Vascular Pathophysiology in Obstructive Sleep Apnea
Status:
Withdrawn
Trial end date:
1969-12-31
Target enrollment:
Participant gender:
Summary
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.