Vascular Pathophysiology in Obstructive Sleep Apnea
| Status: | Withdrawn |
|---|---|
| Conditions: | Insomnia Sleep Studies, Pulmonary, Pulmonary |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
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.
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.
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
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