The Role of Endothelin in the Supine Hypertension of Autonomic Failure

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Hypertension; Pure Autonomic Failure; Multiple System Atrophy	Drug: BQ123; Drug: Bq123; Drug: Saline	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Single (Participant)
Primary Purpose:	Other
Official Title:	The Role of Endothelin in the Supine Hypertension of Autonomic Failure
Study Start Date :	May 2010
Estimated Primary Completion Date :	December 2020
Estimated Study Completion Date :	December 2020

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
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

Outcome Measures

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Primary Outcome Measures :

1. Change in Systolic BP [ Time Frame: 0 -4 hr post infusion ]

Secondary Outcome Measures :

1. Change in cardiac output, stroke volume and systemic vascular resistance [ Time Frame: 0-4 hr post infusion ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 85 Years (Adult, Senior)
Sexes Eligible for Study:	All
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

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Locations

United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

Investigators

Principal Investigator:	Italo Biaggioni, M.D.	Vanderbilt University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Autonomic Dysfunction Center. Vanderbilt University 

Responsible Party:	Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT01119417 History of Changes
Other Study ID Numbers:	091344
First Posted:	May 7, 2010
Last Update Posted:	January 25, 2018
Last Verified:	January 2018

Keywords provided by Italo Biaggioni, 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