An increase or a decrease in PnO GABA levels causes an increase or decrease, respectively, in wakefulness. Hypocretin-1 may promote wakefulness, at least in part, by increasing GABAergic transmission in the PnO.

No abstract

An AHI < 10 events/hr by PAP AED is usually associated with good treatment efficacy. Differences between manually scored and AED events were primarily due to different criteria for hypopnea detection.

Rationale Nitrate-rich beetroot juice has been shown to improve exercise capacity in Heart Failure with Preserved Ejection Fraction (HFpEF), but studies using pharmacologic preparations of inorganic nitrate are lacking. Objectives To determine: (1) the dose-response effect of potassium nitrate (KNO3) on exercise capacity; (2) the population-specific pharmacokinetic and safety profile of KNO3 in HFpEF. Methods and Results We randomized 12 subjects with HFpEF to oral KNO3 (n=9) or potassium chloride (KCl, n=3). Subjects received 6mmol twice-daily during Week-1, followed by 6mmol thrice-daily during Week-2. Supine cycle ergometry was performed at baseline (Visit 1) and after each week (Visits 2&3). Quality of life (QOL) was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The primary efficacy outcome, peak O2-uptake, did not significantly improve (P=0.13). Exploratory outcomes included exercise duration and quality of life. Exercise duration increased significantly with KNO3 (Visit 1: 9.87 [95%CI=9.31–10.43]; Visit 2: 10.73 [95%CI=10.13–11.33]; Visit 3: 11.61 [95%CI=11.05–12.17] minutes, P=0.002). Improvements in the KCCQ total symptom (Visit 1: 58.0 [95%CI=52.5–63.5], Visit 2: 66.8 [95%CI=61.3–72.3]; Visit 3: 70.8 [95%CI=65.3–76.3], P=0.016) and functional status scores (Visit 1: 62.2 [95%CI=58.5–66.0], Visit 2: 68.6 [95%CI=64.9–72.3], Visit 3: 71.1 [95%CI=67.3–74.8]; P=0.01) were seen after KNO3. Pronounced elevations in trough levels of nitric oxide metabolites (NOm) occurred with KNO3 (Visit 2: 199.5 [95%CI=98.7–300.2]; Visit 3: 471.8 [95%CI=377.8–565.8]) versus baseline (Visit 1: 38.0 [95%CI=0.00–132.0] μM; P<0.001). KNO3 did not lead to clinically-significant hypotension or methemoglobinemia. Following 6 mmol of KNO3, systolic blood pressure was reduced by a maximum of 17.9 (95%CI −28.3-[−7.6]) mmHg 3.75 hours later. Peak NOm concentrations were 259.3 (95%CI 176.2–342.4) μM 3.5 hours after ingestion, and the median half-life was 73.0 (IQR 33.4–232.0) minutes. Conclusions KNO3 is potentially well-tolerated and improves exercise duration and QOL in HFpEF. This study reinforces the efficacy of KNO3 and suggests that larger randomized trials are warranted. ClinicalTrials.gov NCT02256345; https://www.clinicaltrials.gov/ct2/show/NCT02256345