Angiotensin-(1-7) Cardiovascular Effects in Aging

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.

Study Overview

• Status: Recruiting
• Conditions: Aging
• Intervention / Treatment: Drug: Angiotensin-(1-7); Drug: Saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Aimee Cauffman, RN; Phone Number: 717-531-1617; Email: acauffman@pennstatehealth.psu.edu
• Study Contact Backup: Name: Amy Arnold, PhD; Phone Number: 717-531-3674; Email: aarnold5@pennstatehealth.psu.edu

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Recruiting
      • Penn State Milton S. Hershey Medical Center
      • Sub-Investigator: Urs A Leuenberger, MD
      • Sub-Investigator: Aimee Cauffman, RN
      • Sub-Investigator: Cheryl Blaha, RN
      • Sub-Investigator: Jian Cui, PhD
      • Contact: Amy Arnold, PhD; Phone Number: 717-531-3674; Email: aarnold5@pennstatehealth.psu.edu
      • Sub-Investigator: Takuto Hamaoka, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 80 years (Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Angiotensin-(1-7); 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); This is a biologically active endogenous angiotensin peptide that may play an important role in regulation of blood pressure.; Other Names: Angiotensin I/II (1-7) Acetate
Placebo Comparator: Saline; 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; Saline will be used as the placebo comparator.; Other Names: Normal saline; 0.9% sodium chloride

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Angiotensin II	Plasma angiotensin II levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.	110 minutes
Change in Angiotensin-(1-7)	Plasma angiotensin-(1-7) levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.	110 minutes
Change in Renin Activity	Plasma renin activity will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.	110 minutes
Change in Aldosterone	Plasma or serum aldosterone levels will be measured in blood samples obtained at baseline and at the end of angiotensin-(1-7) versus saline infusion.	110 minutes

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Amy Arnold, PhD, Pennsylvania State University College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 17, 2022
• First Submitted That Met QC Criteria: March 18, 2022
• First Posted (Actual): March 29, 2022

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: blood pressure; autonomic nervous system; cardiovascular; endothelial; renin-angiotensin system
• Additional Relevant MeSH Terms: Organic Chemicals; Pharmaceutical Preparations; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Inorganic Chemicals; Chlorine Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Fatty Acids, Volatile; Sodium Compounds; Chlorides; Hydrochloric Acid; Saline Solution; Sodium Chloride; Acetates; angiotensin I (1-7)
• Other Study ID Numbers: STUDY 17401; K99HL159272 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No