Cardiovascular Effects of Angiotensin-(1-7) in Obesity Hypertension

Obesity is a global health concern that is associated with high blood pressure and an increased risk for developing cardiovascular disease. The purpose of this study is to find out if the investigational drug angiotensin-(1-7) can improve cardiovascular health in people with obesity and high blood pressure.

A randomized, double blind, placebo controlled, crossover study will be conducted to determine if acute intravenous angiotensin-(1-7) infusion reduces cardiovascular sympathetic tone and blood pressure and improves the function of blood vessels in participants with obesity hypertension. This is an outpatient study that requires a screening visit, and if eligible, two study visits separated by at least one week in the Clinical Research Center within the Penn State Milton S. Hershey Medical Center. The study visits will include intravenous infusion of angiotensin-(1-7) or saline for approximately two hours, starting with increasing doses and holding at a steady-state dose. Endothelial function will be measured and blood samples collected at baseline and at the end of infusion. Blood pressure, heart rate, and muscle sympathetic nerve activity (via microneurography) will be measured continuously throughout the study. Each study visit will last approximately 4 hours.

Eligibility Criteria:
Inclusion Criteria:

* Men and women of all races
* Age 18 to 60 years
* Body mass index (BMI) between 30-40 kg/m2
* Hypertension defined as two or more seated blood pressure readings \>130/80 mmHg or use of antihypertensive medications
* Capable of giving informed consent
* Fluent in written and spoken English
* Satisfactory history and physical exam

Exclusion Criteria:

* Age ≤ 17 or ≥ 61 years
* Taking more than two antihypertensive medications
* Secondary causes of hypertension (e.g., pheochromocytoma, primary aldosteronism, aortic coarctation, adrenal disease)
* Pregnant or nursing women
* Women taking hormone replacement therapy within 6 months
* Decisional impairment
* Prisoners
* Alcohol or drug abuse
* Current smokers
* Highly trained athletes
* Subjects with \>5% weight change in the past 3 months
* Morbid obesity (BMI \> 40 kg/m2)
* 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 disorders
* Impaired hepatic function \[aspartate aminotransferase (AST) or alanine transaminase (ALT) levels \>2 times upper limit of normal range\]
* Impaired renal function (serum creatinine \>2.0 mg/dl)
* Anemia
* Treatment with drugs increasing sympathetic activity \[e.g., serotonin-norepinephrine reuptake inhibitors (SNRIs) or norepinephrine transporter (NET) inhibitors, stimulants\]
* Treatment with phosphodiesterase-5 inhibitors
* Treatment with anticoagulants (e.g. warfarin)
* 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