The Role of Endothelin in the Supine Hypertension of Autonomic Failure - Full Text View

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:

Genetics Home Reference related topics: multiple system atrophy

Genetic and Rare Diseases Information Center resources: Multiple System Atrophy Pure Autonomic Failure

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 2016
Estimated Primary Completion Date:	November 2016 (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

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 (Adult, Senior)
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

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: 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


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:	July 7, 2016
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 Atrophy Multiple System Atrophy Shy-Drager Syndrome Pure Autonomic Failure Vascular Diseases Cardiovascular Diseases Pathological Conditions, Anatomical Primary Dysautonomias Autonomic Nervous System Diseases Nervous System Diseases	Basal Ganglia Diseases Brain Diseases Central Nervous System Diseases Movement Disorders Neurodegenerative Diseases Hypotension Cyclo(Trp-Asp-Pro-Val-Leu) Antihypertensive Agents Endothelin Receptor Antagonists Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 28, 2016