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The Role of Endothelin in the Supine Hypertension of Autonomic Failure

This study is currently recruiting participants.
Verified May 2012 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01119417
First received: May 4, 2010
Last updated: May 10, 2012
Last verified: May 2012
History of Changes
  Purpose

The purpose of this study is to test the hypothesis that endothelin plays a role in the pathogenesis of supine hypertension in pure autonomic failure by increasing vascular resistance. To gauge its contribution to blood pressure regulation, pure autonomic failure and multiple system atrophy patients with supine hypertension will undergo a medication testing with the endothelin blocker, BQ123. We will compare the hemodynamic effects between PAF and MSA patients. Our primary endpoint will be the decrease in blood pressure during the administration of this compound.


Condition Intervention
Hypertension
Pure Autonomic Failure
Multiple System Atrophy
 Drug: BQ123
Drug: Bq123
Drug: Saline

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Official Title: The Role of Endothelin in the Supine Hypertension of Autonomic Failure

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Change in Systolic BP [ Time Frame: 0 -4 hr post infusion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in cardiac output, stroke volume and systemic vascular resistance [ Time Frame: 0-4 hr post infusion ] [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: May 2010
Estimated Study Completion Date: November 2013
Estimated Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BQ123
endothelin blocker
 Drug: BQ123
Low dose day: 25 nmol/min, single IV infusion for 15 min.
Other Name: BQ-123 sodium salt
Drug: BQ123
Low dose day: 50 nmol/min, single IV infusion for 15 min
Other Name: BQ-123 sodium salt
Drug: Bq123
High dose day: 100 nmol/min, single IV infusion for 15 min.
Other Name: BQ-123 sodium salt
Drug: BQ123
High dose day: 300 nmol/min, single IV infusion for 15 min.
Other Name: BQ-123 sodium salt
Placebo Comparator: Saline
IV saline
 Drug: Saline
2-3 IV saline infusions for 15 min each.
Other Name: Normal saline, 0.9% sodium chloride

Detailed Description:

The pathophysiologic mechanisms causing supine hypertension in patients with autonomic failure are not completely understood.In MSA patients, supine hypertension may be explained by residual sympathetic tone, possibly acting on hypersensitive adrenoreceptors and unstrained by the lack of baroreflex modulation. In contrast, the pathogenesis of hypertension in PAF remains unknown. Hypertension in these patients is not related to intravascular volume, residual sympathetic tone, or renin mechanisms. Increased vascular resistance is the underlying hemodynamic mechanism. The driving force of this increased vascular tone, however, is not known.

We hypothesize that endothelin (ET)-l contributes to the increased vascular resistance in pure autonomic failure patients with supine hypertension. To gauge its contribution to blood pressure regulation, we will induce endothelin blockade with acute systemic administration of BQ123 in an ascending dose regimen (25, 50, 100 and 300 nmol/min) and we will compare the hemodynamic effects between PAF and MSA patients.

Subjects will be studied on 3 different days, one with saline (placebo) and two with BQ123: a 'low dose' day (25 and 50 nmol/min infusions separated by 75 min) and a 'high dose' day (100 and 300 nmol/min infusions separated by 75 min). The order of the placebo day will be randomized in a single-blinded manner so that each subject receives it on a different visit. The order of the BQ123 study days will be always the same, starting with the low dose. If SBP drops by >40 mm Hg or SBP < 130 mm Hg during the monitoring period after the first or second infusion, the following dose(s) of BQ123 will not be given and patients will receive normal saline until the study ends.

Ganglionic Blockade with Trimethaphan (optional study day):

The purpose of this study day is to determine the level of residual sympathetic tone that contributes to supine hypertension in each autonomic failure patient by inducing transient withdrawal of the autonomic nervous system. This approach would allow us to identify patients in whom supine hypertension is not driven by sympathetic tone and thus, better characterize the role of endothelin in the hypertension of 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 and supine hypertension from all races, who are in the hospital participating in the study "The Evaluation and Treatment of Autonomic Failure" (IRB# 000814).
  • Supine hypertension, defined as a systolic blood pressure >150 mm Hg or diastolic blood pressure > 90 mm Hg.
  • Males and females, between 18-85yr.
  • Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care.

Exclusion Criteria:

  • Pregnant women.
  • High-risk patients (e.g. heart failure, symptomatic coronary artery disease, liver impairment, history of stroke or myocardial infarction).
  • History of serious allergies or asthma.
  • In the investigator's opinion, have clinically significant abnormalities on clinical, mental examination or laboratory testing.
  • All medical students.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01119417

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

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

Additional Information:
Autonomic Dysfunction Center. Vanderbilt University  This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party: Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01119417     History of Changes
Other Study ID Numbers: 091344
Study First Received: May 4, 2010
Last Updated: May 10, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Vanderbilt University:
supine Hypertension
autonomic failure
BQ123
BQ-123
endothelin

Additional relevant MeSH terms:
Hypertension
Multiple System Atrophy
Shy-Drager Syndrome
Atrophy
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
Pathological Conditions, Anatomical
Cyclo(Trp-Asp-Pro-Val-Leu)
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 22, 2013