Effects of Inorganic Nitrate Supplementation on Heart Rate and Ventilatory Responsiveness to Acute Hypoxia and Blood Pressure in Patients with Obstructive Sleep Apnea

When individuals encounter periods of low oxygen, hypoxia, the peripheral chemoreflex works to restore saturation to normal levels. The peripheral chemoreceptors are responsible for sensing such decreases in oxygen and signaling consequent increases in ventilation and sympathetic-mediated cardiovascular (CV) responses. Aside from oxygen, other molecules like glucose, insulin, leptin, carbon dioxide_, and nitric oxide (NO) have been shown to affect this reflex. NO, specifically, exhibits a reflex blunting effect demonstrated by various animal studies. Obstructive sleep apnea (OSA), a disease characterized by repeated mechanical occlusions of the upper airway during sleep, demonstrates both a pathophysiological sensitization of the peripheral chemoreflex and a noted decrease in bioavailable NO. This study’s purpose was to analyze the effects of acute inorganic nitrate supplementation (beetroot juice), a dietary path for increasing bioavailable NO, on the heart rate and ventilatory response to acute hypoxia and brachial blood-pressure (BP) in subjects with OSA. We hypothesized that, inorganic nitrate would blunt chemoreflex responsiveness as observed through the ventilatory and cardiovascular (HR) biomarkers. The study followed a double-blind, randomized, placebo-controlled format in which 14 subjects with mild-to-moderate OSA, over the course of two study days, consumed both the placebo beetroot juice (BR_P) and the nitrate beetroot juice (BR_N;500mg inorganic-nitrate and 40mg nitrite). Peripheral chemoreflex responsiveness was analyzed as the absolute-change and the linear-regression against SpO₂ for HR and V_E. The ventilatory response was analyzed under two criteria: baseline to target 80% hypoxia (Bl-T) and baseline to peak response (Bl-P). The effects of BR_P and BR_N were analyzed as the comparison between the two bouts of acute hypoxia (pre-vs-post supplementation) conducted on each study day. The intervention successfully increased NO bioavailability (plasma-nitrate: pre:26±11μmol/L , post:292±90μmol/L, pE responsiveness increased in the absolute-change Bl-P-BR_P (pre:3.1±1.2L/min, post:4.3±2.3L/min, p=0.03) but not BR_N (pre:4.3±2.6L/min, post:4.8±2.7L/min, p=0.43). The V_E Bl-T absolute-change (p=0.11), Bl-P linear-regression (p=0.33), and Bl-T linear-regression (p=0.08) also did not change. The HR response to hypoxia (linear-regression and absolute-change) was unaltered in either intervention (p=0.12, p=0.54 respectively). Systolic BP (SBP) increased under BR_P (pre:120±9, post:127±10, pN (pre: 123±13 mmHg, post: 123±9 mmHg, p=0.96)_, DBP did not change in BR_P or BR_N (p=0.08). Holistically, these findings suggest no impact of nitrate supplementation on peripheral chemoreflex effectors (HR and ventilatory response) in OSA. Alternatively, the SBP response to nitrate supplementation may suggest inorganic nitrate can blunt diurnal increases in BP.