Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure

NCT ID: NCT01292694

Last Updated: 2018-08-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2017-03-31

Brief Summary

The purpose of this study is to test the hypothesis that angiotensin II plays a role in the supine hypertension of primary autonomic failure. To determine the contribution of angiotensin II to renin and blood pressure regulation in autonomic failure, patients with multiple system atrophy [MSA] or pure autonomic failure [PAF] and supine hypertension will undergo medication testing with the angiotensin II receptor blocker losartan. The investigators will compare the biochemical and hemodynamic effects between MSA and PAF patients. In a subset of patients, the investigators will also give the ACE inhibitor captopril. Our primary endpoint will be changes in plasma renin activity, and subsequent components of the circulating renin-angiotensin system, in response to angiotensin II blockade. Our secondary outcome will be changes in hemodynamic measures during administration of these drugs.

Detailed Description

Primary autonomic failure is a disabling condition characterized by orthostatic hypotension. It is less well appreciated that at least 50% of these patients have high blood pressure when lying down [supine hypertension]. The mechanisms underlying supine hypertension in autonomic failure remain poorly understood. The hypertension in MSA patients may be explained by residual sympathetic tone, possibly acting on hypersensitive adrenoreceptors and unrestrained by the lack of baroreflex modulation. In contrast, the hypertension in PAF is associated with increased vascular resistance in the absence of residual sympathetic tone. However, the factors driving an elevation in either sympathetic or vascular tone in these patients remain unclear.

The investigators hypothesize that angiotensin II, a hormone widely implicated in blood pressure regulation, plays a role in the supine hypertension of autonomic failure. To determine the contribution of angiotensin II to renin and blood pressure regulation in autonomic failure, the investigators will administer the angiotensin II receptor blocker losartan to MSA and PAF patients with supine hypertension. The primary endpoint will be changes in plasma renin activity, and subsequent components of the circulating renin-angiotensin system, in response to angiotensin II blockade. The secondary outcomes will be the decrease in blood pressure and changes in heart rate, cardiac output, stroke volume and systemic vascular resistance during administration of these drugs.

Subjects will be studied on 2 separate days, one with oral administration of placebo and the other with losartan [50 mg]. The order of administration will be randomized in a single-blind manner. The investigators will collect blood samples before and every 2 hours after administration for up to 6 hours to determine if angiotensin II regulates plasma renin activity, and other components of the circulating renin-angiotensin system, in autonomic failure. The investigators will also obtain hemodynamic measurements before and every 1 hour (blood pressure and heart rate) or 2 hours (cardiac output, stroke volume and systemic vascular resistance) after drug administration.

In a subset of patients the investigators will also administer the ACE inhibitor captopril [50 mg] on a separate study day using the same methods. Captopril is less specific for assessing the role of angiotensin II to hypertension. However, it may provide important information on the mechanism for angiotensin II formation in these patients.

Conditions

Hypertension; Pure Autonomic Failure; Multiple System Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Losartan

Angiotensin II AT1 receptor antagonist which blocks the actions of angiotensin II

Group Type: EXPERIMENTAL

Losartan

Intervention Type: DRUG

Oral, single-dose, 50 mg tablet

Captopril

ACE inhibitor which blocks the formation of angiotensin II

Group Type: EXPERIMENTAL

Captopril

Intervention Type: DRUG

Oral, single-dose, 50 mg tablet

Placebo Tablet

A placebo tablet will be provided by the Vanderbilt Investigational Drug Service for these studies.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral, single administration, gelatin capsule filled with microcrystalline cellulose

Interventions

Losartan

Oral, single-dose, 50 mg tablet

Intervention Type: DRUG

Captopril

Oral, single-dose, 50 mg tablet

Intervention Type: DRUG

Placebo

Oral, single administration, gelatin capsule filled with microcrystalline cellulose

Intervention Type: DRUG

Other Intervention Names

Cozaar; Capoten

Eligibility Criteria

Inclusion Criteria

• Patients with autonomic failure who exhibit supine hypertension and are in the hospital already participating in the study "The Evaluation and Treatment of Autonomic Failure [IRB # 000814]
• Supine hypertension, defined as systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg
• Males and females of all races, between 18 to 85 years of age
• Able and willing to provide informed consent with the understanding that they may withdraw consent at any time without prejudice to future medical care

Exclusion Criteria

• All medical students
• Pregnant women
• Patients with a history of angioedema
• Patients with a known allergy to any ACE inhibitor or angiotensin receptor blocker
• High-risk patients [e.g. heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction]
• Patients with hemoglobin < 10.5 [or hematocrit < 32]
• Inability to give, or withdraw, informed consent
• Other factors which in the investigator's opinion would prevent the patient from completing the protocol including clinically significant abnormalities in clinical, mental or laboratory testing

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Italo Biaggioni

Professor and Associate Director Clinical Research Center

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Italo Biaggioni, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

101618

Identifier Type: -

Identifier Source: org_study_id