Study funding ended prior to completion.

Peripheral arterial disease (PAD) affects over 8 million individuals in the United States alone. This is a form of atherosclerosis in which plaques preferentially build up inside the arteries of the legs to limit blood flow. These patients are at high risk for heart attack and stroke, with at least half dying from coronary artery disease. Our understanding of the causes of PAD remains incomplete. The renin-angiotensin hormone system is one mechanism known to contribute to atherosclerosis. Pharmacologic blockade of the hormone angiotensin II is beneficial in forms of atherosclerosis, including peripheral arterial disease, to improve blood vessel damage and functional outcomes. These therapies also increase circulating levels of angiotensin-(1-7), a hormone that dilates blood vessels. Angiotensin-(1-7) improves blood vessel function and reduces inflammation to protect against atherosclerosis in animal models; however, there are no clinical data in patients with atherosclerosis. The overall goal of this project is to examine the cardiovascular effects of angiotensin-(1-7) in PAD.

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](streamdown:incomplete-link)