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

NCT02245230 | Terminated Phase 1 DMC

• 1 other identifier: 140958
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypertension; Hypertension, Essential

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

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

Secondary Outcomes (2)

• Hemodynamic Measures

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

• Circulating Renin-Angiotensin System Components

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

Study Arms (2)

Intact Study Day

ACTIVE COMPARATOR

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.

Drug: Angiotensin (1-7)

Autonomic Blockade Study Day

EXPERIMENTAL

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.

Drug: Angiotensin (1-7); Drug: Trimethaphan; Drug: Phenylephrine

Interventions

Angiotensin (1-7) DRUG

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.

Also known as: Angiotensin-(1-7), Angiotensin I (1-7)

Autonomic Blockade Study Day; Intact Study Day

Trimethaphan DRUG

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.

Also known as: Trimethaphan Camsylate

Autonomic Blockade Study Day

Phenylephrine DRUG

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.

Also known as: Phenylephrine Hydrochloride

Autonomic Blockade Study Day

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Hypertension; Essential Hypertension

Interventions

angiotensin I (1-7); Trimethaphan; trimethaphan camsylate; Phenylephrine

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Study Officials

• Italo Biaggioni, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: September 17, 2014
• First Posted: September 19, 2014
• Study Start: January 1, 2015
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: January 9, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)