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3.1 Introduction............... .....70 3.2 Properties of nitric oxide ..................70 3.3 Reactions of nitric oxide......... ..........73 3.3.1 Reactive nitrogen species and superoxide reactions.............. ,........73 3.3.2 Reactions with transition metars ind metalroproteins ....................75 3.3.3 Nitrogen thiols and amines .......76 3.3.4 Reaction with amino acids......... ..........,......77 3.3.5 Reaction with lipids. ..........,......77 3.3.6 Reactions with genes ................7g 3.3.7 Making sense of the reactions ....................7g 3.4 Nitric oxide synthase isoenzymes ............... .......7g 3.4.1 Constitutive nitric oxide synthases .............g1 3.4.2 Inducible nitric oxide synthase.... ...............g2 3.4.3 Control of the nitric oxide synthase isoen2ymes................ ............g3 3.4.3 (i) The constitutive forms ......g3 3.4.3 (ii) The inducible form ...........85 3.4.4 Nicotinamide adenosine di-nucleotide phosphate oxidase and inducible nitric oxide synthase ........g7 3'4'5 Drug! & other agents that affect the isoenzymes and nitric oxide production. gg 3.4.5 (i) Drugs ..............88 3.4.5 (ii) Nitric oxide synthase inhibitors.. ........g9 3.5 Chapter summary... .........91 Chapter 4: Methods to measure nitric oxide ................g2 4.1 Introduction............... .....g2 4.2 L-arginine, L-citrulline and cyclic guanosine monophosphate................................93 4.3 Methaemoglobin....... ......g3 4.4 Nitrite and nitrate. ...........g4 4.5 Nitric oxide........ .............95 4.6 Chemiluminescence... .....g7 4.6.1 Calibration ............103 4.6.2 Safety and toxicity ..................104 _ 4.7 Chapter summary... .......10g Chapter 5: Methodological assessment of the chemiluminescence ana1yser................... l l0 5.1 Introduction ............... ... I l0 5.2, The equipment and personnel.. ....... I l0 5.2.I Chemiluminescence Analyser ,Model 2107, ............110 5.2.2 Capnograph, pressure transducer, flow meter and chart recorder.................. I I I 5.2.3 Personnel .............. I 15 5.3 Direct versus reseryoir measurement .............. ................... I 16 5.4 Assessments of the analysers... .......117 5.5 Other measurements............ ...........120 _ 5.6 Chapter summary... .......121 Chapter 6: Methodological studies of exhaled nitric oxide in healthy adult subjects: direct versus t-piece testing ..............122 6.1 Introduction............... ...lLz 6.2 Nitric oxide and the nitric oxide synthases in the lung .......... ..............122 6.3 The need for methodological experiments ............... ..........125 6.4 The aims of the exhaled nitric oxide methodological experiments ...... 130 6.5 Setting up for the experiments........... ...............131 6.5.1 Set-up and calibrations......... ....................131 6.5.2 The exhalation protocol.............. .............. 136 6.5.3 Ethics and Consent................ ...................13g XI
6.5.4 The subjects............... ............. 138 6.5.5 Statistical analysis .................. 138 6.6 Methodological experiment one... ..139 6.6.1 Hypotheses................ ............. 139 6.6.2 Aims .,139 6.6.3 Procedure ............. 139 6.6.4 Results..... ............. 140 6.6.4 (i) Direct versus t-piece nitric oxide and carbon dioxide measurement..... 140 6.6.4 (ii) Peak nitric oxide versus area under the nitric oxide curye ..l4 6.6.4 (iii) Comparison of exhaled nitric oxide and carbon dioxide ..... 146 6.7 Discussion: The origin of the exhaled nitric oxide ............ 148 Chapter 7: Methodological studies of exhaled nitric oxide in healthy adult subjects: investigating test parameters .. 153 7.1 Introduction............... ... 153 7.2 Ethics, subjects, calibrations and statistical analysis .............. ............. 154 7.3 Methodologicalexperimenttwo-effectof expiratoryflow...... .......... 155 7.3.1 Hypothesis ............ 155 7.3.2 Aim.......... ............. 155 7.3.3 Procedure ............. 155 7.3.4 Results..... ............. 156 7 .4 Methodological experiment three - effect of pressure ....... 158 7.4.1 Hypotheses................ ............. 158 7.4.2 Aim.......... ............. 158 7.4.3 Procedure ............. 158 7.4.4 Results..... ............. 160 7.5 Methodological experiment four - effect of ambient nitric oxide ........ 163 7.5.1 Hypothesis ............ 163 7.5.2 Aims ... 163 7.5.3 Procedure ............. 163 7.5.4 Results..... ............. 164 7.6 Methodological experiment five - effect of water consumption........................... 168 7.6.1 Hypothesis ............ 168 7.6.2 Aim.......... ............. 168 7.6.3 Procedure ............. 168 7.6.4 Results..... ............. 169 7.7 Discussion: which measurement factors alter nitric oxide levels? ...... 170 Chapter 8: Exhaled nitric oxide in healthy and asthmatic children ............... 178 8.1 Introduction............... ... 178 8.2 Ethics, consent, statistics and subjects................ ............... 179 8.3 Methodology of exhaled nitric oxide measurement in healthy chi1dren................ 180 8.3.1 Hypotheses................ ............. 180 8.3.2 Aims ... 180 8.3.3 Protocol ................ 180 8.3.4 Results..... ............. 182 8.4 Discussion: exhaled nitric oxide results in healthy children.... ............ 186 8.5 Methodology of exhaled nitric oxide measurement in asthmatic children ............ 191 8.5.1 Background............... ............. 191 8.5.2 The asthmatic subjects ...........I92 8.5.3 Protocol ................ 193 8.5.4 Results..... ............. 193 8.6 Discussion: exhaled nitric oxide in asthmatic children.. .... 196 Chapter 9: Exhaled and nasal NO to today........ ........202 xll
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Page 3 and 4: UNIVERSITV OF AUCKI'AND Abstract -
Page 5 and 6: There was no significant difference
Page 7 and 8: This is Dedicated: Dedication To th
Page 9 and 10: New Zealand The Paediatric Departme
Page 11: Contents Abstract ........tr Dedica
Page 15 and 16: XIV
Page 17 and 18: List of Figures Figure l.l: Top l0
Page 19 and 20: List of Abbreviations ABPA allergic
Page 21 and 22: LADA N*N* dimethyl L-arginine LFA1
Page 23 and 24: t}ryem(eNoS)Typeltrendothelialnifti
Page 25 and 26: area, some of it has been expanded
Page 27 and 28: In addition, both of these groups a
Page 29 and 30: studies conducted throughout the Un
Page 31 and 32: Video clips of infants with a varie
Page 33 and 34: the Paediatric Society of New 7*ala
Page 35 and 36: inhaled anti-cholinergic agents and
Page 37 and 38: ecommended to monitor asthma at hom
Page 39 and 40: improvement to 70Vo PEF would have
Page 41 and 42: Furthermore, investigators have als
Page 43 and 44: poorer predictor of a diagnosis of
Page 45 and 46: Bronsky et al. 1998), and a long-te
Page 47 and 48: SIGN guideline (SIGN 2005) stated "
Page 49 and 50: In brief, the human airway can be d
Page 51 and 52: The ability to biopsy has led to st
Page 53 and 54: small proportion of cells recovered
Page 55 and 56: methodology of sputum induction and
Page 57 and 58: et al. 1999; Giannini, Di Franco et
Page 59 and 60: over a six month treatment prograrn
Page 61 and 62: There are other studies suggesting
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So is induced sputum in adults and
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asymptomatic patients independent o
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onchial hyper-responsiveness (Reich
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led to research which looked for le
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analyser machines. This thesis pres
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The pollution of the 'great smog of
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adults greater than 65 years (Ostro
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levels compared to those children l
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More recently 'Air Quality Indexes'
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acetylcholine. These were known to
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cyclase does not produce significan
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Garthwaite l99l), and the non adren
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significant complication, this trea
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locus for the enzyme is a susceptib
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NO synthesis and in so doing blocke
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3.1 Chapter 3: The synthesis, react
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BHa = tetrahyrobiopterin, FAD = fla
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(Knowles, McWeeny et al. 1974) and
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more potent at low oxygen tensions
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toxic products such as isoprostanes
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Figure 3.3: The nitric oxide syntha
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providing NO as a neurotransmitter
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The enzyme of this second pathway -
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inappropriate production from comme
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Nicotinamide adenosine dinucleotide
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enzyme and are competitively revers
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4.1 Introduction Chapter 4: Methods
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4.4 Nitrite and nitrate The measure
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insensitive (Braker and Mossman 197
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A group of instruments have been de
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The original group demonstrated tha
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equired it. For example, there was
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helium for 30 minutes to remove Oz.
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(Postlethwait and Bidani 1990; Post
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is set at 5ppm (AIHA 1966) based on
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5.1 Chapter 5: Methodological asses
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wanted to compare the patterns of e
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in different colours that became th
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an advisor for this work and main s
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Delay time: the time between turnin
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led to an increased water content t
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Chapter 6: Methodological studies o
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pulmonary circulation appeared to c
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al found levels of 10.3ppb compared
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Authors and Pap€r Sublect numbers
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only those measured by mouth or low
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6. Check that the pens work. Fill w
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keys but it is currently in the mid
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Calibration pressures: the test por
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T-piece: tO The first figure shows
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the rotameter. Tracings of each par
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Figure 6.6: Mean exhaled NO levels
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NO and COz results from single exha
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6.6.4 (iii) Comparison of exhaled n
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Figure 6.11b: COz levels at peak NO
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I also considered whether the diffe
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the direct to the indirect method l
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need for methodological experiments
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The exhalations were carried out in
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Figure 7.2: Example of the tracing
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7.4.4 Results There was an increase
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Table 7.3: NO, COz and duration of
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The second set of exhalations invol
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Figure 7.6: Photographs of the chan
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Table 7.5: Exhaled NO results with
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the NO concentrations taken pre and
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Figure 7.10: Hyperbolic relationshi
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pressure over the likely range enco
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subjects with respiratory disease,
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8.1 Chapter 8: Exhaled nitric oxide
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standard error of the mean (SEM), s
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T-piece sampling system to analyser
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Figure 8.2a: Comparison of peak exh
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if yes who? if yes who? if yes who?
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There are limitations with regard t
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significantly between research grou
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controls. Kharitinov et al reported
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direct method in asthmatic children
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Figure 8.4a: The eftect of commenci
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had last used her p2 agonist inhale
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higher level of exhaled NO at 4.9pp
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9.1 Introduction Chapter 9: Exhaled
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For the oral measurements options i
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Table 9.1: The recommended standard
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taken from the available literature
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compartment correlated with the ser
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measurement with variable expirator
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to settle. We may have been measuri
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9.5 Off-line measurement NO determi
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(Hyde, Geigel et al. 1997; Tsoukias
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9.6 Nasal nitric oxide measurement
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measured over two 24 hour periods,
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women who coincidently experienced
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While these cross-sectional and the
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symptoms. Steroid response was sign
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'difficult asthma' also had higher
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season and then reduced down to bas
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of cross sectional studies with a t
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Ciabattoni et al. 2004; Petersen, A
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FEV9.5, symptom score and airways r
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Indomethacin - This medication alte
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89Vo for PCD, and above that exclud
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This low NO occurs despite higher t
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patients were followed through one
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differences noted based on filter,
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9.L6 Nitric oxide levels in exercis
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another study of 111 school childre
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Almost all studies used sedation, w
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peak exhaled NO production in the f
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flow and to minimize nasal contamin
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ecruit blood vessels in the lung. S
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Chapter 10: Reflections The outcome
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and I enrolled 52 asthmatic childre
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Edwards EA, Douglas C, Broome S, Je
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o Cass Byrnes & Nicky Holt. "Drugs
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o Byrnes CA. Paediatric fibreoptic
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Appendix 2: Questionnaire for enrol
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Al-Ali, M. K. and P. H. Howarth (20
Page 299 and 300:
Archer, S. L., P. J. Shultz, et al.
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Baraldi, E., N. M. Azzolin, et al.
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Belda, J., P. Hussack, et al. (2001
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Bongers, T. and B. R. ODriscoll (20
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Brown, G. C. and C. E. Cooper (1994
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Castro-Rodriguez, J. A., C. J. Holb
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Cockcroft, D. W., D. N. Killian, et
Page 313 and 314:
de Blic, J., V. Marchac, et al. (20
Page 315 and 316:
Donaldson, S. H., W. D. Bennett, et
Page 317 and 318:
Emi-Miwa, M., A. Okitani, et al. (1
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Frey, U., J. Stocks, et al. (2000).
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Gershman, N. H., H. Liu, et al. (19
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Grasemann, H., E. Michler, et al. (
Page 325 and 326:
Hashimoto, T., K. Minoguchi, et al.
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Holgate, S. T., D. E. Davies, et al
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Iriso, R., P. M. Mudido, et al. (20
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Jones, A. W., M. Fransson, et al. (
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Kercsmar, C. M. (2006). Wheezing in
Page 335 and 336:
Kleinert, H., T. Wallerath, et al.
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Lamblin, C., P. Gosset, et al. (199
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Li, X. and J. W. Wilson (1997). "In
Page 341 and 342:
Lymar, S. V. and J. K. Hurst (1996)
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Massaro, A. F., S. Mehta, et al. (1
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Miyabara, Y., R. Yanagisawa, et al.
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contribute to impaired endothelium-
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ODell, T. J., R. D. Hawkins, et al.
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Panza, J. A., C. E. Garcia, et al.
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Peters, S. P. (2006). "Safety of in
Page 355 and 356:
Prieto, L., L. Bruno, et al. (2003)
Page 357 and 358:
Ribbons, K. A., X. J. Zhang, et al.
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Sacco, O., R. Sale, et al. (2003).
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Sessa, W. C., K. Pritchard, et al.
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Silvestri, M., F. Sabatini, et al.
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Stamler, J. S. (1994). "Redox signa
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Stuehr, D. J., N. S. Kwon, et al. (
Page 369 and 370:
Tierney, W. M., J. F. Roesner, et a
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Upchurch, G. R., G. N. Welch, et al
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Wadsworth, R., E. Stankevicius, et
Page 375 and 376:
Williams, O., R. Y. Bhat, et al. (2
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Yates, D. H., S. A. Kharitonov, et
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