Angiotensin-(1-7) in Peripheral Arterial Disease

This is a randomized, double blind, placebo-controlled, crossover study to determine if acute
intravenous Ang-(1-7) infusion can reduce systemic inflammation and improve measures of leg
blood flow in subjects with PAD. The investigators will also measure for changes in blood
pressure and circulating hormones in response to angiotensin-(1-7) infusion. This is an
outpatient study that will be conducted in the Clinical Research Center at the Penn State
Milton S. Hershey Medical Center.

Subjects with PAD will participate in a screening visit, and if eligible, in two separate
study visits in which they will receive intravenous angiotensin-(1-7) or saline infusion.
Each study visit will last approximately 4 hours, with at least one week of washout between
study visits. During study visits, subjects will be instrumented with two intravenous
catheters (one for drug infusion and one for blood sampling), arm and finger blood pressure
cuffs, sticky patches to measure heart rate, a belt around the stomach to measure breathing,
an ultrasound probe on each leg to measure blood flow, a probe on the ear to measure blood
oxygen saturation, a probe on each calf muscle to measure oxygen levels, and probes on the
skin to measure temperature and blood flow. The investigators will obtain baseline measures
of blood pressure and heart rate and collect blood samples to measure hormones in the blood.
After baseline measurements, the investigators will infuse angiotensin-(1-7) or saline for 50
minutes. Finger cuff blood pressure, leg blood flow, and calf muscle oxygen levels will be
measured continuously during infusions. The investigators will measure blood pressure and
heart rate and collect blood samples at the end of the infusion period.

Inclusion Criteria:

- Sex: Male or Female

- Age: 21-80 years of age

- Diagnosed with PAD (e.g. ankle-brachial index below 0.9)

- Fontaine stage II or less (no rest pain)

- Capable of giving informed consent

- Fluent in written and spoken English

Exclusion Criteria:

- Age less than or equal to 20 years or greater than or equal to 81 years

- Pregnant or nursing woman

- Decisional impairment

- Prisoners

- Alcohol or drug abuse

- Evidence of type I or type II diabetes (fasting glucose >126 mg/dl or use of
anti-diabetic medications)

- History of serious cardiovascular disease (e.g. myocardial infarction within 6 months,
symptomatic coronary artery disease, presence of angina pectoris, significant
arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second
or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic
cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke,
transient ischemic attack).

- History or presence of immunological or hematological disease

- Impaired hepatic function [aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) levels > 2 times the upper limit of normal range)

- Impaired renal function (serum creatinine >2.0 mg/dl)

- Anemia

- Treatment with serotonin-norepinephrine reuptake inhibitors (SNRI) or norepinephrine
transporter (NET) inhibitors

- Treatment with phosphodiesterase-5 inhibitors

- Treatment with anticoagulants

- Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1
month)

- Treatment with any investigational drug in the 1-month preceding the study

- Inability to give, or withdraw, informed consent