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And D-Arginine on Exhaled Nitric Oxide in Steroid Naive Asthma Thorax: First Published As 10.1136/Thx.56.8.602 on 1 August 2001

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And D-Arginine on Exhaled Nitric Oxide in Steroid Naive Asthma Thorax: First Published As 10.1136/Thx.56.8.602 on 1 August 2001 602 Thorax 2001;56:602–606 EVect of nebulised L- and D-arginine on exhaled nitric oxide in steroid naive asthma Thorax: first published as 10.1136/thx.56.8.602 on 1 August 2001. Downloaded from D C Chambers, J G Ayres Abstract Nitric oxide (NO) is found in increased Background—Nitric oxide (NO) is a prod- amounts in the exhaled breath of patients with uct of the enzyme nitric oxide synthase asthma and has been implicated in the (NOS) and is found in normal and pathophysiology of the disease.12NO is a gase- asthmatic human airways. The adminis- ous product of the enzyme nitric oxide tration of L-arginine results in an increase synthase (NOS), of which there are both in airway NO production in asthmatic constitutive (nNOS and eNOS) and inducible subjects. This is thought to occur because (iNOS) isoforms. The substrate for NOS is the L-arginine is the substrate for NOS. How- amino acid L-arginine,and the enzyme is stereo- ever, studies in the systemic vasculature isomer specific, suggesting that D-arginine will suggest that other mechanisms may be not act as a substrate for NOS. responsible. The administration, either by nebulisation or Methods—Eight patients with steroid orally, of L-arginine induces an increase in NO production in the respiratory tracts of normal naive asthma each received 2.5 g 34 and asthmatic subjects. L-arginine also pre- L-arginine, 2.5 g D-arginine, and 2.0% saline by ultrasonic nebuliser on separate vents methacholine induced bronchoconstric- tion in isolated guinea pig tracheal segments days in a randomised, single blind man- 5 ner. Exhaled NO was measured by chemi- through an NO dependent mechanism. These findings suggest that, in both normal and asth- luminescence and spirometric tests were matic airways, there is substrate limitation for performed before and for 3 hours after NOS. each administration. The mean concen- Nitric oxide has been much better studied in tration of NO after exposure was calcu- vascular tissue where it was originally de- lated from the area under the curve. scribed as endothelium derived relaxing factor Results—L-arginine, D-arginine, and 2.0% (EDRF) whose main function is to dilate arte- saline induced a mean (95% CI) maximal riolar smooth muscle. In the systemic vascula- bronchoconstriction of 11.9% (–1.7 to http://thorax.bmj.com/ ture L-arginine increased NO production by 25.4), 10.0% (2.8 to 17.2), and 8.5% (–2.5 to endothelial cells,6 an unexpected finding since 19.5) of the starting forced expiratory vol- the normal intracellular concentration of ume in one second (FEV ), respectively. 1 L-arginine in endothelial cells is well above the Exhaled NO declined in proportion to the Km for NOS.78 One possible explanation is degree of bronchoconstriction (r=0.60, that NO may be formed from L-arginine p<0.01). Bronchoconstriction and the non-enzymatically through reaction with reac- acute reduction in exhaled NO resolved tive oxygen species such as hydrogen peroxide.9 within 15 minutes. The mean post- Since asthma is associated with oxidative stress on September 28, 2021 by guest. Protected copyright. exposure concentration of NO was 15.75 and the formation of reactive oxygen spe- parts per billion (ppb) after L-arginine, cies,10 11 it is possible that the increase in respi- 15.16 ppb after D-arginine, and 12.74 ppb ratory tract NO production after inhalation of after 2.0% saline. The mean (95% CI) dif- L-arginine in asthmatic subjects may be at least ference between L-arginine and placebo partially mediated through a non-enzymatic was 3.01 (0.32 to 5.7) ppb, between route. If this is the case, then inhalation of D-arginine and placebo 2.42 (0.10 to D-arginine should lead to an increase in 4.74) ppb, and between L- and D-arginine respiratory tract NO production similar to that 0.59 (–1.56 to 2.74) ppb. observed after the inhalation of L-arginine. The Conclusions—Exhaled NO decreased with aim of this study was to assess whether arginine Heartlands Research Institute, Birmingham acute bronchoconstriction and returned induced increases in pulmonary NO produc- Heartlands NHS to baseline with the resolution of broncho- tion are stereospecific. Trust, Birmingham constriction. Exhaled NO increased fol- B9 5SS, UK lowing the administration of both D C Chambers L-arginine and D-arginine. Since NOS is Methods J G Ayres stereospecific, this finding suggests that SUBJECTS Eight non-smoking subjects with steroid naive Correspondence to: the increase in exhaled NO is not entirely Professor J G Ayres mediated through an increase in NOS asthma were studied. The diagnosis of asthma [email protected] enzyme activity. We suggest that arginine was based on the presence of circadian peak flow variability of more than 20% and/or Received 2 May 2000 may react in a non-stereospecific fashion Returned to authors with reactive oxygen species present in evidence of spirometric reversibility (post- 29 June 2000 asthmatic airways. bronchodilator forced expiratory volume in Revised version received one second (FEV ) more than 15% greater 6 November 2000 (Thorax 2001;56:602–606) 1 Accepted for publication than pre-bronchodilator FEV1) in conjunction 25 April 2001 Keywords: nitric oxide; arginine; asthma with appropriate symptoms (breathlessness, www.thoraxjnl.com EVect of nebulised L- and D-arginine on exhaled NO in steroid naive asthma 603 wheezing and cough). No subject had had an FEV1 revealed a significant (>10%) broncho- upper respiratory tract infection in the 4 weeks constriction. Thorax: first published as 10.1136/thx.56.8.602 on 1 August 2001. Downloaded from prior to the study. â agonist medications were withheld on the morning of each visit. Subjects ASSESSMENT OF EXHALED NO had not been exposed to inhaled steroid medi- Exhaled NO was measured by chemilumines- cation or to other glucocorticoids for at least 2 cence (LR2000, Logan Research, Kent, UK) in months before enrolment. accordance with European Respiratory Society guidelines12 as previously described.13 Briefly, subjects inhaled to total lung capacity and then STUDY DESIGN completed a slow vital capacity exhalation The study was of a randomised, single blind, through a resistance with a flow meter in series. crossover design and was approved by the East A visual feedback display allowed the subject to Birmingham local research and ethics com- maintain a flow rate of approximately 200 ml/s mittee. Each subject attended on three separate during the exhalation, while the resistance days, each at least 3 days apart. The concentra- maintained closure of the soft palate. Nose tion of exhaled NO was measured (mean of five clips were not used. The chemiluminescence measurements within 10%) and spirometric analyser sampled the exhalate in real time at tests were performed (best of three forced 250 ml/min (4.2 ml/s) with a sensitivity of 0.3 exhalations within 5%) (Vitalograph- parts per billion (ppb) and a sampling rate of Compact, Vitalograph Ltd, Buckingham, UK) 15 Hz. Calibration was performed daily. The at baseline. The spirometric tests were always exhaled NO measurement was obtained from performed after measurement of exhaled NO. the plateau phase at 75% of exhaled volume.13 The subjects then received either L-arginine (2.5 g in 20 ml H O, 700 mOsm, pH 6.1), 2 STATISTICAL ANALYSIS D-arginine (2.5 g in 20 ml H2O, 700 mOsm, Exhaled NO and FEV1 (as % of baseline) are pH 6.1), or 2.0% saline control (25 ml, presented graphically as the mean at each time 684 mOsm, pH 6.5 ) nebulised ultrasonically point for each visit. The change in FEV1 (Intersurgical, Wokingham, UK, output ap- immediately following exposure was tested for proximately 4 ml/min). L- and D-arginine were statistical significance using a paired t test. In supplied by Clinalfa AG, Switzerland and order for comparisons to be made between 2.0% saline by Martindale Pharmaceuticals, exposure groups, the serial measures were Essex, UK. The concentration of exhaled NO summarised for each individual for each expo- was measured (mean of three measurements sure from baseline to 180 minutes after within 10%) and spirometric tests were per- exposure using the area under the curve formed immediately after nebulisation and method14 and expressed as an absolute amount then again at 5, 10, 15, 30, 45, 60, 90, 120, 150 by dividing by total time. Statistical signifi- and 180 minutes after nebulisation. A single http://thorax.bmj.com/ cance was tested using paired t tests. A poten- administration of 100 µg salbutamol by inhala- tial correlation between change in exhaled NO tion was allowed if the initial post-nebuliser concentration and change in FEV1 within each Table 1 Demographic details for eight subjects with steroid naive asthma subject was sought using multiple linear regression and dummy variables according to 15 FEV1 FVC NO Salbutamol the method described by Bland and Altman. Subject Age Sex FEV1 (l) (%) FVC (l) (%) (ppb) required 1 46 F 1.84 65 3.11 94.3 23.9 Y Results 2 28 F 2.81 79.3 4.01 99 8.5 Y Demographic and lung function data for the 3 25 F 3.34 95.7 3.77 94.3 8.4 N on September 28, 2021 by guest. Protected copyright. 4 54 F 1.92 72.3 3.07 98.5 5.6 N eight subjects are shown in table 1. Subjects 5 26 F 2.84 95 3.51 102.3 20.4 N who required salbutamol to relieve acute 6 28 M 3.69 84.7 5.01 97.3 29.7 Y 7 25 F 2.85 79.7 4.21 103 3.8 Y bronchoconstriction required it for all three 8 24 F 3.00 88 3.58 92 6.6 N visits.
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