Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 jpmol/L, P<.001) and in the patients (from 72 to 90 !Lmol/L, P<.001).Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 ,mol/L, P<.001) as well as in the patients (from 19 to 42 ,umol/L, P<.01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (02 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (02 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys. decreased formation of this compound,9'0 seems to constitute an important functional component in atherosclerotic vascular disease. An increased formation of NO in activated macrophages has been suggested to be responsible for the hypotension in endotoxin shock." Recently, the application of NO inhalation as a beneficial therapeutic principle was reported in patients with primary pulmonary hypertension12 or adult respiratory distress syndrome.13We assumed that quantitative methods to estimate NO formation might facilitate further evaluation of some of its physiological, pathophysiological, and therapeutic roles. The development of such methods relies on proper knowledge of the inactivation and elimination of NO from the intact organism. However, only little is known concerning the in vivo metabolism of NO and the excretion of its metabolite(s). The amino acid L-arginine, which is a precursor for NO both in macrophages and in endothelial cells,314 is also a precursor for nitrate biosynthesis in humans.15 Furthermore, nitrate is a normal constituent of human urine.16 Based on these observations, it might be speculated that NO is metabolized to nitrate and subsequently excreted as such into the urine. Preliminary support for this hypothesis was obtained earlier in a study on NO degradation in human blood ex vivo.'7 In the present report, the proposed metabolic route for NO is shown to be operative in vivo, in healthy subjects as well as in patients with severe...

No abstract

1 Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects.2 Healthy subjects inhaled "5NO (25 p.p.m.) for 1 h. The plasma and urine levels of`5NO3-were followed for 2 and 48 h, respectively.3 The measured retention of "5NO in the lungs was 224 ± 13 tmol, corresponding to 90 ± 2% of the inhaled amount. Plasma '5NO3-increased during the inhalation of "5NO, to about 15 fimol I', and fell when inhalation of "5NO was terminated. 4 Urinary excretion of`5NO3-during the first 24 h after inhalation was 154 ± 12 1mol. During the following 24 h another 8 ± 2 fImol of 15NO3-appeared in the urine. 5 We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.

In the presence of oxygen NO is oxidised to NO2, which is toxic in higher concentrations. In this technical investigation, we evaluated a dosage system, modified from Stenqvist et al. 1993 (1), regarding NO and NO2 levels. NO was administered before the ventilator and NO2 scavenged using a soda little absorber in the inspiratory limb close to the ventilator. NO/NO2 levels were measured using fuel cell technique. We tested the duration of soda lime scavenging, put in additional soda lime absorbers, used charcoal as absorber and exchanged tubing material. NO was delivered after the ventilator and we studied effect of interruption of ventilation. With concentrations of NO at or below 40 parts per million (ppm) at F1O2 0.9, NO2 levels were 1.2 ppm or lower. Corresponding values for 20 and 10 ppm were 0.4 and 0.2 ppm, respectively. Duration of the soda lime absorber was at least 72 hours. Additional soda lime absorbers did not further reduce NO2 levels. Charcoal absorbers reduced NO2, but also NO by 45% from set value. Tubing materials had no influence on NO and NO2 levels. When administering NO at the Y-piece, levels of NO were increased by 35-60% and NO2 levels by 110-230% compared to set values. Oxidation of NO to NO2 is continuously taking place in the breathing system. Doses of up to 40 ppm NO should be considered safe regarding NO2 levels. Administration of NO at the Y-piece gives high and unpredictable levels of NO2.

This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure.