Vascular Pathophysiology in Obstructive Sleep Apnea

October 6, 2015 updated by: University of Wisconsin, Madison

Influence of Xanthine Oxidase Inhibition on Vascular Function in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a medical problem whose importance is increasing in recognition and awareness. The National Commission on Sleep Disorders estimates that 15 million Americans have OSA, many of whom remain undiagnosed (24). OSA is associated with the development of hypertension and other cardiovascular diseases (1,2). Patients with OSA, like those with congestive heart failure, hypertension, hypercholesterolemia and diabetes, exhibit impaired EDV (25-32). OSA is also associated with impairments in endothelium-dependent cerebral blood flow responses, which may be a risk factor for stroke (33). Impaired EDV is a result of reduced production or inadequate action of nitric oxide. Since EDV worsens with disease progression and improves with disease treatment, it serves as a prognostic marker of vascular function (34-37). In OSA, hypoxia and neurohumoral disturbances increase generation of reactive oxygen species (ROS) that neutralize nitric oxide and impair endothelium-dependent responses (9,10,38). One source of ROS in endothelial cells is the enzyme xanthine oxidase (38). XO is an enzyme present in the vascular endothelium that significantly contributes to generation of ROS in congestive heart failure, hypercholesterolemia and diabetes (13-17). Inhibition of XO improves endothelium-dependent resistance vessel responses in these populations (13-17), but it is unknown if XO significantly contributes to oxidative stress and endothelial dysfunction in OSA. The central hypothesis of this application is that inhibition of XO with allopurinol will reduce oxidative stress and generation of ROS, thereby improving nitric oxide bioavailability and EDV in OSA. Our hypothesis has been formulated on the basis that patients with OSA experience repeated hypoxemia that increases activity of XO and other enzymes, thus increasing the generation of ROS that negatively impact EDV. Hypoxia is detrimental to vascular homeostasis since it increases generation of ROS through direct mechanisms and via activation of XO.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Interventional

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with Sleep Disordered Breathing:
  • Significant obstructive sleep apnea as verified by complete overnight polysomnography with apnea-hypopnea index (AHI) > 10 events per hour.
  • Fasting total cholesterol < 240 mg/dL
  • Fasting blood glucose < 120 mg/dL
  • Control subjects:
  • Free of sleep disordered breathing verified by complete overnight polysomnography or oxygen desaturation screening (AHI < 5 events per hour)
  • Fasting total cholesterol < 240 mg/dL
  • Fasting blood glucose < 120 mg/dL

Exclusion Criteria:

  • Presence of any cardiovascular diseases or medical conditions that will affect vascular responses (other than sleep apnea)
  • Subject taking any vasoactive medications, willing to stop taking vitamins or supplements for study participation
  • Current smokers
  • History of adverse reaction to allopurinol, acetylcholine, nitroprusside, verapamil or lidocaine

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Forearm resistance ratios between the infused and non-infused arms at the highest dose of acetylcholine (30 mcg/minute)

Secondary Outcome Measures

Outcome Measure
Area under the curve in reduction of forearm resistance during acetylcholine following allopurinol compared to placebo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Wisconsin, Madison

Investigators

  • Principal Investigator: John M Dopp, PharmD, University of Wisconsin, Madison

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

First Submitted

September 13, 2005

First Submitted That Met QC Criteria

September 13, 2005

First Posted (Estimate)

September 21, 2005

Study Record Updates

Last Update Posted (Estimate)

October 8, 2015

Last Update Submitted That Met QC Criteria

October 6, 2015

Last Verified

October 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2003-085

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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