currently taking medication for high blood pressure  
 
If your resting blood pressure is greater than 180/100 mmHg or less than 100/60 mmHg, you 
will not be able to  participate. All medications you are taking at the time of this study will be 
evaluated by the investigators on an individual basis, to confirm you are eligible to participate.   
WHAT WILL YOU BE ASKED TO DO?    
Full participation in this study will require 5 visits, for a total of approximately 12 hours. These visits will 
be held at the Nurse Managed Primary Care Center (Visits 1&2) and the Physiology Core Lab (Visits 3-5). 
Both of these facilities are located at 540 S. College Avenue (STAR Health Sciences Complex) in Newark, 
DE.  
Visit 1: Participant Screening (1 visit to the Nurse Managed Primary Care Center; 1 hour in length) 
 This visit will take place in the morning (between 7:30 and 8:30am). You will be asked to not eat food, 
alcohol, and caffeine for 12 hours and to not exercise for 24 hours. This is a screening visit where:  
1). You will complete a medical history and menstrual history questionnaire 
2). Your height and weight will be measured  
3). Resting blood pressure and a resting electrocardiogram (ECG: a test to record        electrical 
activity of the heart) will be measured. 
4). A blood sample will be collected by inserting a needle into an arm vein (approximately 3 
tablespoons of blood will be removed). The blood sample will be used to measure liver and 
kidney function, electrolytes such as sodium, cholesterol, red blood cells, glucose (blood 
sugar), and C-reactive protein.  
The results from the screening, as well as the medical history form, will be reviewed by a nurse practitioner 
to determine if you qualify for the study. The investigators will discuss the results of these tests with you, 
and will make copies of the results available to you. In the event that one of the test results is abnormal, you 
will be referred to your personal physician for a follow-up exam and will not be able to participate in the 
research study. The results of your screening visit will be provided to you.  
At the end of this visit, you will be given a 24-hour blood pressure monitor, and review instructions on how 
to wear the monitor. You will wear the monitor during the 24 hours after visit 1. The monitor measures 
blood pressure every 20 minutes during the day and every 30 minutes at night. You will return the monitor 
to the Physiology Core Lab the next day, at which time we will take your blood pressure again (3 
measurements) with a standard automated cuff on your upper arm. You will be seated for ~5-10 minutes. At 
the end of this visit we will give you a blood pressure monitor to take home. You will be asked to take your 
blood pressure 3 days each week for the following 2 weeks. On each day you take your blood pressure, you 
will do so at 3 separate times: morning, noon, and evening. You should be seated for the readings. The 
device is worn on the upper arm and will take 3 measures and provide a reading which is the average of the 
three readings. You will be asked to write this number down in the space provided on the record log sheet. 


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We will give you instructions and show you how to use the monitor. You will return the monitor at your 
next visit along with the record log. 
2-3 days before Visit 2, you will come to the lab to pick up a 24-hour blood pressure monitor, and review 
instructions on how to wear the monitor. You will wear the monitor during the 24 hours before visit 2. 
 
Visit 2: Blood Vessel Function Assessment (Physiology Core Lab; 4.5 hours in length) 
This visit will occur within 2 weeks of Visit 1. You will be asked not to drink alcohol and caffeine for 12 
hours, food for at least 4 hours, and refrain from exercise for 24 hours prior to this visit. You will be asked to 
bring or wear a short sleeve shirt and shorts. During this visit the following will occur: 
 You will have 3 self-adhesive electrodes placed on your chest to monitor heart rate, and a blood 
pressure cuff around the upper arm and finger to measure blood pressure. 
 A catheter (i.e., a small needle encased in a flexible tube that is inserted into a vein) will be placed 
into a vein in your arm. The catheter in the vein will permit us to take a blood sample; approximately 
6 tablespoons / 90 mL of blood will be drawn in total.  The blood sample will be used to analyze 
hormones (estradiol, progesterone, follicle stimulating hormone, angiotensin II, aldosterone, renin, 
norepinephrine, and testosterone), a protein involved in regulating blood vessel function (endothelin-
1), and cellular markers of blood vessel dysfunction. Blood samples will be stored in the freezer until 
the time of sample processing. Once processing is complete the samples 
will be destroyed.  
 We will collect some cells from the wall of the vein. To do this, we will 
pass a very thin j-shaped wire through the catheter (see photo at right) 
and gently move it back and forth so it scrapes against the side of the 
vein wall. When this wire is moved against the vein wall, it will pick up 
some “endothelial” cells.  We will then make measurements of different 
proteins in these cells that we collect.  
 Next we will assess large blood vessel function using two separate non-invasive techniques. First we 
will place blood pressure cuffs around your arm and thigh and take measurements. Then we will record 
the pulse in your neck (carotid artery) by placing a pressure probe on the skin over the artery. The 
pressure probe looks like a pen. A cloth tape measure will be used to measure the distance between your 
neck and thigh. Second, a small blood pressure cuff will be placed on your forearm close to your elbow.  
We will use an ultrasound to take pictures of the blood vessel in your upper arm (brachial artery). The 
cuff will then be inflated for 5 minutes; the sensation felt will be similar to having fallen asleep on your 
arm (slight numbness). We will deflate the cuff and continue to take ultrasound pictures for 2 minutes. 
 Next we will then prepare your arm for the microdialysis procedure. We will place a tight band around 
your upper arm to see your veins clearly. We will make 4 pairs of pen marks on your arm 
approximately 1 inch apart and away from veins to identify where the microdialysis tubing will be 
placed. We will then clean your arm with an orange-colored betadine fluid and alcohol. We will place 
an ice bag on your arm for 10 minutes to numb your skin. Then we will insert a thin needle into your 


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skin at each entry mark. The needle’s tip travels 
between the layers of skin for 2 cm and leaves 
your skin at the matching exit mark (See Figure 
1). The microdialysis tubing is threaded 
through the needle, and then we will remove 
the needle leaving the tubing in your skin. You 
will have 4 sets of tubing in your skin. Any 
redness of your skin typically subsides in about 
60 minutes.  
 After the tubing is placed, we will tape a thin probe (Laser Doppler) and its holder over each area 
where the tubing is located. This probe uses a weak laser light to measure blood flowing in the small 
vessels in your skin. We can also control the temperature of the holders. The temperature will start at 
91.4˚F. Then we will start a salt like solution (Lactated Ringer’s solution) to flow (perfuse) through 
the tubing in your skin (60-90 min). Lactated Ringer’s solution is a salt like solution containing 
sodium, chloride, potassium, calcium, and lactate.  
 When the redness on your arm is gone, the experiment begins. We will make resting measures for 
~20 minutes. Then we will add the test substances to the plain fluid running through the tubing for 
45 minutes: 
  
 
-Tubing site 1 will receive salt like solution (Lactated Ringer) 
  
 
-Tubing site 2 will receive salt like solution + ET-A receptor blockade (BQ-123) 
 
 
-Tubing site 3 will receive salt like solution + ET-B receptor blockade (BQ-788) 
 
 
-Tubing site 4 will receive salt like solution + BQ-123 + BQ-788 
 After 45 minutes we will increase the temperature of the local heaters to 104˚F and heat the small 
area of your skin. We maintain this temperature for about 40 minutes. When the skin blood flow 
becomes stable again, we will stop the flow of test substances through the tubing. Lastly, the salt like 
solution + SNP will flow through all of the tubing and we heat the skin to 108˚F for 30-45 minutes. 
This creates the greatest amount of blood flow possible. 
 The trial then ends. We will remove the tubing from your arm and clean all the places on your arm 
where the tubing was with alcohol. We place a sterile bandage over the sites where the tubing was in 
your skin. We will check your heart rate and blood pressure again before you leave. 
 At the end of the visit you will be given the study medication, losartan, which is a drug that blocks 
the receptor for angiotensin II. You will be given 7 days of the medication, and instructed to take 1 
pill each day at nighttime (before bed). You should avoid alcohol while using losartan, and not take 
any potassium supplements or salt substitutes, or NSAIDs (advil, ibuprofen).   
 
Visit 3: Blood draw to assess electrolytes and kidney function (Physiology Core Lab; 30 min in length) 
This visit will occur on day 7 of taking losartan. You will be asked to report to the laboratory in the morning 
after an overnight fast for a blood draw and blood pressure recording. The blood draw will be used to assess 
your blood electrolytes and markers of kidney function. The study physician will review the results to 
determine if you can continue the study medication.  


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 If your blood electrolyte levels or markers of kidney function are elevated, you may be instructed to 
stop the study medication, and may be excluded from the study. Rarely, if these markers are severely 
elevated, you may be instructed to go to the emergency room.  
 If your blood pressure recording is less than 100/60 mmHg, you may be instructed to stop the study 
medication, and may be excluded from the study. 
 You will be given another 7 days of the study medication, and instructed to take 1 pill each day at 
nighttime (before bed). At the completion of this visit, you will be given a 24-hour blood pressure 
monitor, and review instructions on how to wear the monitor. You will wear the monitor during the 
24 hours preceding visit 4.  
 
Visit 4: Blood Vessel Function Assessment (Physiology Core Lab; 4.5 hours in length) 
This visit will occur 1week after Visit 3, or 2 weeks after starting losartan, and will be approximately 4.5 
hours in length. You will be asked not to drink alcohol and caffeine for 12 hours, food for at least 4 hours, 
and refrain from exercise for 24 hours prior to this visit. This visit will be identical to visit 2. 
 
Visit 5: Exercise Test (VO2max test; Nurse Managed Primary Care Center, 1 hour in length) 
 Your screening and health information will be reviewed by the study physician, Dr. Stillabower, for 
clearance to perform the exercise test. You will be asked to not eat food for 4 hours, alcohol or 
caffeine for 12 hours, and to not exercise for 24 hours prior to this visit. You will be asked to bring 
or wear comfortable clothing and athletic shoes (sneakers) to walk on the treadmill.  
 We will place 10 electrodes on your torso to monitor your heart at rest and throughout the test. We 
will also measure your blood pressure at rest and throughout the test. If your resting BP is >200/110 
mmHg we will not proceed with the test. You will wear a small mask over your nose and mouth so 
that we can measure the oxygen and carbon dioxide you breathe at rest and throughout the test.  
 You will begin the test with a warm up by walking on the treadmill. Then, every 1.5 minutes the 
speed and grade (incline) of the treadmill will increase. We will ask you to rate how hard you are 
working by using a number scale (Borg scale) that we will explain to you before the start of the test. 
The test will last ~8-10 minutes.  
 We may stop the test at any time because of signs of fatigue or changes in your heart rate, 
electrocardiogram, or blood pressure, or symptoms you may experience (for example, chest pain, 
dizziness). You may also stop the test because of feelings of fatigue or any other discomfort.  
 We will continue to measure your heart rate and blood pressure for at least 5 minutes after the end of 
the test, while you will complete a ‘cool down’ period (walking slowing on the treadmill with no 
incline). We will continue to measure your heart rate and blood pressure for an additional 5-10 
minutes after you are off the treadmill. The results of the test will be reviewed with the study 
physician. In addition, the NMPCC will send the test results to be read and interpreted by their 


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cardiologist, Dr. Goldenberg. In the event of a positive test or if additional follow up is needed, the 
NMPCC will contact your primary care doctor.  
 
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
 There are no known risks associated with obtaining your height, weight, resting electrocardiogram, or 
resting blood pressure. You may have pain and/or bruising at the site where blood is taken, and there 
is a small risk of infection (this will be minimized by using sterile, single-use catheters).  Signs of 
infection include pain, swelling, and redness. If these signs occur, you should contact the study 
investigators. Fainting sometimes occurs during or shortly after blood is drawn. There are minimal 
risks associated with the assessment of blood vessel function.  You may feel some pressure or minor 
discomfort from the probes. You may feel minor discomfort when the blood pressure cuff is inflated, 
and may feel numbness and tingling in your arm and hand (similar to if your arm fell asleep). The 24-
hour blood pressure monitor may wake you up during your sleep. 
 There may also be risks associated with obtaining endothelial cells from your vein. The risks 
associated with endothelial cell collection are similar to those of an intravenous catheter and include 
pain, inflammation of the vein, infection and blood clots, although the risks of blood clots and infection 
may be slightly greater (compared to intravenous placement alone) due to increased manipulation of 
the blood vessel. There is a low likelihood that the j-shaped wire could get stuck in the vein and/or be 
damaged; if this were to happen the nurse will assess the situation and call 911 if needed. If you require 
additional medical treatment, you will be responsible for the cost. 
 Microdialysis fiber placement into the skin may produce some short-term pain or discomfort. Risks 
associated with insertion of the microdialysis fiber include irritation to the skin, and rarely, infection.  
You will probably experience some pain and bruising like that from a blood draw. However, we use 
ice to numb your skin during insertion of the tubing. Also, the small needle reduces pain during 
placement of the tubing. You will probably not have pain after the tubing is in place. You may feel a 
little pain when the tubing is removed from your skin. You may become lightheaded or faint. Mild 
pressure with sterile gauze stops any slight bleeding that may occur. Infection is possible. Sterile 
techniques and supplies like those used in a hospital keep the risk minimal. We apply a sterile bandage 
after the experiment and tell you how to take care of the site. 
 The amount of drug that enters the skin is very small. However, there is a chance of you having a bad 
reaction to the substances. This reaction could produce redness, itching, rash, and/or swelling. 
Although unlikely, it is possible that a worse reaction could also cause fever, breathing problems, 
changes in heart rate, convulsions, and/or collapse. If a bad reaction should occur, medical help will 
be summoned right away. We have no knowledge of any adverse events associated with these 
substances utilized during this technique. 
 Lactated Ringer’s solution: The fluid is similar to natural fluids in your skin. This fluid contains salt, 
potassium, lactate, and chloride. The acid content is like that of your body’s fluids. A bad reaction to 
this fluid is highly unlikely. 


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     Participant’s Initials _________ 
 ET-A receptor blockade (BQ-123), ET-B receptor blockade (BQ-788) and sodium nitroprusside 
(SNP): Only minute amounts of these substances enter the nickel-sized area of skin around the tubing. 
Other researchers have used these substances in human skin and there have been no reports of bad 
reactions. 
 Laser Doppler: The laser Doppler will not damage the skin. Lasers can damage the eye if pointed into 
the eye for a prolonged period of time. We will not turn the laser on until it is taped to the skin surface 
and will turn it off before removing it.  
 Local Heating: We measure the temperature of your skin under the holders. The skin will feel very 
warm but will not hurt. The heating will make the skin of your arm under the holders red like when 
you take a hot bath. The redness will not last more than several hours. Some people may be more 
sensitive to the heating than others. If your arm feels too hot, you will tell us, and we will reduce or 
stop the heating. 
 Losartan is a medication that is commonly prescribed for high blood pressure. Common side effects 
may include cold or flu symptoms (stuffy/runny nose, sneezing, sore throat, fever), dry cough, muscle 
cramps, pain in the legs or back, stomach pain, nausea, or diarrhea, headache, low blood pressure, 
dizziness or light-headed, high potassium levels, tired feeling, trouble concentrating, or sleep problems 
(insomnia). Other side effects may include pain or burning when urinating, wheezing or chest pain, 
rapid heart rate, increased thirst, loss of appetite, swelling, weight gain, urinating less than usual or 
not at all, confusion, or mood changes. You will be given a sheet with potential side effects and 
instructions to either call the study investigators (PI, Megan Wenner, 609-413-1418) or 911 if a severe 
allergic reaction should occur. 
 Exercise Test: The risks of performing an exercise test are low. As summarized in the American 
College of Sports Medicine Guidelines for Exercise Testing and Prescription (10th ED, 2018), there 
are ~6 cardiac events per 10,000 tests. The study physician, Dr. Stillabower, will determine whether 
you are able to complete the exercise test based on your blood pressure and screening results. 
 What steps will be taken to minimize risks? 
 
- The risk of infection during blood draws, endothelial cell collection, and microdialysis fiber 
placement is minimized by using sterile materials and technique throughout the protocol. Discomfort due 
to microdialysis fiber placement is minimized by the application of ice to the area for 10 minutes prior to 
fiber insertion.  Losartan is a drug commonly used to treat patients with high blood pressure. Using 
losartan may cause an electrolyte imbalance, and rarely kidney failure. You will be instructed not to drink 
alcohol while taking losartan, and also to avoid potassium supplements or salt substitutes. We will assess 
your electrolytes and creatinine levels on day 7 of losartan administration. If serum potassium is >5.2 
mmol/L or creatinine is >50% over baseline, the study physician will be contacted. He may advise you to 
discontinue the study medication and determine if you should discontinue the study. In rare cases, severe 
elevations in these blood markers may require you to go to the emergency room. You will keep in close 
contact with study investigators. A list of potential side effects of using losartan will be given to you, with 
instructions to either call 911 (if signs of an allergic reaction occur such as hives, difficulty breathing, 
swelling of the face, lips, tongue, or throat), or to call the study investigators. You will be given contact 
information to reach the study investigator and Nurse Managed Primary Care Center if questions or 


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     Participant’s Initials _________ 
concerns arise during the study protocol. The study investigator can reach Dr. Stillabower, who can then 
call you if needed. A clinical exercise physiologist and nurse practitioner will directly supervise the 
exercise test, and follow set guidelines published by the American College of Sports Medicine for stopping 
the test.  
 
WHAT IF YOU ARE INJURED DURING YOUR PARTICIPATION IN THE STUDY?  
If you are injured during research procedures, you will be offered first aid at no cost to you. If you need 
additional medical treatment, the cost of this treatment will be your responsibility or that of your third-party 
payer (for example, your health insurance). By signing this document, you are not waiving any rights that you 
may have if injury was the result of negligence of the university or its investigators.  
WHAT ARE THE POTENTIAL BENEFITS? 
You may benefit directly from taking part in this research. Using the drug losartan may lower your blood 
pressure; however there is no guarantee. Furthermore, the knowledge gained from this study may contribute 
to our understanding of blood pressure control in adults (particularly women) with high blood pressure. The 
data collected at the screening session will be provided to you upon completion of the study. 
 
NEW INFORMATION THAT COULD AFFECT YOUR PARTICIPATION:  
During the course of this study, we may learn new information that could be important to you. This may 
include information that could cause you to change your mind about participating in the study. We will 
notify you as soon as possible if any new information becomes available.  
HOW WILL CONFIDENTIALITY BE MAINTAINED? WHO MAY KNOW THAT YOU 
PARTICIPATED IN THIS RESEARCH? 
 Information obtained from this study will be kept strictly confidential. Subjects will not be individually 
identified, except by subject number, known only to the investigators. All data stored as paper files or 
digitally will be kept indefinitely. The paper files are stored in a locked cabinet. A list of names and 
participant numbers will be kept on a password-protected computer and will be encrypted. The list 
will be kept for 5 years after study completion; the list will be deleted and digital media scrubbed.  All 
de-identified data will be stored in a locked cabinet or encrypted password protected computer 
indefinitely.  All data will be encrypted. The data will be stored and archived for potential use in other, 
future studies. 
 Information obtained in the medical history form is used only by the Nurse Managed Health Center 
at the University of Delaware, and electronic records are stored in a secure HIPAA compliant 
database. Information obtained from the medical history in participants who are not allowed to 
participate will be stored in a locked cabinet or encrypted password protected computer indefinitely 
(HIPAA compliant database at the Nurse Managed Health Center). 


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     Participant’s Initials _________ 
 In the event of any publication or presentation resulting from the research, no personally identifiable 
information will be revealed. 
 The confidentiality of your records will be protected to the extent permitted by law. Your research 
records may be viewed by the University of Delaware Institutional Review Board, which is a 
committee formally designated to approve, monitor, and review biomedical and behavioral research 
involving humans. This research is being funded by the National Institutes of Health (NIH); thereby 
they have the right to view the research data. 
 A description of this clinical trial will be made available on http://www.ClinicalTrials.gov as required 
by U.S.Law. This website will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site any time. 
 
HIPAA AUTHORIZATION  
State and federal privacy laws protect your Protected Health Information (PHI). These laws say that, in most 
cases, your health care provider can release your PHI for the purpose of conducting research only if you 
give permission by signing an Authorization. 
If you agree to participate in the research study, the research team will need to collect and use your PHI. To 
allow your health care provider to share your PHI with the research team, your approval is required. Signing 
this Authorization is completely voluntary. However, if you do not sign this Authorization, then you may not 
participate in the research study. 
 
 
Who May Disclose and Who may Use and/or Receive my PHI?  
 
By signing this document, you are hereby permitting the Nurse Managed Primary Care Center at the 
University of Delaware to disclose the PHI described in this Authorization to the research team involved in 
this project; the study sponsor and its employees; the Institutional Review Board (IRB) and other regulatory 
agencies responsible for overseeing research.  
Once your PHI is shared with these persons, you understand that the PHI may no longer be protected by 
federal or state privacy laws.  
 
What PHI Will Be Disclosed and Used, and for What Purpose? 
 
The following PHI may be disclosed to, collected by, used by and shared with those listed above for the 
following purpose 
to 
determine 
your 
eligibility for this 
study: 
Medical 
history/treatment; 
Laboratory/diagnostic tests; EKG/EEG report.  
 
This Authorization will expire at the conclusion of the research study. You may cancel this Authorization at 
any time before, during, or after your participation in this study by giving a written request with your signature 


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     Participant’s Initials _________ 
on it to the Principal Investigator at mwenner@udel.edu. If you cancel this Authorization, your PHI obtained 
before that date may still be used for this research study. 
 
 
 
I hereby authorize the disclosure and use of my Protected Health Information.  
 
_______________________________________       
            ______________ 
Signature of Patient or Authorized Representative  
 
Date 
 
Printed Name of Person Signing: ___________________________________ 
 
Relationship to Patient: ___________________________________________ 
 
WILL THERE BE ANY COSTS TO YOU FOR PARTICIPATING IN THIS RESEARCH? 
 There are no costs associated with participating in the study. 
 
WILL YOU RECEIVE ANY COMPENSATION FOR PARTICIPATION?                                   
 You will receive $275.00 for completion of all aspects of the study.  You will receive compensation 
at completion of the study. If you drop out or are excluded after Visit 3 (Blood draw to check 
electrolytes and kidney function), you will receive $100.00. If you complete 4 visits (everything except 
the exercise test) you will receive $225.00.  
 
DO YOU HAVE TO TAKE PART IN THIS STUDY? 
Taking part in this research study is entirely voluntary. You do not have to participate in this research. If 
you choose to take part, you have the right to stop at any time. If you decide not to participate or if you 
decide to stop taking part in the research at a later date, there will be no penalty or loss of benefits to which 
you are otherwise entitled. Your decision to stop participation, or not to participate, will not influence 
current or future relationships with the University of Delaware. 
 
WHO SHOULD YOU CALL IF YOU HAVE QUESTIONS OR CONCERNS? 
If you have any questions about this study, please contact the Principal Investigator, Megan M. Wenner, 
PhD, Assistant Professor, Department of Kinesiology and Applied Physiology (302-831-7343), study 


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     Participant’s Initials _________ 
physician, Michael Stillabower (302-463-5371), or Nurse Managed Primary Care Center (302-831-3195; 
during normal business hours). 
If you have any questions or concerns about your rights as a research participant, you may contact the 
University of Delaware Institutional Review Board at hsrb-research@udel.edu or (302) 831-2137. 
 
 
Your signature on this form means that: 1) you are at least 18 years old; 2) you have read and 
understand the information given in this form; 3) you have asked any questions you have about the 
research and those questions have been answered to your satisfaction; 4) you accept the terms in the 
form and volunteer to participate in the study. You will be given a copy of this form to keep.  
 
_____________________________  
 
________________________ 
 
_________ 
Printed Name of Participant  
 
 
Signature of Participant                              
Date                           
 
 
______________________________ 
 
________________________                    
_________ 
Person Obtaining Consent  
 
 
   
Person Obtaining Consent 
 
             Date 
     (PRINTED NAME) 
 
                         (SIGNATURE) 
 
 
 
 
 
 
OPTIONAL CONSENT TO BE CONTACTED FOR FUTURE STUDIES:  
 
Do we have your permission to contact you regarding participation in future studies?  Please write your 
initials next to your preferred choice.  
 
________ YES 
 
 
________ NO