Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome

doi:10.1016/S1389-9457(03)00102-3

Sleep Medicine

Volume 4, Issue 5, September 2003, Pages 403-407

https://doi.org/10.1016/S1389-9457(03)00102-3 Get rights and content

Abstract

Objectives and background: Nocturnal apnea and hypoxia are implicated in the pathogenesis of pulmonary and systemic hypertension in obstructive sleep apnea syndrome (OSAS). We have hypothesized that vasodilating factors including nitric oxide (NO) are affected by nocturnal apnea and hypoxia in patients with OSAS.

Method: We examined the serum level of NO production in 24 patients with OSAS (mean age 54.2±7.9 years) and 24 age-matched control subjects (53.4±8.1 years) and tested the effects of oxygen administration on the production of NO in the patients.

Results: The serum level of nitrite/nitrates (NO_x), which are stable metabolites of NO, was lower in patients with OSAS than in control subjects. Administration of 1–2 l/min of oxygen during night increased the patients' NO_x level from 35.6±7.3 to 57.8±11.6 μM. Compressed air administration did not affect the NO_x level in the patients.

Conclusion: These results indicate that systemic NO production is impaired in OSAS patients, possibly due to nocturnal hypoxia.

Introduction

Obstructive sleep apnea syndrome (OSAS) is now recognized as an important sleep disorder, contributing to excessive daytime sleepiness, cardiovascular dysfunction, and the impairment of health-related quality of life [1], [2], [3], [4], [5], [6]. Hypoxia, hypertension, hypoxic pulmonary vasoconstriction, pulmonary hypertension, and altered cardiovascular variability are implicated in the subsequent development of overt cardiovascular diseases, resulting in increased mortality [7], [8]. However, the mechanisms underlying the causal relationship between OSAS and cardiovascular diseases are largely unknown. Nitric oxide (NO) is one of the key regulators of vascular physiology [9], [10]. Abnormalities of NO productions have been implicated in the pathogenesis of pulmonary hypertension [11], [12]. The concentration of NO in the exhaled air appears to be reduced in patients with pulmonary hypertension [13]. Treatment of pulmonary hypertension with NO inhalation reduces pulmonary vascular resistance in patients with pulmonary hypertension [14]. We thus speculated that the production of NO might be impaired in patients with OSAS.

The aim of the present study was to compare the serum level of NO production between OSAS and control subjects. Furthermore, to examine the relationship between NO production and nocturnal hypoxemia in patients with OSAS, we examined the effects of oxygen administration on the production of NO in patients with OSAS.

Section snippets

Subjects

All patients referred for PSG had daytime fatigue, sleepiness, and/or snoring. From April 2000 to November 2001, we invited all patients who had been referred for a diagnostic PSG to participate in this study. Once consent had been received, patients underwent a diagnostic polysomnography (PSG).

Twenty-four patients with OSAS (19 men, 5 women, mean (±SD) aged 56±4 (range 35–66)) and 24 age-matched controls (20 men; 4 women, mean (±SD) aged 53±4 (range 30–68)) were studied. OSAS was defined as

Sleep study

All subjects were admitted for two or more consecutive nights for polysomnographic study. Polysomnography consisted of 8 h of overnight monitoring using a standard technique [16]. Respiratory effort was measured by respiratory inductance plethymography (Respitrace Corp., USA), and airflow at the nose and mouth was measured with thermistors. Surface electrodes were applied to obtain an electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram, and a record of heart rate. Arterial

Results

In the current study, all the participants in both the OSAS group (body mass index (BMI)=28.8±2.0) and the control group (BMI=28.4±3.3) were obese. The control subjects were matched for age and BMI. spirometric indices, and variables of arterial blood gas were within normal range in all subjects. Anthropometric and pulmonary function data are shown in Table 1. The control subjects were also matched for parameters of pulmonary function testing and blood gas analysis. In the OSAS group, all 20

Discussion

The present study demonstrates that the serum levels of nitrite/nitrate (NO_x), which are stable metabolites of NO, were smaller in OSAS patients than in control subjects. It has recently been reported that the early morning serum NO_x levels were significantly lower in OSAS subjects than in control subjects (OSAS=38.9 μM, control subjects=63.1 μM) [18]. Schulz and coworkers have reported that NO_x levels were 21.7 μM in OSA patients, compared with 42.6 μM in healthy volunteers and 36.7 μM in

Acknowledgements

This study was supported by the 21st Medical frontier research grant from the Ministry of Health and Welfare and Japan Arteriosclerosis Prevention Fund.

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A primary characteristic of obstructive sleep apnea (OSA) is chronic exposure to intermittent hypoxia (IH) due to repeated upper airway obstruction. Chronic IH exposure is believed to increase OSA severity over time by enhancing the acute ventilatory response to hypoxia (AHVR), thus promoting ventilatory overshoot when apnea ends and perpetuation of apnea during sleep. Continuous positive airway pressure (CPAP), the gold-standard treatment of OSA, reduces the AHVR, believed to result from correction of IH. However, CPAP also corrects ancillary features of OSA such as intermittent hypercapnia, negative intrathoracic pressure and surges in sympathetic activity, which may also contribute to the reduction in AHVR. Therefore, the objective of this study was to investigate the impact of nocturnal oxygen therapy (to remove IH only) and CPAP (to correct IH and ancillary features of OSA) on AHVR in newly diagnosed OSA patients. Fifty-two OSA patients and twenty-two controls were recruited. The AHVR was assessed using a 5 min iscopanic-hypoxic challenge before, and after, treatment of OSA by nocturnal oxygen therapy and CPAP. Following baseline measurements, OSA patients were randomly assigned to nocturnal oxygen therapy (Oxygen, n = 26) or no treatment (Air; n = 26). The AHVR was re-assessed following two weeks of oxygen therapy or no treatment, after which all patients were treated with CPAP. The AHVR was quantified following ~4 weeks of adherent CPAP therapy (n = 40). Both nocturnal oxygen and CPAP treatments improved hypoxemia (p < 0.05), and, as expected, nocturnal oxygen therapy did not completely abolish respiratory events (i.e., apneas/hypopneas). Averaged across all OSA patients, nocturnal oxygen therapy did not change AHVR from baseline to post-oxygen therapy. Similarly, the AHVR was not altered pre- and post-CPAP (p > 0.05). However, there was a significant decrease in AHVR with both nocturnal oxygen therapy and CPAP in patients in the highest OSA severity quartile (p < 0.05). Nocturnal oxygen therapy and CPAP both reduce the AHVR in patients with the most severe OSA. Therefore, IH appears to be the primary mechanism producing ventilatory instability in patients with severe OSA via enhancement of the AHVR.
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Moderate to severe obstructive sleep apnea (OSA) occurs in 10–17% of middle aged men and 3–9% of middle-aged women with a higher prevalence among obese subjects. This condition is an independent risk factor for many cardiovascular diseases. Intermittent hypoxia is a major pathophysiologic character of OSA; it can lead to oxidative stress and inflammation, which in their turn cause endothelial dysfunction, a hallmark of atherosclerosis. Many animal models have been designed to mimic OSA in human patients to allow more in-depth investigation of biological and cellular mechanisms of this condition. This review discusses the cardiovascular outcomes of OSA and some of the animal models that are being used to investigate it.
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Increasing data support a connection between obstructive sleep apnea (OSA) and cognitive impairment but a causal link has yet to be established. Although neuronal loss has been linked to cognitive impairment, emerging theories propose that changes in synaptic plasticity can cause cognitive impairment. Studies demonstrate that disruption to the blood–brain barrier (BBB), which is uniquely structured to tightly maintain homeostasis inside the brain, leads to changes in the brain's microenvironment and affects synaptic plasticity. Cyclical intermittent hypoxia is a stressor that could disrupt the BBB via molecular responses already known to occur in either OSA patients or animal models of intermittent hypoxia. However, we do not yet know if or how intermittent hypoxia can cause cognitive impairment by mechanisms operating at the BBB. Therefore, we propose that initially, adaptive homeostatic responses at the BBB occur in response to increased oxygen and nutrient demand, specifically through regulation of influx and efflux BBB transporters that alter microvessel permeability. We further hypothesize that although these responses are initially adaptive, these changes in BBB transporters can have long-term consequences that disrupt the brain's microenvironment and alter synaptic plasticity leading to cognitive impairment.
Serum nitrite and nitrate levels in children with obstructive sleep-disordered breathing
2010, Sleep Medicine
Citation Excerpt :
Three recent studies using 24-h ambulatory blood pressure monitoring and one population-based investigation have demonstrated increased blood pressure levels in pediatric patients with sleep apnea [25–27,40]. The absence of a significant association between levels of NO metabolites and blood pressure in participants of the current report as well as in adult participants of the majority of published studies [17,18,38] may be due to several different reasons. First, blood pressure alterations related to SDB in childhood are generally subtle (as little as 3 mm Hg) and may be detectable only by using 24-h ambulatory blood pressure monitoring or by studying large patient samples [25,40].
Diminished nitric oxide (NO) levels have been reported in adults with obstructive sleep apnea but no data are available for children with obstructive sleep-disordered breathing (SDB).
To assess levels of serum NO metabolites in children with SDB and to explore the effects of NO metabolites, SDB and their interaction on blood pressure.
Morning nitrite, the sum of nitrite and nitrate (NO_x), and the average of evening and morning blood pressure were assessed in children with SDB referred for polysomnography and in controls without SDB.
Forty-three children with SDB (age: 5.8 ± 2.1 years) had moderate-to-severe nocturnal hypoxemia (SpO₂ nadir: 85.6 ± 4%), 54 subjects (6.6 ± 2.7 years) had mild hypoxemia (SpO₂ nadir: 91.4 ± 1.3%) and 20 subjects were controls free of SDB (6.7 ± 3.7 years). Subjects with moderate-to-severe hypoxemia had significantly lower ln-transformed NO metabolites (1.4 ± 0.7, nitrites; 2.6 ± 0.5, NO_x) compared to those with mild hypoxemia (1.9 ± 0.8, nitrites; 3 ± 0.6, NO_x) and controls (2.2 ± 0.7, nitrite; 3 ± 0.6, NO_x; p < 0.05). The effects of NO metabolites and SDB or their interaction on blood pressure were not significant (p > 0.05).
Moderate-to-severe hypoxemia accompanying SDB is associated with reduced concentrations of morning serum NO metabolites, but NO levels do not seem to affect blood pressure.
Defining common outcome metrics used in obstructive sleep apnea
2008, Sleep Medicine Reviews
Citation Excerpt :
Sympathetic activation via OSA, obesity, and hypoxemia may be contributing factors to these differences.50,57 Similarly, Teramoto et al. have shown that nitric oxide production is impaired in patients with OSA, likely due to nocturnal hypoxia.59 In obese subjects, reduction of TNF activity with etanercept, a TNF-α antagonist, results in marked reductions in objective but not subjective sleepiness, AHI, and IL-6 levels.60
Sleep-disordered breathing a spectrum that ranges from snoring through disorder of increased airway resistance, to overt sleep apnea affects many clinical disease outcomes. Traditionally, disease outcomes have been measured by polysomnography, with the most common metric being the apnea hypopnea index (AHI). Multiple other clinical metrics are commonly used to assess the severity and impact of disease on important outcomes of obstructive sleep apnea (OSA). These allow assessment of sleepiness, quality of life, performance, and medical, especially cardiovascular outcomes. Currently the available metrics only partially explain the associated disease outcomes in different patients. This review highlights the available clinical, physiological and biomarker metrics in measuring OSA and associated co-morbidities and defines treatment goals.
Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: A randomised trial
2009, Thorax
Previous studies have presented contradictory data concerning obstructive sleep apnoea syndrome (OSAS), lipid oxidation and nitric oxide (NO) bioavailability. This study was undertaken to (1) compare the concentration of 8-isoprostane and total nitrate and nitrite (NOx) in plasma of middle-aged men with OSAS and no other known co-morbidity and healthy controls of the same age, gender and body mass index; and (2) test the hypothesis that nasal continuous positive airway pressure (CPAP) therapy attenuates oxidative stress and nitrate deficiency.
A prospective, randomised, placebo controlled, double-blind, crossover study was performed in 31 consecutive middle-aged men with newly diagnosed OSAS and 15 healthy control subjects. Patients with OSAS were randomised to receive sham CPAP or effective CPAP for 12 weeks. Blood pressure, urinary catecholamine levels and plasma 8-isoprostane and NOx concentrations were obtained before and after both treatment modalities.
Patients with OSAS had significantly higher 8-isoprostane levels (median (IQR) 42.5 (29.2–78.2) vs 20.0 (12.5–52.5) pg/ml, p = 0.041, Mann-Whitney test) and lower NOx levels (264 (165–650) vs 590 (251–1465) μmol/l, p = 0.022) than healthy subjects. Body mass index, blood pressure and urinary catecholamines were unchanged by CPAP therapy, but 8-isoprostane concentrations decreased (38.5 (24.2–58.7) pg/ml at baseline vs 22.5 (16.2–35.3) pg/ml on CPAP, p = 0.0001) and NOx levels increased (280 (177–707) vs 1373 (981–1517) μmol/l, p = 0.0001) after CPAP.
OSAS is associated with an increase in oxidative stress and a decrease in NOx that is normalised by CPAP therapy.

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Original articleOxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome

Abstract

Introduction

Section snippets

Subjects

Sleep study

Results

Discussion

Acknowledgements

Lancet

Lancet

Jpn J Pharmacol

Jpn J Pharmacol

Lancet

Chest

Chest

The sleep apnea syndromes

Annu Rev Med

The occurrence of sleep-disordered breathing among middle-aged adults

N Engl J Med

Does the altered cardiovascular variability associated with obstructive sleep apnea contribute to development of cardiovascular disease in patients with obstructive sleep apnea syndrome?

Circulation

Original article
Oxygen administration improves the serum level of nitric oxide metabolites in patients with obstructive sleep apnea syndrome