|Jmol-3D images||Image 1|
|Molar mass||30.01 g mol−1|
|Density||1.3402 g dm−3|
|Melting point||−164 °C; −263 °F; 109 K|
|Boiling point||−152 °C; −242 °F; 121 K|
|Solubility in water||74 cm3 dm−3|
|Refractive index (nD)||1.0002697|
|Molecular shape||linear (point group C∞v)|
|210.76 J K−1 mol−1|
|Std enthalpy of
|90.29 kJ mol−1|
|Metabolism||via pulmonary capillary bed|
|EU classification||O T|
|R-phrases||R8, R23, R34, R44|
|S-phrases||(S1), S17, S23, S36/37/39, S45|
|Related nitrogen oxides||Dinitrogen pentoxide
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Nitric oxide, or nitrogen oxide, also known as nitrogen monoxide, is a molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry. Nitric oxide is a by-product of combustion of substances in the air, as in automobile engines, fossil fuel power plants, and is produced naturally during the electrical discharges of lightning in thunderstorms.
In mammals including humans, NO is an important cellular signaling molecule involved in many physiological and pathological processes. 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 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.
- 1 Reactions
- 2 Production
- 3 Environmental effects
- 4 Technical applications
- 5 Biological functions
- 6 Medical use
- 7 References
- 8 Further reading
- 9 External links
- 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 N2O2 is formed when nitric oxide is cooled.
- Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or nitrosohydroxylamine and methyl acetate:
- 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.
- 4 NH3 + 5 O2 → 4 NO + 6 H2O
The uncatalyzed endothermic reaction of O2 and 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
- 8 HNO3 + 3 Cu → 3 Cu(NO3)2 + 4 H2O + 2 NO
- 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.
NO reacts with all transition metals to give complexes called metal nitrosyls. 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.
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. 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.
Nitric oxide concentration can be determined using a simple chemiluminescent reaction involving ozone: 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 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).
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 engines has drastically increased the presence of nitric oxide in the environment. One purpose of catalytic converters in cars is to minimize NO emission by catalytic reversion to O2 and N2.
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.
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. It finds use in the semiconductor industry for various processes. In one of its applications, it is used along with nitrous oxide to form oxynitride gates in CMOS devices.
Nitric oxide can be used for detecting surface radicals on polymers. Quenching of surface radicals with nitric oxide results in incorporation of nitrogen, which can be quantified by means of X-ray photoelectron spectroscopy.
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 biological messenger, playing a role in a variety of biological processes. It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.
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) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels 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 (released from one cell type and acting on another cell type in very close proximity) signaling molecule.
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. 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-hypertensive persons. 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. 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.
The production of nitric oxide is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation. Effects include vasodilatation, neurotransmission (see gasotransmitters), modulation of the hair cycle, production of reactive nitrogen intermediates and penile erections (through its ability to vasodilate). 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 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. A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.
Nitric oxide is also generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response. 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. 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. Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania and malaria; the mechanism for this includes DNA damage and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.
In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance. Because nitric oxide might serve as an inflammetur[clarification needed] 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.
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, (although the existence of animal NOS homologs in plants is debated), (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.
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. 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.
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. 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.
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.
Nitric oxide/oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat primary pulmonary hypertension in neonatal patients 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.
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.
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.
Inhaled nitric oxide is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood.
Nitric oxide is considered an antianginal 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.
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 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, 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.
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.
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.
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.
- "Nitric Oxide (CHEBI:16480)". Chemical Entities of Biological Interest (ChEBI). UK: European Bioinformatics Institute.
- IUPAC nomenclature of inorganic chemistry 2005. PDF.
- Lund, Anders; Shimada, Shigetaka; Shiotani, Masaru (2011). Principles and Applications of ESR Spectroscopy. Springer. ISBN 978-1-4020-5344-3.
- Hou, YC; Janczuk, A; Wang, PG (1999). "Current trends in the development of nitric oxide donors". Current pharmaceutical design 5 (6): 417–41. PMID 10390607.
- Culotta, Elizabeth and Koshland, Daniel E. Jr (1992). "NO news is good news". Science 258 (5090): 1862–1864. doi:10.1126/science.1361684. PMID 1361684.
- Traube, Wilhelm (1898). "Ueber Synthesen stickstoffhaltiger Verbindungen mit Hülfe des Stickoxyds". Justus Liebig's Annalen der Chemie 300: 81. doi:10.1002/jlac.18983000108.
- Derosa, Frank; Keefer, Larry K.; Hrabie, Joseph A. (2008). "Nitric Oxide Reacts with Methoxide". The Journal of Organic Chemistry 73 (3): 1139–42. doi:10.1021/jo7020423. PMID 18184006.
- Crabtree, Robert H. (2005). The Organometallic Chemistry of the Transition Metals. John Wiley and Sons. p. 32. ISBN 9780471718758.
- Crabtree, Robert H. (2005). The Organometallic Chemistry of the Transition Metals. John Wiley and Sons. pp. 96–98. ISBN 9780471718758.
- Fontijn, Arthur.; Sabadell, Alberto J.; Ronco, Richard J. (1970). "Homogeneous chemiluminescent measurement of nitric oxide with ozone. Implications for continuous selective monitoring of gaseous air pollutants". Analytical Chemistry 42 (6): 575. doi:10.1021/ac60288a034.
- Vanin, A; Huisman, A; Van Faassen, E (2002). "Iron dithiocarbamate as spin trap for nitric oxide detection: Pitfalls and successes". Methods in enzymology. Methods in Enzymology 359: 27–42. doi:10.1016/S0076-6879(02)59169-2. ISBN 9780121822620. PMID 12481557.
- Nagano, T; Yoshimura, T (2002). "Bioimaging of nitric oxide". Chemical reviews 102 (4): 1235–70. doi:10.1021/cr010152s. PMID 11942795.
- "Production: Growth is the Norm". Chemical and Engineering News 84 (28): 59. July 10, 2006. doi:10.1021/cen-v084n028.p059.
- Weller, Richard, Could the sun be good for your heart? TedxGlasgow. Filmed March 2012, posted January 2013
- Roszer, T (2012) The Biology of Subcellular Nitric Oxide. ISBN 978-94-007-2818-9
- Stryer, Lubert (1995). Biochemistry, 4th Edition. W.H. Freeman and Company. p. 732. ISBN 0-7167-2009-4.
- "Plant-based Diets | Plant-based Foods | Beetroot Juice | Nitric Oxide Vegetables". Berkeley Test. Retrieved 2013-10-04.
- Ghosh, S. M.; Kapil, V.; Fuentes-Calvo, I.; Bubb, K. J.; Pearl, V.; Milsom, A. B.; Khambata, R.; Maleki-Toyserkani, S.; Yousuf, M.; Benjamin, N.; Webb, A. J.; Caulfield, M. J.; Hobbs, A. J.; Ahluwalia, A. (2013). "Enhanced Vasodilator Activity of Nitrite in Hypertension: Critical Role for Erythrocytic Xanthine Oxidoreductase and Translational Potential". Hypertension 61 (5): 1091–102. doi:10.1161/HYPERTENSIONAHA.111.00933. PMID 23589565.
- Webb, A. J.; Patel, N.; Loukogeorgakis, S.; Okorie, M.; Aboud, Z.; Misra, S.; Rashid, R.; Miall, P.; Deanfield, J.; Benjamin, N.; MacAllister, R.; Hobbs, A. J.; Ahluwalia, A. (2008). "Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite". Hypertension 51 (3): 784–90. doi:10.1161/HYPERTENSIONAHA.107.103523. PMC 2839282. PMID 18250365.
- Hezel, MP; Weitzberg, E (2013). "The oral microbiome and nitric oxide homoeostasis". Oral Diseases: n/a. doi:10.1111/odi.12157.
- Green, Shawn J. (2013-07-25). "Turning DASH Strategy into Reality for Improved Cardio Wellness Outcomes: Part II". Real World Health Care. Retrieved 2013-10-04.
- Proctor, PH (August 1989). "Endothelium-Derived Relaxing Factor and Minoxidil: Active Mechanisms in Hair Growth". Archives in Dermatology 125 (8): 1146. doi:10.1001/archderm.1989.01670200122026. PMID 2757417.
- Dessy, C.; Ferron, O. (2004). "Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature". Current Medical Chemistry – Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 3 (3): 207–216. doi:10.2174/1568014043355348.
- Osanai, T; Fujiwara, N; Saitoh, M; Sasaki, S; Tomita, H; Nakamura, M; Osawa, H; Yamabe, H; Okumura, K (2002). "Relationship between salt intake, nitric oxide, and asymmetric dimethylarginine and its relevance to patients with end-stage renal disease". Blood purification 20 (5): 466–8. doi:10.1159/000063555. PMID 12207094.
- Green, SJ; Mellouk, S; Hoffman, SL; Meltzer, MS; Nacy, CA (1990). "Cellular mechanisms of nonspecific immunity to intracellular infection: Cytokine-induced synthesis of toxic nitrogen oxides from L-arginine by macrophages and hepatocytes". Immunology letters 25 (1–3): 15–9. doi:10.1016/0165-2478(90)90083-3. PMID 2126524.
- Gorczyniski and Stanely, Clinical Immunology. Landes Bioscience; Austin, TX. ISBN 1-57059-625-5
- Green, SJ; Nacy, CA; Schreiber, RD; Granger, DL; Crawford, RM; Meltzer, MS; Fortier, AH (1993). "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". Infection and immunity 61 (2): 689–98. PMC 302781. PMID 8423095.
- Kamijo, R; Gerecitano, J; Shapiro, D; Green, SJ; Aguet, M; Le, J; Vilcek, J (1995). "Generation of nitric oxide and clearance of interferon-gamma after BCG infection are impaired in mice that lack the interferon-gamma receptor". Journal of inflammation 46 (1): 23–31. PMID 8832969.
- Green, SJ; Scheller, LF; Marletta, MA; Seguin, MC; Klotz, FW; Slayter, M; Nelson, BJ; Nacy, CA (1994). "Nitric oxide: Cytokine-regulation of nitric oxide in host resistance to intracellular pathogens". Immunology letters 43 (1–2): 87–94. doi:10.1016/0165-2478(94)00158-8. PMID 7537721.
- Green, SJ; Crawford, RM; Hockmeyer, JT; Meltzer, MS; Nacy, CA (1990). "Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha". Journal of immunology 145 (12): 4290–7. PMID 2124240.
- Seguin, M. C.; Klotz, FW; Schneider, I; Weir, JP; Goodbary, M; Slayter, M; Raney, JJ; Aniagolu, JU; Green, SJ (1994). "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". Journal of Experimental Medicine 180 (1): 353–8. doi:10.1084/jem.180.1.353. PMC 2191552. PMID 7516412.
- Mellouk, S; Green, SJ; Nacy, CA; Hoffman, SL (1991). "IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism". Journal of immunology 146 (11): 3971–6. PMID 1903415.
- Klotz, FW; Scheller, LF; Seguin, MC; Kumar, N; Marletta, MA; Green, SJ; Azad, AF (1995). "Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites". Journal of immunology 154 (7): 3391–5. PMID 7534796.
- Wink, D.; Kasprzak, K.; Maragos, C.; Elespuru, R.; Misra, M; Dunams, T.; Cebula, T.; Koch, W.; Andrews, A.; Allen, J.; Et, al. (1991). "DNA deaminating ability and genotoxicity of nitric oxide and its progenitors". Science 254 (5034): 1001–3. doi:10.1126/science.1948068. PMID 1948068.
- Nguyen, T.; Brunson, D.; Crespi, C. L.; Penman, B. W.; Wishnok, J. S.; Tannenbaum, S. R. (1992). "DNA Damage and Mutation in Human Cells Exposed to Nitric Oxide in vitro". Proceedings of the National Academy of Sciences 89 (7): 3030. doi:10.1073/pnas.89.7.3030. Free text.
- Li, Chun-Qi; Pang, Bo; Kiziltepe, Tanyel; Trudel, Laura J.; Engelward, Bevin P.; Dedon, Peter C.; Wogan, Gerald N. (2006). "Threshold Effects of Nitric Oxide-Induced Toxicity and Cellular Responses in Wild-Type and p53-Null Human Lymphoblastoid Cells". Chemical Research in Toxicology 19 (3): 399–406. doi:10.1021/tx050283e. PMC 2570754. PMID 16544944. free text
- Hibbs, John B.; Taintor, Read R.; Vavrin, Zdenek; Rachlin, Elliot M. (1988). "Nitric oxide: A cytotoxic activated macrophage effector molecule". Biochemical and Biophysical Research Communications 157 (1): 87–94. doi:10.1016/S0006-291X(88)80015-9. PMID 3196352.
- Janeway, C. A. et al. (2005). Immunobiology: the immune system in health and disease (6th ed.). New York: Garland Science. ISBN 0-8153-4101-6.
- Jacobs, Lotte; Nawrot, Tim S; De Geus, Bas; Meeusen, Romain; Degraeuwe, Bart; Bernard, Alfred; Sughis, Muhammad; Nemery, Benoit; Panis, Luc (2010). "Subclinical responses in healthy cyclists briefly exposed to traffic-related air pollution: An intervention study". Environmental Health 9: 64. doi:10.1186/1476-069X-9-64. PMC 2984475. PMID 20973949.
- Corpas, F. J. (2004). "Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants". Plant Physiology 136 (1): 2722–33. doi:10.1104/pp.104.042812. PMC 523336. PMID 15347796.
- Corpas, F. J. (2006). "Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development". Planta 224 (2): 246–54. doi:10.1007/s00425-005-0205-9. PMID 16397797.
- Valderrama, R. (2007). "Nitrosative stress in plants". FEBS Lett 581 (3): 453–61. doi:10.1016/j.febslet.2007.01.006. PMID 17240373.
- Corpas, F. J.; Barroso, Juan B.; Del Rio, Luis A. (2004). "Enzymatic sources of nitric oxide in plant cells – beyond one protein–one function". New Phytologist 162 (2): 246–7. doi:10.1111/j.1469-8137.2004.01058.x.
- Siegel-Itzkovich, J. (1999). "Viagra makes flowers stand up straight". BMJ 319 (7205): 274. doi:10.1136/bmj.319.7205.274a. PMC 1126920. PMID 10426722.
- van Faassen, E. and Vanin, A. (eds.) (2007) Radicals for life: The various forms of nitric oxide. Elsevier, Amsterdam, ISBN 978-0-444-52236-8
- van Faassen, E. and Vanin, A. (2004) "Nitric Oxide", in Encyclopedia of Analytical Science, 2nd ed., Elsevier, ISBN 0127641009.
- Shami, PJ; Moore, JO; Gockerman, JP; Hathorn, JW; Misukonis, MA; Weinberg, JB (1995). "Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells". Leukemia research 19 (8): 527–33. doi:10.1016/0145-2126(95)00013-E. PMID 7658698.
- Kaibori M., Sakitani K., Oda M., Kamiyama Y., Masu Y. and Okumura T. (1999). "Immunosuppressant FK506 inhibits inducible nitric oxide synthase gene expression at a step of NF-κB activation in rat hepatocytes". J. Hepatol. 30 (6): 1138–1145. doi:10.1016/S0168-8278(99)80270-0. PMID 10406194.
- Rhoades, RA; Tanner, GA (2003). Medical physiology 2nd edition. PMID 174.
- Finer NN, Barrington KJ (2006). "Nitric oxide for respiratory failure in infants born at or near term". In Finer, Neil. Cochrane Database Syst Rev (4): CD000399. doi:10.1002/14651858.CD000399.pub2. PMID 17054129.
- Chotigeat U, Khorana M, Kanjanapattanakul W (2007). "Inhaled nitric oxide in newborns with severe hypoxic respiratory failure". J Med Assoc Thai 90 (2): 266–71. PMID 17375630.
- Hayward, CS; Kelly, RP; MacDonald, PS (1999). "Inhaled nitric oxide in cardiology practice". Cardiovascular research 43 (3): 628–38. doi:10.1016/S0008-6363(99)00114-5. PMID 10690334.
- Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D. (December 22, 2005). "Inhaled Nitric Oxide Therapy in Adults". N Engl J Med 353 (25): 2683–2695. doi:10.1056/NEJMra051884. PMID 16371634.
- Summerfield DT, Desai H, Levitov A, Grooms D, Marik PE (2011). "Inhaled Nitric Oxide as Salvage Therapy in Massive Pulmonaryembolism: A Case Series". Respir Care 57 (3): 444–8. doi:10.4187/respcare.01373. PMID 22005573.
- Abrams, J (1996). "Beneficial actions of nitrates in cardiovascular disease". The American Journal of Cardiology 77 (13): 31C–7C. doi:10.1016/S0002-9149(96)00186-5. PMID 8638524.
- Moro, C; Leeds, C; Chess-Williams, R (January 2012). "Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide". Eur J Pharmacol. 674 (2–3): 445–449. doi:10.1016/j.ejphar.2011.11.020. PMID 22119378.
- Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C et al. (2006). "Early inhaled nitric oxide therapy in premature newborns with respiratory failure". N Engl J Med 355 (4): 354–64. doi:10.1056/NEJMoa060442. PMID 16870914.
- Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD et al. (2006). "Inhaled nitric oxide in preterm infants undergoing mechanical ventilation". N Engl J Med 355 (4): 343–53. doi:10.1056/NEJMoa061088. PMID 16870913.
- Butler A. and Nicholson R.; "Life, death and NO." Cambridge 2003. ISBN 978-0-85404-686-7.
- van Faassen, E. E.; Vanin, A. F. (eds); "Radicals for life: The various forms of Nitric Oxide." Elsevier, Amsterdam 2007. ISBN 978-0-444-52236-8.
- Ignarro, L. J. (ed.); "Nitric oxide:biology and pathobiology." Academic Press, San Diego 2000. ISBN 0-12-370420-0.
- International Chemical Safety Card 1311
- CDC – NIOSH Pocket Guide to Chemical Hazards
- 1998 Nobel Prize in Physiology/Medicine for discovery of NO's role in cardiovascular regulation
- Nitric Oxide and its Role in Diabetes, Wound Healing and Peripheral Neuropathy
- Microscale Gas Chemistry: Experiments with Nitrogen Oxides
- Your Brain Boots Up Like a Computer – new insights about the biological role of nitric oxide.
- Assessing The Potential of Nitric Oxide in the Diabetic Foot
- New Discoveries About Nitric Oxide Can Provide Drugs For Schizophrenia
- Nitric Oxide at the Chemical Database