Angiotensin-(1-7) Cardiovascular Effects in Aging

Study Overview
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Brief Summary
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Aging is an independent risk factor for developing hypertension and cardiovascular disease; however, the mechanisms underlying age-related cardiovascular disease remain poorly understood. One hallmark of aging is an increase in sympathetic nervous system activity, which can decrease the number and/or sensitivity of β2 adrenergic receptors to reduce dilation of blood vessels and increase blood pressure. Identifying new targets to restore vascular β2 adrenergic receptor signaling may help reduce cardiovascular risk in aging. This study will test the hypothesis that angiotensin-(1-7), a protective hormone of the renin-angiotensin system, can reduce cardiovascular sympathetic outflow and blood pressure and improve endothelial function in older healthy humans.

Detailed Description
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A randomized, double blind, placebo-controlled, crossover study will be conducted to determine if acute intravenous angiotensin-(1-7) infusion can reduce cardiovascular sympathetic tone and blood pressure and improve the function of blood vessels in older healthy individuals. 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 and endothelial cells collected at baseline and at the end of infusions. Blood pressure, heart rate, and muscle sympathetic nerve activity via microneurography will be measured throughout the study. Each study visit will last approximately 4 hours.

Official Title
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Angiotensin-(1-7) Cardiovascular Effects in Aging

Conditions
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Aging

Intervention / Treatment
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* Drug: Angiotensin-(1-7)
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women of all races and ethnicities Capable of giving informed consent Fluent in written and spoken English Age 65-80 years Body mass index (BMI) between 18.5 and 30 kg/m2 Normotensive defined as seated blood pressure <130/80 mmHg and without hypertensive medications Satisfactory history and physical exam Exclusion Criteria: Age < 65 or > 80 years Women who are pregnant, nursing, or taking hormone replacement therapy Decisional impairment Prisoners Current or recent (less than 6 months) recreational drug history or excessive alcohol abuse history (greater than 14 drinks per week) Current smokers Highly trained athletes Evidence of type I or type II diabetes (fasting glucose > 126 mg/dL or use of anti-diabetic medications) Hypertension or 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 aminotransferase (ALT) levels >2 times upper limit of normal range] Impaired renal function (serum creatinine >2.0 mg/dl) Anemia Taking drugs known to influence sympathetic activity (e.g. serotonin-norepinephrine reuptake inhibitors, norepinephrine transporter inhibitors, stimulants). Treatment with anticoagulants (e.g. warfarin) Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month in the 1-month preceding the study) Treatment with any investigational drug in the 1-month preceding the study Known allergy or contraindication to angiotensin converting enzyme inhibitors or angiotensin receptor blockers, both of which increase endogenous angiotensin-(1-7) levels as part of their mechanism of action Inability to give, or withdraw, informed consent

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Angiotensin-(1-7)<br>Participants will receive intravenous angiotensin-(1-7) at one study visit for 110 minutes. Angiotensin-(1-7) will be given in escalating doses of 2 ng/kg/min, 4 ng/kg/min, and 8 ng/kg/min. Each of these doses will be infused for 10 minutes. Following the dose escalation, angiotensin-(1-7) will be given at 8 ng/kg/min for an additional 80 minutes. Infusion rates will be calculated for each participant based on body mass. | Drug: Angiotensin-(1-7)<br>* This is a biologically active endogenous angiotensin peptide that may play an important role in regulation of blood pressure.<br>* Other names: Angiotensin I/II (1-7) Acetate;|
| Placebo Comparator: Saline<br>Participants will receive intravenous saline at one study visit for 110 minutes total. The volume of saline will match the volume of angiotensin-(1-7) infused. Infusion rates will be calculated for each participant based on body mass. | Drug: Saline<br>* Saline will be used as the placebo comparator.<br>* Other names: 0.9% sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Muscle Sympathetic Nerve Burst Rate | Muscle sympathetic nerve burst rate will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion. | 110 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Muscle Sympathetic Nerve Burst Incidence | Muscle sympathetic nerve burst incidence will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Muscle Sympathetic Nerve Amplitude | Muscle sympathetic nerve amplitude will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Muscle Sympathetic Nerve Total Activity | Muscle sympathetic nerve total activity will be measured continuously using peroneal nerve microneurography during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Brachial Artery Diameter | A blood pressure cuff will be inflated to a suprasystolic pressure for 5 minutes then deflated. Brachial artery diameter will be measured continuously before, during, and after cuff inflation using duplex ultrasound at baseline and at the end of angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Systolic and Diastolic Blood Pressure | Blood pressure will be measured continuously with a finger and arm cuff during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Heart Rate | Heart rate will be measured continuously by electrocardiogram during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Heart Rate Variability | Heart rate variability will be calculated from the continuous electrocardiogram recordings obtained during angiotensin-(1-7) versus saline infusion. | 110 minutes | 
| Change in Plasma Catecholamines | Circulating catecholamine levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion. | 110 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiovascular, blood pressure, autonomic nervous system, renin-angiotensin system, endothelial