Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01292694
First received: February 8, 2011
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention
Hypertension
Pure Autonomic Failure
Multiple System Atrophy
Drug: Losartan
Drug: Captopril
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
Official Title: Contribution of Angiotensin II to Supine Hypertension in Autonomic Failure

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Changes in plasma renin activity and subsequent components of the circulating renin-angiotensin system [ Time Frame: 0 - 6 hours post administration ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Changes in blood pressure [ Time Frame: 0 - 6 hours post administration ] [ Designated as safety issue: No ]
  • Changes in heart rate, cardiac output, stroke volume and systemic vascular resistance [ Time Frame: 0 - 6 hours post administration ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: April 2011
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Losartan
Angiotensin II AT1 receptor antagonist which blocks the actions of angiotensin II
Drug: Losartan
Oral, single-dose, 50 mg tablet
Other Name: Cozaar
Experimental: Captopril
ACE inhibitor which blocks the formation of angiotensin II
Drug: Captopril
Oral, single-dose, 50 mg tablet
Other Name: Capoten
Placebo Comparator: Placebo Tablet
A placebo tablet will be provided by the Vanderbilt Investigational Drug Service for these studies.
Drug: Placebo
Oral, single administration, gelatin capsule filled with microcrystalline cellulose

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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01292694

Contacts
Contact: Bonnie K Black, RN 615-322-3304 adcresearch@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Bonnie K Black, RN    615-322-3304    adcresearch@vanderbilt.edu   
Principal Investigator: Italo Biaggioni, MD         
Sub-Investigator: Amy C Arnold, PhD         
Sub-Investigator: Alfredo Gamboa, MD         
Sub-Investigator: Luis E Okamoto, MD         
Sub-Investigator: Cyndya A Shibao, MD         
Sub-Investigator: Andre Diedrich, MD/PhD         
Sub-Investigator: Satish Raj, MD, MSCI         
Sub-Investigator: David H Robertson, MD         
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Italo Biaggioni, MD Vanderbilt University
  More Information

Additional Information:
No publications provided

Responsible Party: Italo Biaggioni, Professor and Associate Director Clinical Research Center, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01292694     History of Changes
Other Study ID Numbers: 101618
Study First Received: February 8, 2011
Last Updated: May 27, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Vanderbilt University:
supine hypertension
autonomic failure
angiotensin
losartan
captopril

Additional relevant MeSH terms:
Multiple System Atrophy
Shy-Drager Syndrome
Hypertension
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Hypotension
Losartan
Captopril
Angiotensin II
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014