Background: Raised concentrations of nitrate and nitrite have been found in exhaled breath condensate (EBC) in airway disease, and it has been postulated that this reflects increased nitric oxide (NO) metabolism. However, the chemical and anatomical origin of nitrate and nitrite in the airways has not yet been sufficiently studied. Methods: The fraction of exhaled NO at an exhalation flow rate of 50 ml/s (FE NO ) and nitrite and nitrate in EBC, nasal condensate, and saliva were measured in 17 tracheostomised and 15 non-tracheostomised subjects, all of whom were non-smokers without respiratory disease. Tracheal and oral samples were taken from the tracheostomised subjects and nasal (during velum closure) and oral samples from the nontracheostomised subjects. Measurements were performed before and after sodium nitrate ingestion (10 mg/kg) and use of antibacterial mouthwash (chlorhexidine 0.2%). Results: In tracheostomised subjects oral FE NO increased by 90% (p,0.01) while tracheal FE NO was not affected 60 minutes after nitrate ingestion. Oral EBC nitrite levels were increased 23-fold at 60 minutes (p,0.001) whereas the nitrite levels in tracheal EBC showed only a minor increase (fourfold, p,0.05). Nitrate was increased the same amount in oral and tracheal EBC at 60 minutes (2.5-fold, p,0.05). In non-tracheostomised subjects oral FE NO and EBC nitrite increased after nitrate ingestion and after chlorhexidine mouthwash they approached baseline levels again (p,0.001). Nasal NO, nitrate, and nitrite were not affected by nitrate intake or mouthwash. At baseline, mouthwash with deionised water did not affect nitrite in oral EBC or saliva, whereas significant reductions were seen after antibacterial mouthwash (p,0.05 and p,0.001, respectively). Conclusions: Besides the salivary glands, plasma nitrate is taken up by the lower airways but not the nasal airways. Nitrate levels in EBC are thus influenced by dietary intake. Nitrate is reduced to nitrite by bacterial activity which takes place primarily in the oropharyngeal tract of healthy subjects. Only oropharyngeal nitrite seems to contribute to exhaled NO in non-inflamed airways, and there is also a substantial contribution of nitrite from the oropharyngeal tract during standard collection of EBC.

Increased levels of exhaled carbon monoxide (fractional concentration of CO in expired gas (FE,CO)), measured with an electrochemical sensor, have been reported in patients with inflammatory airway disorders, such as asthma, rhinitis and cystic fibrosis. This study aimed to evaluate these findings by using a fast-response nondisperse infrared (NDIR) analyser, and to compare these measurements with the fractional concentration of nitric oxide in exhaled air (FE,NO). Thirty-two steroid-naïve asthmatics, 24 steroid-treated asthmatics (16 patients with allergic rhinitis, nine patients with cystic fibrosis), and 30 nonsmoking healthy controls were included. CO measurements with the NDIR analyser were performed simultaneously with nitric oxide (NO) analysis (chemiluminescence technique). After 15 s of breath-hold, single-breath exhalations over 10 s were performed at two flow rates and end-tidal plateau concentrations were registered. An electrochemical CO sensor was used independently with an exhalation to residual volume, after a 15 s breath-hold. None of the two CO analysers gave a significant increase in FE,CO in the groups of patients with inflammatory airway disorders compared to controls. FE,NO was significantly elevated in steroid-naïve asthmatics and subjects with allergic rhinitis, but not in steroid-treated asthmatics and subjects with cystic fibrosis. Reducing exhalation flow rate by 50% gave a two-fold increase in FE,NO, while FE,CO was unaffected. A significant increase was seen in FE.CO, but not in FE,NO, when comparing with and without a 10 s breath-hold. In conclusion, the fractional concentration of carbon monoxide in expired gas was not increased in any of the patient groups, while the fractional concentration of nitric oxide in expired gas was significantly elevated in patients with steroid-naïve asthma and allergic rhinitis. Moreover, carbon monoxide was unaffected by flow rate but increased with breath-hold, suggesting an origin in the alveoli rather than the conducting airways.

Nitric oxide (NO) is produced at different sites in the human airways and may have several physiological effects. Orally-produced NO seems to contribute to the levels found in exhaled air. Autoinhalation of nasal NO increases oxygenation and reduces pulmonary artery pressure in humans. The aim of this study was to measure the concentration and output of NO during nasal, oral and tracheal controlled exhalation and inhalation.Ten tracheotomized patients and seven healthy subjects were studied. The mean ¡ SEM fraction of exhaled NO from the nose, mouth and trachea was 56 ¡ 8, 14 ¡ 4 and 6 ¡ 1 parts per billion (ppb), respectively. During single-breath nasal, oral and tracheal inhalation the fraction of inhaled NO was 64 ¡ 14, 11 ¡ 3 and 4 ¡ 1, respectively. There was a marked flow dependency on nasal NO output in the healthy subjects, which was four-fold greater at the higher flow rates, during inhalation when compared to exhalation.There is a substantial contribution of nasal and oral nitric oxide during both inhalation and exhalation. Nasal nitric oxide output is markedly higher during inhalation, reaching levels similar to those that are found to have clinical effects in the trachea. These findings have implications for the measurement of nitric oxide in exhaled air and the physiological effects of autoinhaled endogenous nitric oxide.

EBC nitrite mainly originates in the pharyngo-oral tract and its increase in CF is possibly explained by a regional change in bacterial activity. The limited lower airway contribution supports the view of a genuinely impaired formation and metabolism of NO in CF, rather than poor diffusion of the molecule.

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