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

Primary Purpose

Hypertension, Hypertension, Essential

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Angiotensin (1-7)

Trimethaphan

Phenylephrine

About this trial

This is an interventional other trial for Hypertension focused on measuring Hypertension, Autonomic Nervous System, Renin-Angiotensin System, Angiotensin (1-7), Ganglionic Blockers, Trimethaphan, Blood Pressure, Hemodynamics

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Males and females of all races between 18 and 60 years of age
Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg. This will allow us to include subjects with "pre-hypertension."
Able and willing to provide informed consent

Exclusion Criteria:

Pregnancy or breast feeding
Current smokers or history of heavy smoking (>2 packs/day)
History of alcohol or drug abuse
Previous allergic reaction to study medications
Evidence of type I or type II diabetes (i.e. fasting glucose >126 mg/dl, use of anti-diabetic medications)
Cardiovascular disease other than hypertension such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy
History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or transient ischemic attack
History or presence of immunological or hematological disorders
Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) > 2.0 x upper limit of normal range]
Impaired renal function (serum creatinine >1.5 mg/dl)
Anemia (hemoglobin <13.5 g/dl in males or <12.5 g/dl in females)
Treatment with phosphodiesterase 5 inhibitors
Treatment with anticoagulants
Treatment with chronic systemic glucocorticoid therapy (more than 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
Other factors which in the investigator's opinion would prevent the subject from completing the protocol (i.e. clinically significant abnormalities on clinical, mental examination or laboratory testing or inability to comply with protocol)

Sites / Locations

Vanderbilt University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Intact Study Day

Autonomic Blockade Study Day

Arm Description

Subjects will receive saline infusion for 60 minutes followed by five ascending doses of Angiotensin (1-7) ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.

Autonomic blockade will be induced by continuous intravenous infusion of trimethaphan starting at 0.5-1.0 mg/min and increasing by 1.0 mg/min every 2 to 6 minutes up to an infusion rate of 5 mg/min. Blood pressure will be restored to pre-trimethaphan levels with intravenous phenylephrine infusion at individually titrated doses, starting with 0.1 ug/kg/min. Angiotensin (1-7) will then be infused in five ascending doses ranging from 0.5 to 20 ng/kg/min. Each dose will be maintained for 10 minutes with hemodynamic measurements and blood samples collected at the end of each dosing period.

Outcomes

Primary Outcome Measures

Systolic Blood Pressure

The primary outcome will be the change in systolic blood pressure from baseline produced by the Angiotensin (1-7) infusion, with comparisons made between intact and autonomic blockade study days.

Secondary Outcome Measures

Hemodynamic Measures

We will examine for changes in cardiac output, stroke volume, and systemic vascular resistance to determine hemodynamic mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.

Circulating Renin-Angiotensin System Components

We will examine for changes in plasma renin activity, angiotensin II, Angiotensin (1-7), and aldosterone levels to determine renin-angiotensin system hormonal mechanisms underlying any changes in blood pressure during Angiotensin (1-7) infusion.

Full Information

NCT ID

NCT02245230

First Posted

September 17, 2014

Last Updated

January 2, 2023

Sponsor

Vanderbilt University

1. Study Identification

Unique Protocol Identification Number

NCT02245230

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 2015 (Actual)

Primary Completion Date

December 2025 (Anticipated)

Study Completion Date

December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to better understand the cardiovascular effects of the vasodilatory peptide Angiotensin (1-7) in human hypertension. In this study, the investigators will test the hypothesis that systemic Angiotensin (1-7) infusion produces negligible effects with intact baroreceptors, and that the cardiovascular effects of this peptide are unmasked following elimination of baroreflex buffering.

Detailed Description

Pharmacologic approaches to increase levels or actions of the vasodilatory peptide Angiotensin (1-7) are currently in development for the treatment of hypertension based on findings from animal studies. There are limited and contradictory clinical studies, however, and it is unclear if this peptide even contributes to blood pressure regulation in humans. The purpose of this study is to learn more about the cardiovascular effects of Angiotensin (1-7) in essential hypertension, and to examine interactions of this peptide with the autonomic nervous system for blood pressure regulation. The investigators propose that the difficulties in showing Angiotensin (1-7) cardiovascular effects in previous clinical studies relates to the buffering capacity of the baroreceptor reflex to prevent changes in blood pressure. In this study, the investigators will test the hypothesis that Angiotensin (1-7) produces negligible effects with intact baroreceptors, and that the cardiovascular effects of this peptide are unmasked following elimination of baroreflex buffering. To test this hypothesis, the investigators will examine the effects of acute intravenous Angiotensin (1-7) infusion on blood pressure in subjects with essential hypertension under intact conditions and following acute autonomic withdrawal with the ganglionic blocker trimethaphan. The primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7) infusion, with comparisons made between intact and blocked study days. As a secondary objective, the investigators will examine for changes in systemic hemodynamics and circulating hormones in response to the Angiotensin (1-7) infusion, to determine potential mechanisms underlying any changes in blood pressure.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension, Hypertension, Essential

Keywords

Hypertension, Autonomic Nervous System, Renin-Angiotensin System, Angiotensin (1-7), Ganglionic Blockers, Trimethaphan, Blood Pressure, Hemodynamics

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intact Study Day

Arm Type

Active Comparator

Arm Description

Arm Title

Autonomic Blockade Study Day

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Angiotensin (1-7)

Other Intervention Name(s)

Angiotensin-(1-7), Angiotensin I (1-7)

Intervention Description

Angiotensin (1-7) is a peptide produced by the body. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 20 ng/kg/min.

Intervention Type

Drug

Intervention Name(s)

Trimethaphan

Other Intervention Name(s)

Trimethaphan Camsylate

Intervention Description

Trimethaphan is a Nn-nicotinic receptor antagonist that blocks sympathetic and parasympathetic transmission at the level of the autonomic ganglia. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 5.0 mg/min.

Intervention Type

Drug

Intervention Name(s)

Phenylephrine

Other Intervention Name(s)

Phenylephrine Hydrochloride

Intervention Description

Phenylephrine is an alpha 1-adrenergic agonist. It will be administered as an acute intravenous infusion to restore blood pressure following trimethaphan with doses ranging from 0.1 to 0.5 ug/kg/min.

Primary Outcome Measure Information:

Title

Systolic Blood Pressure

Description

The primary outcome will be the change in systolic blood pressure from baseline produced by the Angiotensin (1-7) infusion, with comparisons made between intact and autonomic blockade study days.

Time Frame

Change from baseline in systolic blood pressure over the 50-minute infusion period

Secondary Outcome Measure Information:

Title

Hemodynamic Measures

Description

Time Frame

Change from baseline in hemodynamic measures over the 50-minute infusion period

Title

Circulating Renin-Angiotensin System Components

Description

Time Frame

Change from baseline in circulating renin-angiotensin system components over the 50-minute infusion period

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Males and females of all races between 18 and 60 years of age Hypertension defined by two or more properly measured seated blood pressure readings >130/85 mmHg. This will allow us to include subjects with "pre-hypertension." Able and willing to provide informed consent Exclusion Criteria: Pregnancy or breast feeding Current smokers or history of heavy smoking (>2 packs/day) History of alcohol or drug abuse Previous allergic reaction to study medications Evidence of type I or type II diabetes (i.e. fasting glucose >126 mg/dl, use of anti-diabetic medications) Cardiovascular disease other than hypertension such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy History of serious cerebrovascular disease such as cerebral hemorrhage, stroke, or transient ischemic attack History or presence of immunological or hematological disorders Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) > 2.0 x upper limit of normal range] Impaired renal function (serum creatinine >1.5 mg/dl) Anemia (hemoglobin <13.5 g/dl in males or <12.5 g/dl in females) Treatment with phosphodiesterase 5 inhibitors Treatment with anticoagulants Treatment with chronic systemic glucocorticoid therapy (more than 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 Other factors which in the investigator's opinion would prevent the subject from completing the protocol (i.e. clinically significant abnormalities on clinical, mental examination or laboratory testing or inability to comply with protocol)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Italo Biaggioni, MD

Organizational Affiliation

Vanderbilt University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Vanderbilt University

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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

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