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'{{distinguish|nitrous oxide|nitrogen oxides}} {{Chembox | Verifiedfields = changed | verifiedrevid = 477001381 | ImageFile = Nitric-oxide-2D.png | ImageFile_Ref = {{chemboximage|correct|??}} | ImageSize = 121 | ImageName = Skeletal formula of nitric oxide with bond length | ImageFileL1 = Nitric oxide.svg | ImageNameL1 = Skeletal formula showing three lone pairs and one unpaired electron | ImageFileR1 = Nitric-oxide-3D-vdW.png | ImageFileR1_Ref = {{chemboximage|correct|??}} | ImageSizeR1 = 121 | ImageNameR1 = Space-filling model of nitric oxide | IUPACName = Nitric oxide | SystematicName = Oxidonitrogen(•)<ref>{{cite web|title = Nitric Oxide (CHEBI:16480)|url = https://www.ebi.ac.uk/chebi/searchId.do?chebiId=16480|work = Chemical Entities of Biological Interest (ChEBI)|location = UK|publisher = European Bioinformatics Institute}}</ref> (additive) | OtherNames = Nitrogen monoxide<br /> Nitrogen(II) oxide | Section1 = {{Chembox Identifiers | CASNo = 10102-43-9 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1200689 | CASNo_Ref = {{cascite|correct|CAS}} | PubChem = 145068 | PubChem_Ref = {{Pubchemcite|correct|pubchem}} | ChemSpiderID = 127983 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | UNII = 31C4KY9ESH | UNII_Ref = {{fdacite|correct|FDA}} | EINECS = 233-271-0 | UNNumber = 1660 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00435 | KEGG = D00074 | KEGG_Ref = {{keggcite|correct|kegg}} | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 16480 | RTECS = QX0525000 | Gmelin = 451 | 3DMet = B00122 | ATCCode_prefix = R07 | ATCCode_suffix = AX01 | SMILES = [N]=O | StdInChI = 1S/NO/c1-2 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | InChI = 1/NO/c1-2 | StdInChIKey = MWUXSHHQAYIFBG-UHFFFAOYSA-N | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | InChIKey = MWUXSHHQAYIFBG-UHFFFAOYAI }} | Section2 = {{Chembox Properties | N = 1 | O = 1 | ExactMass = 29.997988627 g mol⁻¹ | Appearance = Colourless gas | Density = 1.3402 g dm⁻³ | MeltingPtC = −164 | BoilingPtC = −152 | Solubility = 74 cm³ dm⁻³ | RefractIndex = 1.0002697 }} | Section3 = {{Chembox Structure | MolShape = linear ([[point group]] C_∞''v'') }} | Section4 = {{Chembox Thermochemistry | DeltaHf = 90.29 kJ mol⁻¹ | Entropy = 210.76 J K⁻¹ mol⁻¹ }} | Section5 = {{Chembox Pharmacology | AdminRoutes = [[Inhalation]] | Bioavail = good | Metabolism = via pulmonary capillary bed | HalfLife = 2–6 seconds }} | Section6 = {{Chembox Hazards | ExternalMSDS = [http://avogadro.chem.iastate.edu/MSDS/nitric_oxide.pdf External MSDS] | EUClass = {{Hazchem O}} {{Hazchem T}} | RPhrases = {{R8}}, {{R23}}, {{R34}}, {{R44}} | SPhrases = {{S1}}, {{S17}}, {{S23}}, {{S36/37/39}}, {{S45}} | NFPA-H = 3 | NFPA-F = 0 | NFPA-R = 3 | NFPA-O = OX }} | Section7 = {{Chembox Related | Function = [[nitrogen]] [[oxide]]s | OtherFunctn = [[Dinitrogen pentoxide]]<br /> [[Dinitrogen tetroxide]]<br /> [[Dinitrogen trioxide]]<br /> [[Nitrogen dioxide]]<br /> [[Nitrous oxide]] }} }} '''Nitric oxide''', or [[nitrogen oxide]],<ref>{{cite book|title=New Oxford Dictionary for Scientific Writers and Editors|url=http://old.iupac.org/publications/books/rbook/Red_Book_2005.pdf}}</ref> also known as '''nitrogen monoxide''', is a [[molecule]] with [[chemical formula]] [[Nitrogen|N]][[Oxygen|O]]. It is a [[free radical]]<ref>''Principles and Applications of ESR Spectroscopy'' , Anders Lund,Masaru Shiotani,Shigetaka Shimada 2010</ref> and is an important [[Reaction intermediate|intermediate]] in the [[chemical industry]]. Nitric oxide is a by-product of combustion of substances in the air, as in [[automobile]] [[engine]]s, fossil fuel [[power plant]]s, and is produced naturally during the [[electrical discharge]]s of [[lightning]] in [[thunderstorms]]. In mammals including humans, NO is an important cellular [[signaling molecule]] involved in many physiological and pathological processes.<ref>{{cite journal|pmid=10390607|year=1999|last1=Hou|first1=YC|last2=Janczuk|first2=A|last3=Wang|first3=PG|title=Current trends in the development of nitric oxide donors|volume=5|issue=6|pages=417–41|journal=Current pharmaceutical design}}</ref> It is a powerful vasodilator with a short half-life of a few seconds in the blood. Long-known pharmaceuticals such as [[nitroglycerine]] and [[amyl nitrite]] were discovered, more than a century after their first use in medicine, to be active through the mechanism of being precursors to nitric oxide. Low levels of nitric oxide production are important in protecting organs such as the liver from [[ischemic damage]]. Nitric oxide should not be confused with [[nitrous oxide]] (N₂O), an [[general anaesthetic|anaesthetic]] and [[greenhouse gas]], or with [[nitrogen dioxide]] (NO₂), a brown [[toxic gas]] and a major [[air pollutant]]. However, nitric oxide is rapidly oxidised in air to nitrogen dioxide. [[Humphry Davy]] discovered this to his discomfort, when he inhaled the gas early in his career. Despite being a simple molecule, NO is an important biological regulator and is a fundamental component in the fields of [[neuroscience]], [[physiology]], and [[immunology]], with discovery of its key roles leading to Nobel Prize-winning research in these areas. It was proclaimed “[[Molecule of the Year]]” in 1992.<ref name="undefined">{{cite journal | author = Elizabeth Culotta and Daniel E. Koshland Jr | year = 1992 | title = NO news is good news. (nitric oxide; includes information about other significant advances & discoveries of 1992) (Molecule of the Year) | journal = Science | volume = 258 | issue = 5090 | pages = 1862–1864 | doi = 10.1126/science.1361684 | pmid = 1361684 }}</ref> ==Reactions== *When exposed to [[oxygen]], NO is converted into [[nitrogen dioxide]]. :: 2 NO + O₂ → 2 NO₂ :This conversion has been speculated as occurring via the ONOONO intermediate. In water, NO reacts with oxygen and water to form HNO₂ or [[nitrous acid]]. The reaction is thought to proceed via the following [[stoichiometry]]: :: 4 NO + O₂ + 2 H₂O → 4 HNO₂ *NO will react with [[fluorine]], [[chlorine]], and [[bromine]] to form the XNO species, known as the nitrosyl halides, such as [[nitrosyl chloride]]. Nitrosyl iodide can form but is an extremely short-lived species and tends to reform I₂. :: 2 NO + Cl₂ → 2 NOCl *[[Nitroxyl]] (HNO) is the reduced form of nitric oxide. * Nitric oxide dimer N₂O₂is formed when nitric oxide is cooled. *Nitric oxide reacts with [[acetone]] and an [[alkoxide]] to a ''diazeniumdiolate'' or ''nitrosohydroxylamine'' and [[methyl acetate]]:<ref>{{cite journal|doi=10.1002/jlac.18983000108|title=Ueber Synthesen stickstoffhaltiger Verbindungen mit Hülfe des Stickoxyds|year=1898|last1=Traube|first1=Wilhelm|journal=Justus Liebig's Annalen der Chemie|volume=300|page=81}}</ref> :[[File:TraubeReaction.svg|400px|Traube reaction]] :This is a very old reaction (1898) but of interest today in NO [[prodrug]] research. Nitric oxide can also react directly with sodium methoxide, forming [[sodium formate]] and [[nitrous oxide]].<ref>{{cite journal|doi=10.1021/jo7020423|title=Nitric Oxide Reacts with Methoxide|year=2008|last1=Derosa|first1=Frank|last2=Keefer|first2=Larry K.|last3=Hrabie|first3=Joseph A.|journal=The Journal of Organic Chemistry|volume=73|pages=1139–42|pmid=18184006|issue=3}}</ref> ===Preparation=== [[File:Nitric oxide production.png|thumb|250px|Nitric oxide production.]] In commerce, NO is produced by the [[oxidation]] of [[ammonia]] at 750°C to 900°C (normally at 850°C) with [[platinum]] as [[catalyst]]: :4 NH₃ + 5 O₂ → 4 NO + 6 H₂O The uncatalyzed [[endothermic]] reaction of [[Oxygen|O₂]] and [[Nitrogen|N₂]], which is performed at high temperature (>2000 °C) by lightning has not been developed into a practical commercial synthesis (see [[Birkeland–Eyde process]]): :N₂ + O₂ → 2 NO In the laboratory, nitric oxide is conveniently generated by reduction of dilute [[nitric acid]] with [[copper]]: :8 HNO₃ + 3 Cu → 3 Cu(NO₃)₂ + 4 H₂O + 2 NO or by the reduction of nitrous acid in the form of [[sodium nitrite]] or [[potassium nitrite]]: : 2 NaNO₂ + 2 NaI + 2 H₂SO₄ → I₂ + 4 NaHSO₄ + 2 NO : 2 NaNO₂ + 2 FeSO₄ + 3 H₂SO₄ → Fe₂(SO₄)₃ + 2 NaHSO₄ + 2 H₂O + 2 NO : 3 KNO₂ (l) + KNO₃ (l) + Cr₂O₃(s) → 2 K₂CrO₄(s) + 4 NO (g) The iron(II) sulfate route is simple and has been used in undergraduate laboratory experiments. So-called [[NONOate]] compounds are also used for NO generation. ===Coordination chemistry=== {{Main|Metal nitrosyl}} NO reacts with all [[transition metal]]s to give complexes called [[metal nitrosyl]]s. The most common bonding mode of NO is the terminal linear type (M-NO). The angle of the M-N-O group varies from 160° to 180° but is still termed "linear". In this case, the NO group is considered a 3-electron donor under the covalent (neutral) method of electron counting, or a 2-electron donor under the ionic method.<ref>{{Cite book|first=Robert H.| last=Crabtree |url=http://books.google.com/books?id=0bXMwefSs-kC&pg=PA32 |title=The Organometallic Chemistry of the Transition Metals|publisher= John Wiley and Sons|year= 2005|page=32|issn= 0-471-66256-9|isbn=9780471718758}}</ref> In the case of a bent M-N-O conformation, the NO group can be considered a one-electron donor using neutral counting, or a 2-electron donor using ionic counting.<ref>{{Cite book|first=Robert H.| last=Crabtree |url=http://books.google.com/books?id=0bXMwefSs-kC&pg=PA32 |title=The Organometallic Chemistry of the Transition Metals|publisher= John Wiley and Sons|year= 2005|page=96–98|issn= 0-471-66256-9|isbn=9780471718758}}</ref> One can view such complexes as derived from NO⁺, which is isoelectronic with CO. Nitric oxide can serve as a one-electron pseudohalide. In such complexes, the M-N-O group is characterized by an angle between 120° and 140°. The NO group can also bridge between metal centers through the nitrogen atom in a variety of geometries. ===Concentration measurement=== [[File:The production and diffusion of nitric oxide (NO) (white) in the cytoplasm (green) of clusters of conifer cells one hour after mechanical agitation.jpg|thumb|250px|Nitric oxide (white) in [[pinophyta|conifer]] cells, visualized using DAF-2 DA (diaminofluorescein diacetate)]] Nitric oxide concentration can be determined using a simple [[chemiluminescence|chemiluminescent reaction]] involving [[ozone]]:<ref>{{cite journal |title=Homogeneous chemiluminescent measurement of nitric oxide with ozone. Implications for continuous selective monitoring of gaseous air pollutants|year=1970 |last1=Fontijn |first1=Arthur. |last2=Sabadell |first2=Alberto J. |last3=Ronco |first3=Richard J. |journal=Analytical Chemistry |volume=42 |issue=6 |page=575 |doi=10.1021/ac60288a034}}</ref> A sample containing nitric oxide is mixed with a large quantity of ozone. The nitric oxide reacts with the ozone to produce [[oxygen]] and [[nitrogen dioxide]]. This reaction also produces [[light]] ([[chemiluminescence]]), which can be measured with a [[photodetector]]. The amount of light produced is proportional to the amount of nitric oxide in the sample. : NO + O₃ → NO₂ + O₂ + light Other methods of testing include [[electrochemistry|electroanalysis]] (amperometric approach), where NO reacts with an electrode to induce a current or voltage change. The detection of NO radicals in biological tissues is particularly difficult due to the short lifetime and concentration of these radicals in tissues. One of the few practical methods is [[spin trapping]] of nitric oxide with iron-[[dithiocarbamate]] complexes and subsequent detection of the mono-nitrosyl-iron complex with [[electron paramagnetic resonance]] (EPR).<ref>{{cite journal |last1=Vanin |first1=A |last2=Huisman |first2=A |last3=Van Faassen |first3=E |year=2002 |title=Iron dithiocarbamate as spin trap for nitric oxide detection: Pitfalls and successes |journal=Methods in enzymology |volume=359 |pages=27–42 |pmid=12481557 |doi=10.1016/S0076-6879(02)59169-2 |series=Methods in Enzymology |isbn=9780121822620}}</ref><ref>{{cite journal |last1=Nagano |first1=T |last2=Yoshimura |first2=T |year=2002 |title=Bioimaging of nitric oxide |journal=Chemical reviews |volume=102 |issue=4 |pages=1235–70 |doi=10.1021/cr010152s |pmid=11942795}}</ref> A group of [[fluorescent dye]] indicators that are also available in [[acetyl]]ated form for intracellular measurements exist. The most common compound is [[4,5-diaminofluorescein]] (DAF-2).<ref name="undefined">{{cite journal | author = Kojima H, Nakatsubo N, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, Hirata Y, Nagano T | year = 1998 | title = Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins | journal = Anal. Chem. | volume = 70 | issue = 13 | pages = 2446–2453| pmid = 9666719 | doi = 10.1021/ac9801723 }}</ref> == Production == From a thermodynamic perspective, NO is unstable with respect to O₂ and N₂, although this conversion is very slow at ambient temperatures in the absence of a [[catalyst]]. Because the heat of formation of NO is [[endothermic]], its synthesis from molecular nitrogen and oxygen requires elevated temperatures above 1000 °C. A major natural source is [[lightning]]. The use of [[internal combustion engine]]s has drastically increased the presence of nitric oxide in the environment. One purpose of [[catalytic converter]]s in cars is to minimize NO emission by catalytic reversion to O₂ and N₂. == Environmental effects == Nitric oxide in the air may convert to [[nitric acid]], which has been implicated in [[acid rain]]. However, it is an important source of nutrition for [[plant]] life in the form of [[nitrates]]. Furthermore, both NO and NO₂ participate in [[ozone layer depletion]]. Nitric oxide is a small highly diffusible gas and a ubiquitous bioactive molecule. ==Technical applications== Although NO has relatively few direct uses, it is produced on a massive scale as an intermediate in the [[Ostwald process]] for the synthesis of [[nitric acid]] from [[ammonia]]. In 2005, the US alone produced 6 million metric tons of nitric acid.<ref>{{Cite journal|title=Production: Growth is the Norm|journal= Chemical and Engineering News|date= July 10, 2006|page= 59}}</ref> It finds use in the [[semiconductor]] industry for various processes. In one of its applications, it is used along with [[nitrous oxide]] to form [[silicon oxynitride|oxynitride]] gates in [[CMOS]] devices. ===Miscellaneous applications=== Nitric oxide can be used for detecting surface radicals on polymers. Quenching of surface [[Radical (chemistry)|radicals]] with nitric oxide results in incorporation of nitrogen, which can be quantified by means of [[X-ray photoelectron spectroscopy]]. ==Biological functions== {{Main|Biological functions of nitric oxide}} NO is one of the few gaseous signalling molecules known and is additionally exceptional due to the fact that it is a radical gas. It is a key [[vertebrate]] [[signal transduction|biological messenger]], playing a role in a variety of biological processes.<ref>Weller, Richard, [http://www.ted.com/talks/richard_weller_could_the_sun_be_good_for_your_heart.html Could the sun be good for your heart?] TedxGlasgow March 2012, posted January 2013</ref> It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.<ref>Roszer, T (2012) The Biology of Subcellular Nitric Oxide. ISBN 978-94-007-2818-9</ref> Nitric oxide, known as the '[[endothelium-derived relaxing factor]]', or 'EDRF', is biosynthesized endogenously from [[L-arginine]], [[oxygen]], and [[NADPH]] by various [[nitric oxide synthase]] (NOS) [[enzyme]]s. Reduction of inorganic nitrate may also serve to make nitric oxide. The [[endothelium]] (inner lining) of [[blood vessel]]s uses nitric oxide to signal the surrounding [[smooth muscle]] to relax, thus resulting in [[vasodilation]] and increasing blood flow. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient [[paracrine]] (between adjacent cells) and [[autocrine]] (within a single cell) signaling molecule.<ref name="stryer">{{cite book|last = Stryer| first = Lubert| title = Biochemistry, 4th Edition| publisher = W.H. Freeman and Company|year = 1995| page = 732| isbn = 0-7167-2009-4}}</ref> Independent of [[nitric oxide synthase]], an alternative pathway, coined the nitrate-nitrite-nitric oxide pathway, elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods.<ref>{{cite web|url=http://www.berkeleytest.com/plant-based.html |title=Plant-based Diets &#124; Plant-based Foods &#124; Beetroot Juice &#124; Nitric Oxide Vegetables |publisher=Berkeley Test |date= |accessdate=2013-10-04}}</ref> Nitrate-rich vegetables, in particular leafy greens, such as [[spinach]], [[arugula]], and [[beetroot]], have been shown to increase cardioprotective levels of nitric oxide with a corresponding reduction in blood pressure in pre-[[hypertension|hypertensive]] persons.<ref>{{cite journal|doi=10.1161/HYPERTENSIONAHA.111.00933|title=Enhanced Vasodilator Activity of Nitrite in Hypertension: Critical Role for Erythrocytic Xanthine Oxidoreductase and Translational Potential|year=2013|last1=Ghosh|first1=S. M.|last2=Kapil|first2=V.|last3=Fuentes-Calvo|first3=I.|last4=Bubb|first4=K. J.|last5=Pearl|first5=V.|last6=Milsom|first6=A. B.|last7=Khambata|first7=R.|last8=Maleki-Toyserkani|first8=S.|last9=Yousuf|first9=M.|last10=Benjamin|first10=N.|last11=Webb|first11=A. J.|last12=Caulfield|first12=M. J.|last13=Hobbs|first13=A. J.|last14=Ahluwalia|first14=A.|journal=Hypertension|volume=61|issue=5|pages=1091–102|pmid=23589565}}</ref><ref>{{cite journal|doi=10.1161/​HYPERTENSIONAHA.107.103523|title=Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite|year=2008|last1=Webb|first1=A. J.|last2=Patel|first2=N.|last3=Loukogeorgakis|first3=S.|last4=Okorie|first4=M.|last5=Aboud|first5=Z.|last6=Misra|first6=S.|last7=Rashid|first7=R.|last8=Miall|first8=P.|last9=Deanfield|first9=J.|last10=Benjamin|first10=N.|last11=MacAllister|first11=R.|last12=Hobbs|first12=A. J.|last13=Ahluwalia|first13=A.|journal=Hypertension|volume=51|issue=3|pages=784–90|pmid=18250365|pmc=2839282}}</ref> For the body to generate nitric oxide through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite occurs in the mouth, by commensal bacteria, an obligatory and necessary step.<ref>{{cite journal|doi=10.1111/odi.12157|title=The oral microbiome and nitric oxide homoeostasis|year=2013|last1=Hezel|first1=MP|last2=Weitzberg|first2=E|journal=Oral Diseases|pages=n/a}}</ref> Monitoring nitric oxide status by [[saliva testing]] detects the bioconversion of plant-derived nitrate into nitric oxide. A rise in salivary levels is indicative of diets rich in leafy vegetables which are often abundant in anti-hypertensive diets such as the [[DASH diet]].<ref>{{cite web|last=Green |first=Shawn J. |url=http://www.realworldhealthcare.org/2013/07/turning-dash-strategy-into-reality-for-improved-cardio-wellness-outcomes-part-ii/ |title=Turning DASH Strategy into Reality for Improved Cardio Wellness Outcomes: Part II |publisher=Real World Health Care |date=2013-07-25 |accessdate=2013-10-04}}</ref> The production of nitric oxide is elevated in populations living at high altitudes, which helps these people avoid [[Hypoxia (medical)|hypoxia]] by aiding in pulmonary vasculature [[vasodilation]]. Effects include vasodilatation, [[neurotransmitter|neurotransmission]] (see [[gasotransmitters]]), modulation of the [[Human hair growth|hair cycle]],<ref>{{cite journal|url=http://www.drproctor.com/Archd.htm |title=Endothelium-Derived Relaxing Factor and Minoxidil: Active Mechanisms in Hair Growth |pmid=2757417 |journal= Archives in Dermatology|volume= 125|month= August|year= 1989|last1=Proctor|first1=PH|issue=8|pages=1146 }}</ref> production of reactive nitrogen intermediates and [[erection|penile erections]] (through its ability to [[vascular resistance|vasodilate]]). [[Glyceryl trinitrate (pharmacology)|Nitroglycerin]] and [[amyl nitrite]] serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drug [[minoxidil]] contains an NO moiety and may act as an NO agonist. Likewise, [[Sildenafil|Sildenafil citrate]], popularly known by the trade name ''Viagra'', stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis. Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with [[atherosclerosis]], [[diabetes]], or [[hypertension]] often show impaired NO pathways.<ref>{{cite journal |last = Dessy |first = C. |last2 = Ferron |first2 = O. |title = Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature|doi=10.2174/1568014043355348 |journal = Current Medical Chemistry – Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry |volume = 3 |issue = 3 |pages = 207–216 |year = 2004}}</ref> A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.<ref>{{cite journal|url=http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223997&Ausgabe=228460&ArtikelNr=63555|pmid=12207094|year=2002|last1=Osanai|first1=T|last2=Fujiwara|first2=N|last3=Saitoh|first3=M|last4=Sasaki|first4=S|last5=Tomita|first5=H|last6=Nakamura|first6=M|last7=Osawa|first7=H|last8=Yamabe|first8=H|last9=Okumura|first9=K|displayauthors=1000|title=Relationship between salt intake, nitric oxide, and asymmetric dimethylarginine and its relevance to patients with end-stage renal disease|volume=20|issue=5|pages=466–8|journal=Blood purification|doi=10.1159/000063555}}</ref> Nitric oxide is also generated by phagocytes ([[monocyte]]s, [[macrophage]]s, and [[neutrophil]]s) as part of the human [[immune response]].<ref>{{Cite journal|pmid=2126524|year=1990|last1=Green|first1=SJ|last2=Mellouk|first2=S|last3=Hoffman|first3=SL|last4=Meltzer|first4=MS|last5=Nacy|first5=CA|title=Cellular mechanisms of nonspecific immunity to intracellular infection: Cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes|volume=25|issue=1–3|pages=15–9|journal=Immunology letters|doi=10.1016/0165-2478(90)90083-3}}</ref> Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by [[interferon-gamma]] (IFN-γ) as a single signal or by [[tumor necrosis factor]] (TNF) along with a second signal.<ref>Gorczyniski and Stanely, Clinical Immunology. Landes Bioscience; Austin, TX. ISBN 1-57059-625-5</ref><ref>{{Cite journal|pmid=8423095|year=1993|last1=Green|first1=SJ|last2=Nacy|first2=CA|last3=Schreiber|first3=RD|last4=Granger|first4=DL|last5=Crawford|first5=RM|last6=Meltzer|first6=MS|last7=Fortier|first7=AH|title=Neutralization of gamma interferon and tumor necrosis factor alpha blocks in vivo synthesis of nitrogen oxides from L-arginine and protection against Francisella tularensis infection in Mycobacterium bovis BCG-treated mice|volume=61|issue=2|pages=689–98|pmc=302781|journal=Infection and immunity}}</ref><ref>{{Cite journal|pmid=8832969|year=1995|last1=Kamijo|first1=R|last2=Gerecitano|first2=J|last3=Shapiro|first3=D|last4=Green|first4=SJ|last5=Aguet|first5=M|last6=Le|first6=J|last7=Vilcek|first7=J|title=Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor|volume=46|issue=1|pages=23–31|journal=Journal of inflammation}}</ref> On the other hand, [[transforming growth factor-beta]] (TGF-β) provides a strong inhibitory signal to iNOS, whereas [[interleukin]]-4 (IL-4) and IL-10 provide weak inhibitory signals. In this way, the immune system may regulate the [[armamentarium]] of phagocytes that play a role in inflammation and immune responses.<ref>{{Cite journal|pmid=7537721|year=1994|last1=Green|first1=SJ|last2=Scheller|first2=LF|last3=Marletta|first3=MA|last4=Seguin|first4=MC|last5=Klotz|first5=FW|last6=Slayter|first6=M|last7=Nelson|first7=BJ|last8=Nacy|first8=CA|title=Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens|volume=43|issue=1–2|pages=87–94|journal=Immunology letters|doi=10.1016/0165-2478(94)00158-8}}</ref> Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including ''[[Leishmania]]''<ref>{{Cite journal|pmid=2124240|year=1990|last1=Green|first1=SJ|last2=Crawford|first2=RM|last3=Hockmeyer|first3=JT|last4=Meltzer|first4=MS|last5=Nacy|first5=CA|title=Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha|volume=145|issue=12|pages=4290–7|journal=Journal of immunology (Baltimore, Md. : 1950)}}</ref> and [[malaria]];<ref>{{cite journal|doi=10.1084/jem.180.1.353|title=Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: Involvement of interferon gamma and CD8+ T cells|year=1994|last1=Seguin|first1=M. C.|journal=Journal of Experimental Medicine|volume=180|pages=353–8|pmid=7516412|last2=Klotz|first2=FW|last3=Schneider|first3=I|last4=Weir|first4=JP|last5=Goodbary|first5=M|last6=Slayter|first6=M|last7=Raney|first7=JJ|last8=Aniagolu|first8=JU|last9=Green|first9=SJ|displayauthors=22|issue=1|pmc=2191552}}</ref><ref>{{Cite journal|pmid=1903415|year=1991|last1=Mellouk|first1=S|last2=Green|first2=SJ|last3=Nacy|first3=CA|last4=Hoffman|first4=SL|title=IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism|volume=146|issue=11|pages=3971–6|journal=Journal of immunology (Baltimore, Md. : 1950)}}</ref><ref>{{Cite journal|pmid=7534796|year=1995|last1=Klotz|first1=FW|last2=Scheller|first2=LF|last3=Seguin|first3=MC|last4=Kumar|first4=N|last5=Marletta|first5=MA|last6=Green|first6=SJ|last7=Azad|first7=AF|title=Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites|volume=154|issue=7|pages=3391–5|journal=Journal of immunology (Baltimore, Md. : 1950)}}</ref> the mechanism for this includes DNA damage<ref> {{cite journal|doi=10.1126/science.1948068|title=DNA deaminating ability and genotoxicity of nitric oxide and its progenitors|year=1991|last1=Wink|first1=D.|last2=Kasprzak|first2=K.|last3=Maragos|first3=C.|last4=Elespuru|first4=R.|last5=Misra|first5=M|last6=Dunams|first6=T.|last7=Cebula|first7=T.|last8=Koch|first8=W.|last9=Andrews|first9=A.|last10=Allen|first10=J.|last11=Et|first11=al.|journal=Science|volume=254|issue=5034|pages=1001–3|pmid=1948068 }} About killing of salmonella bacteria.</ref><ref> {{cite journal|doi=10.1073/pnas.89.7.3030|title=DNA Damage and Mutation in Human Cells Exposed to Nitric Oxide in vitro|year=1992|last1=Nguyen|first1=T.|journal=Proceedings of the National Academy of Sciences|volume=89|issue=7|pages=3030}} Free text.</ref><ref>{{cite journal|doi=10.1021/tx050283e|title=Threshold Effects of Nitric Oxide-Induced Toxicity and Cellular Responses in Wild-Type and p53-Null Human Lymphoblastoid Cells|year=2006|last1=Li|first1=Chun-Qi|last2=Pang|first2=Bo|last3=Kiziltepe|first3=Tanyel|last4=Trudel|first4=Laura J.|last5=Engelward|first5=Bevin P.|last6=Dedon|first6=Peter C.|last7=Wogan|first7=Gerald N.|journal=Chemical Research in Toxicology|volume=19|issue=3|pages=399–406|pmid=16544944|pmc=2570754}} free text</ref> and degradation of iron sulfur centers into iron ions and [[metal nitrosyl|iron-nitrosyl]] compounds.<ref>{{cite journal|doi=10.1016/S0006-291X(88)80015-9|title=Nitric oxide: A cytotoxic activated macrophage effector molecule|year=1988|last1=Hibbs|first1=John B.|last2=Taintor|first2=Read R.|last3=Vavrin|first3=Zdenek|last4=Rachlin|first4=Elliot M.|journal=Biochemical and Biophysical Research Communications|volume=157|pages=87–94|pmid=3196352|issue=1}}</ref> In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.<ref>{{cite book |author=C. A. Janeway, et al. |title=Immunobiology: the immune system in health and disease |publisher=Garland Science |location=New York |year=2005 |edition=6th |isbn=0-8153-4101-6}}</ref> Because nitric oxide might serve as an ''inflammometer'' in conditions like [[asthma]], there has been increasing interest in the use of [[exhaled nitric oxide]] as a [[breath test]] in diseases with [[airway]] inflammation. Reduced levels of exhaled NO have been associated with exposure to air pollution in cyclists and smokers, but, in general, increased levels of exhaled NO are associated with exposure to air pollution.<ref name="Jacobs">{{cite journal|doi=10.1186/1476-069X-9-64|title=Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: An intervention study|year=2010|last1=Jacobs|first1=Lotte|last2=Nawrot|first2=Tim S|last3=De Geus|first3=Bas|last4=Meeusen|first4=Romain|last5=Degraeuwe|first5=Bart|last6=Bernard|first6=Alfred|last7=Sughis|first7=Muhammad|last8=Nemery|first8=Benoit|last9=Panis|first9=Luc|displayauthors=222|journal=Environmental Health|volume=9|pages=64|pmid=20973949|pmc=2984475}}</ref> Nitric oxide can contribute to [[reperfusion injury]] when an excessive amount produced during reperfusion (following a period of [[ischemia]]) reacts with [[superoxide]] to produce the damaging oxidant [[peroxynitrite]]. In contrast, inhaled nitric oxide has been shown to help survival and recovery from [[paraquat]] poisoning, which produces lung tissue–damaging superoxide and hinders NOS metabolism. In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase,<ref>{{cite journal|title=Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants|author=Corpas, F. J. ''et al.''|journal=Plant Physiology|volume=136 |issue=1 |pages=2722–33 |year=2004|doi=10.1104/pp.104.042812|pmid=15347796|pmc=523336|first2=JB|first3=A|first4=M|first5=AM|first6=MC|first7=FJ|first8=R|first9=JM|first10=LM|first11=M|first12=LA}}</ref><ref>{{cite journal |author=Corpas, F. J. ''et al.''|title=Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development|journal=Planta|volume=224|issue=2 |pages=246–54|year=2006|doi=10.1007/s00425-005-0205-9 |pmid=16397797 |first2=Juan B. |first3=Alfonso |first4=Raquel |first5=José M. |first6=Ana M. |first7=Luisa M. |first8=Luis A}}</ref><ref>{{cite journal |author=Valderrama, R. ''et al.''|title=Nitrosative stress in plants|journal=FEBS Lett|volume=581|issue=3 |pages=453–61|year=2007|doi=10.1016/j.febslet.2007.01.006 |pmid=17240373 |first2=Francisco J. |first3=Alfonso |first4=Ana |first5=Mounira |first6=Francisco |first7=María V. |first8=Pilar |first9=Luis A. |first10=Juan B.}}</ref> (although the existence of animal NOS homologs in plants is debated),<ref>{{cite journal |author=Corpas et al.|title=Enzymatic sources of nitric oxide in plant cells – beyond one protein–one function|journal=New Phytologist|volume=162|issue= 2|pages=246–7|year=2004|doi=10.1111/j.1469-8137.2004.01058.x |last2=Barroso |first2=Juan B. |last3=Del Rio |first3=Luis A.}}</ref> (ii) plasma membrane-bound [[nitrate reductase]], (iii) mitochondrial electron transport chain, or (iv) non-enzymatic reactions. It is a signaling molecule, acts mainly against [[oxidative stress]] and also plays a role in plant pathogen interactions. Treating cut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting.<ref>Judy Siegel-Itzkovich. [http://www.studentbmj.com/issues/99/09/news/313.php Viagra makes flowers stand up straight]. ''[[Student BMJ]]'', September 1999.</ref> Two important biological reaction mechanisms of nitric oxide are S-[[nitrosation]] of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of [[thiol]] groups, including [[cysteine]] residues in proteins, to form S-nitrosothiols (RSNOs). S-[[Nitrosation]] is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.<ref>E. van Faassen and A. Vanin,eds. ''Radicals for life: The various forms of nitric oxide''. Elsevier, Amsterdam 2007, ISBN 978-0-444-52236-8</ref> The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron or copper. In this function, NO is referred to as a nitrosyl ligand. Typical cases involve the nitrosylation of heme proteins like cytochromes, thereby disabling the normal enzymatic activity of the enzyme. Nitrosylated ferrous iron is particularly stable, as the binding of the nitrosyl ligand to ferrous iron (Fe(II)) is very strong. Hemoglobin is a prominent example of a heme protein that may be modified by NO by both pathways: NO may attach directly to the heme in the nitrosylation reaction, and independently form S-nitrosothiols by S-nitrosation of the thiol moieties.<ref>E. van Faassen and A. Vanin, ''Nitric Oxide'', in Encyclopedia fo Analytical Science, 2nd ed., Elsevier 2004.</ref> ===Mechanism of action=== There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as [[ribonucleotide reductase]] and [[aconitase]], activation of the soluble [[guanylate cyclase]], ADP ribosylation of proteins, protein sulfhydryl group [[nitrosylation]], and iron regulatory factor activation.<ref>{{cite journal|pmid=7658698|year=1995|last1=Shami|first1=PJ|last2=Moore|first2=JO|last3=Gockerman|first3=JP|last4=Hathorn|first4=JW|last5=Misukonis|first5=MA|last6=Weinberg|first6=JB|title=Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells|volume=19|issue=8|pages=527–33|journal=Leukemia research|doi=10.1016/0145-2126(95)00013-E}}</ref> NO has been demonstrated to activate [[NF-κB]] in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.<ref>{{cite journal|url=http://www.jhep-elsevier.com/article/S0168-8278(99)80270-0/abstract|author=Kaibori M., Sakitani K., Oda M., Kamiyama Y., Masu Y. and Okumura T.|year=1999|title=Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-κB activation in rat hepatocytes|journal=J. Hepatol.|volume=30|pages=1138–1145|doi=10.1016/S0168-8278(99)80270-0|pmid=10406194|issue=6}}</ref> It was found that NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP. Cyclic-GMP activates [[protein kinase G]], which causes reuptake of Ca²⁺ and the opening of calcium-activated potassium channels. The fall in concentration of Ca²⁺ ensures that the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell.<ref>{{cite book|pmid=174|year=2003|last1=Rhoades|first1=RA|last2=Tanner|first2=GA|title=Medical physiology 2nd edition}}</ref> ==Medical use== === Neonatal use === Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat primary [[pulmonary hypertension]] in neonatal patients<ref>{{cite journal |author=Finer NN, Barrington KJ |title=Nitric oxide for respiratory failure in infants born at or near term |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD000399 |year=2006 |pmid=17054129 |doi=10.1002/14651858.CD000399.pub2 |editor1-last=Finer |editor1-first=Neil}}</ref><ref>{{cite journal |author=Chotigeat U, Khorana M, Kanjanapattanakul W |title=Inhaled nitric oxide in newborns with severe hypoxic respiratory failure |journal=J Med Assoc Thai |volume=90 |issue=2 |pages=266–71 |year=2007 |pmid=17375630}}</ref> post-meconium aspiration and related to birth defects. These are often a last-resort gas mixture before the use of [[extracorporeal membrane oxygenation]] (ECMO). Nitric oxide therapy has the potential to significantly increase the quality of life and, in some cases, save the lives of infants at risk for pulmonary vascular disease.<ref>{{cite journal|pmid=10690334|year=1999|last1=Hayward|first1=CS|last2=Kelly|first2=RP|last3=MacDonald|first3=PS|title=Inhaled nitric oxide in cardiology practice|volume=43|issue=3|pages=628–38|journal=Cardiovascular research|doi=10.1016/S0008-6363(99)00114-5}}</ref> === Pediatric and adult use === Currently in the United States, nitric oxide use is not approved for any population other than neonates. In the adult ICU setting, inhaled NO can improve hypoxemia in [[acute lung injury]], [[acute respiratory distress syndrome]], and severe [[pulmonary hypertension]], although the effects are short-lived and there are no studies demonstrating improved clinical outcomes. It is used on an individualized basis in ICUs as an adjunct to other definitive therapies for reversible causes of hypoxemic respiratory distress. <ref>{{cite journal |author=Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D. |title= Inhaled Nitric Oxide Therapy in Adults |journal=N Engl J Med |year=2005 |volume=353 |page=2683–2695 |date=December 22, 2005 |doi=10.1056/NEJMra051884 |issue=25}}</ref> === Dosage and strength === Currently in the United States, nitric oxide is a gas available in concentrations of only 100 ppm and 800 ppm. Overdosage with inhaled nitric oxide will be seen by elevations in [[methemoglobin]] and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause [[acute lung injury]]. === Contraindications === Inhaled nitric oxide is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood. === Pulmonary embolism === Nitric oxide is also administered as [[salvage therapy]] in patients with acute [[right ventricular failure]] secondary to [[pulmonary embolism]].<ref name="pmid22005573">{{cite journal| author=Summerfield DT, Desai H, Levitov A, Grooms D, Marik PE| title=Inhaled Nitric Oxide as Salvage Therapy in Massive Pulmonaryembolism: A Case Series | journal=Respir Care | year= 2011 | volume= 57| issue= 3| pages= 444–8| pmid=22005573 | doi=10.4187/respcare.01373 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22005573}}</ref> === Pharmacology === Nitric oxide is considered an [[Antianginal|anti]][[Angina pectoris|anginal]] drug: It causes [[vasodilation]], which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating (expanding) the veins, nitric oxide drugs lower arterial pressure and left ventricular filling pressure.<ref name="Jonathan Abrams 1996">{{cite journal|doi=10.1016/S0002-9149(96)00186-5|title=Beneficial actions of nitrates in cardiovascular disease|year=1996|last1=Abrams|first1=J|journal=The American Journal of Cardiology|volume=77|pages=31C–7C|pmid=8638524|issue=13}}</ref> This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood. Nitroglycerin pills, taken sublingually (under the tongue), are used to prevent or treat acute chest pain. The nitroglycerin reacts with a [[thiol|sulfhydryl]] group (–SH) to produce nitric oxide, which eases the pain by causing vasodilation. There is a potential role for the use of nitric oxide in alleviating bladder contractile dysfunctions,<ref name="Moro et al. 2013">{{cite journal | last1 = Moro| first1 = C | last2 = Leeds | first2 = C | last3 = Chess-Williams | first3 = R | title = Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide | journal = Eur J Pharmacol. | year = 2012| month = January| volume = 674| issue = 2–3 | pages = 445–449| pmid = 22119378 | doi = 10.1016/j.ejphar.2011.11.020}}</ref> and recent evidence suggests that nitrates may be beneficial for treatment of angina due to reduced myocardial oxygen consumption both by decreasing preload and afterload and by some direct vasodilation of coronary vessels.<ref name="Jonathan Abrams 1996"/> === Associated problems === There are some associated complaints with utilization of nitric oxide in neonatal patients. Some of them include dose errors associated with the delivery system, headaches associated with environmental exposure of nitric oxide in hospital staff, hypotension associated with acute withdrawal of the drug, hypoxemia associated with acute withdrawal of the drug, and pulmonary edema in patients with CREST syndrome. === Mechanism of action === Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic-guanosine 3’,5’-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide dilates the pulmonary vasculature and, because of efficient scavenging by hemoglobin, has minimal effect on the vasculature of the entire body.<ref name="pmid16870914">{{cite journal| author=Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C et al.| title=Early inhaled nitric oxide therapy in premature newborns with respiratory failure | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 4 | pages= 354–64 | pmid=16870914 | doi=10.1056/NEJMoa060442 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16870914 }}</ref> Inhaled nitric oxide appears to increase the [[partial pressure of arterial oxygen]] (PaO₂) by dilating pulmonary vessels in better-ventilated areas of the lung, moving pulmonary blood flow away from lung segments with low ventilation/perfusion (V/Q) ratios toward segments with normal or better ratios.<ref name="pmid16870913">{{cite journal| author=Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD et al.| title=Inhaled nitric oxide in preterm infants undergoing mechanical ventilation | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 4 | pages= 343–53 | pmid=16870913 | doi=10.1056/NEJMoa061088 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16870913 }}</ref> ==== Pharmacokinetics ==== Nitric oxide is absorbed systemically after inhalation. Most of it moves across the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. [[Nitrate]] is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration. ==References== {{Reflist|2}} ==Further reading== *Butler A. and Nicholson R.; [http://books.google.com/books?id=0d1Z0m76YeYC&printsec=frontcover "Life, death and NO."] Cambridge 2003. ISBN 978-0-85404-686-7. *van Faassen, E. E.; Vanin, A. F. (eds); [http://books.google.com/books?id=UJ4glFNEcn0C&printsec=frontcover "Radicals for life: The various forms of Nitric Oxide."] Elsevier, Amsterdam 2007. ISBN 978-0-444-52236-8. *Ignarro, L. J. (ed.); [http://books.google.com/books?id=h5FugARr4bgC&printsec=frontcover "Nitric oxide:biology and pathobiology."] Academic Press, San Diego 2000. ISBN 0-12-370420-0. ==External links== *[http://www.inchem.org/documents/icsc/icsc/eics1311.htm International Chemical Safety Card 1311] *[http://www.cdc.gov/niosh/npg/npgd0448.html CDC - NIOSH Pocket Guide to Chemical Hazards] *[http://www.npi.gov.au/database/substance-info/profiles/67.html National Pollutant Inventory – Oxides of nitrogen Fact Sheet] *[http://www.nobel.se/medicine/laureates/1998/index.html 1998 Nobel Prize in Physiology/Medicine for discovery of NO's role in cardiovascular regulation] *[http://www.diabetesincontrol.com/annodyne/burkeseries.php Nitric Oxide and its Role in Diabetes, Wound Healing and Peripheral Neuropathy] *[http://mattson.creighton.edu/NOx/index.html Microscale Gas Chemistry: Experiments with Nitrogen Oxides] *[http://www.livescience.com/980-brain-boots-computer.html Your Brain Boots Up Like a Computer] – new insights about the biological role of nitric oxide. *[http://www.podiatrytoday.com/article/5164 Assessing The Potential of Nitric Oxide in the Diabetic Foot] *[http://www.sciencedaily.com/releases/2007/11/071121213845.htm New Discoveries About Nitric Oxide Can Provide Drugs For Schizophrenia] *[http://ull.chemistry.uakron.edu/erd/Chemicals/8000/6828.html Nitric Oxide at the Chemical Database] {{Neurotransmitters}} {{DEFAULTSORT:Nitric Oxide}} [[Category:Oxides]] [[Category:Inorganic nitrogen compounds]] [[Category:Neurotransmitters]] [[Category:Nitrogen metabolism]] [[Category:Free radicals]]'