Study of Cardiovascular Disease and Obstructive Sleep Apnea (CVD/OSA)

• Aortic Pulse Wave Velocity [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  measurement of vascular stiffness assessed before and after study drug treatment
• Cerebral Blood Flow [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessment measures of cerebral and forearm blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Plasma catecholamine concentrations before and after study drug and change in plasma catecholamines during hypoxia will be assessed as a secondary indicator of sympathetic activation.
• Forearm Blood Flow [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessment measurements of forearm blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Plasma catecholamines during hypoxia will be assessed as a secondary indicator of sympathetic activation.
• Minute ventilation at rest and during hypoxia [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Aortic Augmentation Index [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• % Vasodilation [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  Flow-mediated vasodilation (measurement of vascular endothelilal function) assessed before and after study drug treatment
• Apnea Threshold [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Apnea-Hypopnea Index [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• % Time Spent Below 90% Oxygen Saturation [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Mean Blood Pressure [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  Mean 24 hour blood pressure, mean nighttime blood pressure, mean daytime blood pressure, blood pressure load, and night/day pressure ratio assessed before and after study drug treatment

• Aortic Pulse Wave Velocity [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  measurement of vascular stiffness assessed before and after study drug treatment
• Cerebral Blood Flow [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessment measures of cerebral and forearm blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Plasma catecholamine concentrations before and after study drug and change in plasma catecholamines during hypoxia will be assessed as a secondary indicator of sympathetic activation.
• Forearm Blood Flow [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessment measurements of forearm blood flow during basal conditions and during graded hypoxia before and after study drug treatment. Plasma catecholamines during hypoxia will be assessed as a secondary indicator of sympathetic activation.
• Ventilation Outcome Variable [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Aortic Augmentation Index [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• % Vasodilation [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  Flow-mediated vasodilation (measurement of vascular endothelilal function) assessed before and after study drug treatment
• Apnea Threshold [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Apnea-Hypopnea Index [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• % Time Spent Below 90% Oxygen Saturation [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  assessed before and after study drug treatment
• Mean Blood Pressure [ Time Frame: baseline and 6 weeks ] [ Designated as safety issue: No ]
  Mean 24 hour blood pressure, mean nighttime blood pressure, mean daytime blood pressure, blood pressure load, and night/day pressure ratio assessed before and after study drug treatment

The purpose of this study is to determine if two medicines (allopurinol and losartan) can influence heart and blood vessel health compared to placebo in patients with sleep apnea who are using continuous positive airway pressure (CPAP).

The specific aims of this research project are: 1) Determine if treatment with losartan, an angiotensin type I receptor (AT1R) antagonist, or allopurinol, a XO inhibitor, normalize chemoreflex control of sympathetic outflow and ventilation and improve local vascular regulation and stiffness; and 2) Determine if these interventions reduce the severity of sleep disordered breathing and lower diurnal blood pressure.

• Severe Obstructive Sleep Apnea (Apnea Hypopnea Index > 30 Events/Hour)
• Hypertension

• Drug: Losartan
  Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic. Remain at 50 mg daily for 4 more weeks or removed from study if symptomatic.
• Drug: Allopurinol
  Allopurinol 300 mg daily for 6 weeks
• Drug: Placebo
  Placebo capsule daily for 6 weeks

• Active Comparator: Losartan
  Losartan 50 mg daily for two weeks, then increased to 100mg daily for 4 weeks if asymptomatic and blood pressure within range.
  Intervention: Drug: Losartan
• Active Comparator: Allopurinol
  Allopurinol 300 mg daily for 6 weeks
  Intervention: Drug: Allopurinol
• Placebo Comparator: Placebo
  Placebo capsule daily for 6 weeks
  Intervention: Drug: Placebo

Inclusion Criteria:

• Males and females between ages of 21 and 55 years
• Apnea hypopnea index greater than 30 events per hour
• Subjects eligible for CPAP therapy
• Subjects on CPAP required to have 3 months or more of treatment
• Hypertension by clinical history/diagnosis (may be controlled with non- exclusionary medications) or average blood pressure > 140/90 mm Hg (using last two measurements in 3 months - 1 prior blood pressure and 1 blood pressure at screening)

Exclusion Criteria:

• If subject not using CPAP, having AHI > 60 events/hour or oxygen saturation ≤ 65% during sleep
• Presence of clinical CV disease (coronary artery disease, angina, arrhythmias (subjects with sinus arrhythmias will be reviewed by PI for enrollment), stroke, TIA, cor pulmonale, etc.), heart failure, bruits, or diabetes mellitus by clinical diagnosis/history
• Presence of pulmonary disease that results in significant hypoxemia (resting SaO2 < 88%)
• Hypertriglyceridemia (triglycerides >150 mg/dL), diabetes or impaired glucose tolerance (fasting plasma glucose > 100 mg/dL)
• Patients taking angiotensin converting enzyme inhibitors, beta blockers, phosphodiesterase type 5 inhibitors, alpha blockers, angiotensin receptor antagonists, potassium-sparing diuretics (without accompanying loop/thiazide diuretic), allopurinol, oxypurinol, febuxostat, amoxicillin, ampicillin, azathioprine or mercaptopurine.
• Patients with chronic kidney disease (Serum creatinine >1.5 mg/dL) or history of significant hyperkalemia (Serum potassium > 5.2 mEq/L) with ARB therapy
• Patients with history of angioedema
• Patients with bilateral,modified radical or radical mastectomies
• Patients who have a Serum potassium > 5.0 mEq/L at the screening visit
• Female patients who are pregnant (determined by urine pregnancy test) or breastfeeding
• Patients with active MRSA or VRE (vancomycin resistant enterococcus) infection
• History of adverse reaction to allopurinol,losartan, or zolpidem**
• Patients who cannot swallow oral capsules
• Patients who are hospitalized or who have been recently hospitalized (last 2 weeks)
• Inability to comply with or complete the protocol or other reasons at the discretion of the investigators