Nitric oxide

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Nitric oxide
Identifiers
CAS number	[10102-43-9]
Properties
Molecular formula	NO
Molar mass	30.0061
Appearance	colourless gas
Density	1.3 × 103 kg m−3 (liquid) 1.34 g dm−3 (vapour)
Melting point	−163.6°C (109.6 K)
Boiling point	−151.7°C (121.4 K)
Hazards
EU classification	Toxic (T), corrosive (C)
NFPA 704	0 3 2
R-phrases	R23, R24, R25, R34, R44
S-phrases	S23, S36, S37, S39
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Nitric oxide or Nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of mammals, including humans, and is an extremely important intermediate in the chemical industry. It is also a toxic air pollutant produced by automobile engines and power plants.

NO is an important messenger molecule involved in many physiological and pathological processes within the mammalian body both beneficial and detrimental. ^[1]. Appropriate levels of NO production are important in protecting an organ such as the liver from ischemic damage. However sustained levels of NO production result in direct tissue toxicity and contribute to the vascular collapse associated with septic shock, whereas chronic expression of NO is associated with various carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and ulcerative colitis. ^[2]

Nitric oxide should not be confused with nitrous oxide (N₂O), a general anaesthetic, or with nitrogen dioxide (NO₂) which is another poisonous air pollutant. The nitric oxide molecule is a free radical, which is relevant to understanding its high reactivity. It reacts with the ozone in air to form nitrogen dioxide, signalled by the appearance of the reddish-brown color.

Despite being a startlingly simple molecule, NO is a fundamental player in the fields of neuroscience, physiology, and immunology, and was proclaimed “Molecule of the Year” in 1992^[3]

Contents 1 Production environmental effects 2 Mechanism of action 3 Technical applications 3.1 Miscellaneous applications 4 Biological functions 5 Use in Pediatric Intensive Care 6 Reactions 6.1 Preparation 7 Coordination Chemistry 8 Measurement of nitric oxide concentration 9 References 10 Further reading 11 External links

[edit] Production environmental effects

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, >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. Furthermore, both NO and NO₂ participate in ozone layer depletion. Nitric oxide is a small highly diffusible gas and a ubiquitous bioactive molecule.

[edit] 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 sulphhydryl group nitrosylation, and iron regulatory factor activation. ^[4] NO has been demonstrated to activate NFkB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation. ^[5]. 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 kinases and leads ultimately to the dephosphorylation of the myosine light chain. ^[6]

[edit] 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 6M metric tons of nitric acid.^[7] 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.

[edit] Miscellaneous applications

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.

[edit] Biological functions

Main article: Endothelium-derived relaxing factor

NO is one of the few gaseous signaling molecules known. It is a key vertebrate biological messenger, playing a role in a variety of biological processes. Nitric oxide, known as the 'endothelium-derived relaxing factor', or 'EDRF', is biosynthesised endogenously from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by reduction of inorganic nitrate. The endothelium (inner lining) of blood vessels use 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 signal molecule between adjacent cells and within cells.^[8] The production of nitric oxide is elevated in populations living at high-altitudes, which helps these people avoid hypoxia. Effects include blood vessel dilatation, neurotransmission (see Gasotransmitters), modulation of the hair cycle, and penile erections. Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. Sildenafil, 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. In humans, a high-salt intake was demonstrated to attenuate NO production. ^[9]

Nitric oxide is also generated by macrophages and neutrophils as part of the human immune response. Nitric oxide is toxic to bacteria and other human pathogens. In response, however, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.^[10]

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 free radical 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 ^[11], ^[12],^[13],(although the existence animal NOS homologs in plants is debated)^[14],(ii) by plasma membrane-bound nitrate reductase, (iii) by mitochondrial electron transport chain, or (iv) by 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.^[15]

A biologically important reaction of nitric oxide is S-nitrosylation, the conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosylation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.

[edit] Use in Pediatric Intensive Care

Nitric Oxide/Oxygen blends are used in critical care to promote capillary and pulmonary dilation to treat Primary Pulmonary Hypertension in neonatal patients^[16][17] post meconium aspiration and related to birth defect. These are often a last-resort gas mixture before the use of ECMO. NO 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. ^[18]

[edit] Reactions

• When exposed to oxygen, NO is converted into nitrogen dioxide.

2NO + O₂ → 2NO₂

This conversion has been speculated as occurring via the ONOONO intermediate. In water, NO react 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 from 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.

2NO + Cl₂ → 2NOCl

• Nitroxyl (HNO) is the reduced form of nitric oxide.

• Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or nitrosohydroxylamine and Methyl acetate ^[19]:

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 ^[20].

[edit] Preparation

• As stated above, nitric oxide is produced industrially by the direct reaction of O₂ and N₂ at high temperatures. In the laboratory, it is conveniently generated by reduction of nitric acid:

8HNO₃ + 3Cu → 3Cu(NO₃)₂ + 4H₂O + 2NO

• or by the reduction of nitrous acid:

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.

• Commercially, NO is produced by the oxidation of ammonia at 750°C to 900°C (normally at 850°C) in the presence of platinum as catalyst:

4NH₃ + 5O₂ → 4NO + 6H₂O

The uncatalyzed endothermic reaction of O₂ and N₂ which is performed at high temperature (>2000°C) with lightning has not been developed into a practical commercial synthesis:

N₂ + O₂ → 2NO

[edit] Coordination Chemistry

Main article: metal nitrosyl

NO forms complexes 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 can vary from 160-180° but are still termed as "linear". In this case the NO group is formally considered a 3-electron donor. In the case of a bent M-N-O conformation the NO group can be considered a one electron donor.^[21]. Alternatively, 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 120-140°.

The NO group can also bridge between metal centers through the nitrogen atom in a variety of geometries.

[edit] Measurement of nitric oxide concentration

The concentration of nitric oxide can be determined using a simple chemiluminescent reaction involving ozone:^[22] 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).^[23][24]

A group of fluorescent dye indicators exist that are also available in acetylated form for intracellular measurements. The most common compound is 4,5-diaminofluorescein (DAF-2).^[3]

[edit] References

1. ^ Hou Y.C., Janczuk A. and Wang P.G. (1999): Current trends in the development of nitric oxide donors. Curr. Pharm. Des. June, 5 (6): 417- 471
2. ^ Tylor B.S., Kion Y.M., Wang Q.I., Sharpio R.A., Billiar T.R. and Geller D.A. (1997): Nitric oxide down regulates hepatocyte-inducible nitric oxide synthase gene expression. Arch. Surg. 1, (32). Nov.; 1177-1182.
3. ^ ^{a b} Elizabeth Culotta and Daniel E. Koshland Jr (December 1992). "NO news is good news. (nitric oxide; includes information about other significant advances & discoveries of 1992) (Molecule of the Year).". Science 258 (5090): 1862-1864. 
4. ^ Shami P.J., Moore J.O., Cockerman J.P., Halhorn W.J., Misukonis M.A., and Weinberg J.B. (1995): Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukaemia cells. Leukaemia Research; 19(8): 527 - 534.
5. ^ Kaibori M., Sakitani K., Oda M., Kamiyama Y., Masu Y. and Okumura T.(1999). Immunosuppressant FK56 inhibits iNOS gene expression at a step of NK-Kappa B activation in rat hepatocytes. J. Hepatol. Jan; 30 (6): 1138-1145.
6. ^ Denninger J.W. and Marletta M.A. (1999): Guanylate cyclase and the No/cGMP singling pathway. Biochem. Biophys. Acta, May; 1411 (2-3): 334-356.
7. ^ “Production: Growth is the Norm” Chemical and Engineering News, July 1 0, 2006, p. 59.
8. ^ Stryer, Lubert (1995). Biochemistry, 4th Edition. W.H. Freeman and Company, pp. 732. ISBN 0-7167-2009-4. 
9. ^ [1]
10. ^ C. A. Janeway, et al. (2005). Immunobiology: the immune system in health and disease, 6th ed., New York: Garland Science. ISBN 0-8153-4101-6. 
11. ^ Corpas et al. (2004). "Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants". Plant Physiology 136 (1): 2722-33. 
12. ^ Corpas et al. (2006). "Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development". Planta 224 (2): 246-54. 
13. ^ Valderrama et al. (2007). "Nitrosative stress in plants". FEBS Lett 581 (3): 453-61. 
14. ^ Corpas et al. (2004). "Enzymatic sources of nitric oxide in plant cells – beyond one protein–one function". New Phytologist 162: 246-7. 
15. ^ Judy Siegel-Itzkovich. Viagra makes flowers stand up straight. Student BMJ, September 1999.
16. ^ Finer NN, Barrington KJ (2006). "Nitric oxide for respiratory failure in infants born at or near term". Cochrane Database Syst Rev (4): CD000399. doi:10.1002/14651858.CD000399.pub2. PMID 17054129. 
17. ^ Chotigeat U, Khorana M, Kanjanapattanakul W (February 2007). "Inhaled nitric oxide in newborns with severe hypoxic respiratory failure". J Med Assoc Thai 90 (2): 266–71. PMID 17375630. 
18. ^ Hayward C.S., Kelly R.P. and Macdonald P.S. (1999): Inhaled nitric oxide in cardiology practice. Cadio. Vasc. Res. Aug.; 15, 43 (3): 628 - 638.
19. ^ Ueber Synthesen stickstoffhaltiger Verbindungen mit Hülfe des Stickoxyds Justus Liebig's Annalen der Chemie Volume 300, Issue 1, Date: 1898, Pages: 81-128 Wilhelm Traube doi:10.1002/jlac.18983000108
20. ^ Nitric Oxide Reacts with Methoxide Frank DeRosa, Larry K. Keefer, and Joseph A. Hrabie J. Org. Chem. 2008, 73, 1139-1142 doi:10.1021/jo7020423
21. ^ Catherine E. Housecroft and Alan G. Sharpe: "Inorganic Chemistry", page 570. Pearson Education Limited 2001, 2005
22. ^ Fontijn, A., A. J. Sabadell and R. J. Ronco (1970). "Homogeneous chemiluminescent measurement of nitric oxide with ozone." Analytical Chemistry 42(6): 575-579.
23. ^ Vanin A. F.; Huisman A.; van Faassen E.E.; Methods in Enzymology vol 359 (2002) 27 - 42
24. ^ Nagano T.; Yoshimura T.; "Bioimaging of nitric oxide", Chemical Reviews vol 102 (2002) 1235 - 1269.

[edit] Further reading

• Butler A. and Nicholson R.; " Life, death and NO." Cambridge 2003. ISBN-13: 978-0-85404-686-7.
• Corpas FJ et al “Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development” Planta 2006 224(2):246-54.
• Corpas FJ, del Río LA, Barroso JB. "Need of biomarkers of nitrosative stress in plants" Trends Plant Sci. 2007 12(10):436-8.
• van Faassen, E. E.; Vanin, A. F. (eds); " Radicals for life: The various forms of Nitric Oxide." Elsevier, Amsterdam 2007. ISBN-13: 978-0-444-52236-8.
• F.A. Cotton, G. Wilkinson, C.A. Murillo, M. Bochmann; Advanced Inorganic Chemistry, 6th ed. Wiley-Interscience, New York, 1999.
• K.J. Gupta , M. Stoimenova, and W. M. Kaiser "In higher plants, only root mitochondria, but not leaf mitochondria reduce nitrite to NO, in vitro and in situ" Journal of Experimental Botany 2005 56(420):2601-2609.
• E.Planchet, K.J. Gupta, M .Sonada & W.M.Kaiser (2005) "Nitric oxide emission from tobacco leaves and cell suspensions: rate limiting factors and evidence for the involvement of mitochondrial electron transport"The Plant Journal 41 (5), 732-743.
• Stöhr, C.; Stremlau, S. "Formation and possible roles of nitric oxide in plant roots" Journal of Experimental Botany 2006 57(3):463-470.
• Pacher, P.; Beckman, J. S.; Liaudet, L.; “Nitric Oxide and Peroxynitrite: in Health and disease” Physiological Reviews 2007, volume 87(1), page 315-424. PMID 17237348.
• Valderrama et al. "Nitrosative stress in plants" FEBS Lett. 2007 581(3):453-61.

[edit] External links

• National Pollutant Inventory - Oxides of nitrogen Fact Sheet
• 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
• Biomap on nitric oxide biochemistry
• Biomap on nitric oxide biology & cancer