Nitric oxide

Structural formula
General
Surname	Nitric oxide
other names	Nitric oxide Nitric oxide
Molecular formula	NO
Brief description	colorless and odorless gas
External identifiers / databases
CAS number 10102-43-9 EC number 233-271-0 ECHA InfoCard 100.030.233 PubChem 145068 DrugBank DB00435 Wikidata Q207843
Drug information
ATC code	R07 AX01
properties
Molar mass	30.01 g mol −1
Physical state	gaseous
density	1.25 kg m −3 (15 ° C, 1 bar)
Melting point	−164 ° C
boiling point	−152 ° C
solubility	60 mg l −1 in water (20 ° C)
Dipole moment	0.15872 D (5.29 * 10 -31  C  *  m )
Refractive index	1,000297 (0 ° C, 101.325 kPa)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 270-280-330-314 EUH: 071 P: 260-280-244-220-304 + 340-303 + 361 + 353-305 + 351 + 338-370 + 376-315-405-403
MAK	DFG : 0.5 ml m −3 or 0.63 mg m −3 Switzerland: 25 ml m −3 or 30 mg m −3
Toxicological data	5000 ppm · 25 min −1 ( LC Lo ,  dog ,  inh. ) 320 ppm ( LC Lo ,  mouse ,  inh. ) 1068 mg m −3 4 h −1 ( LC 50 ,  rat ,  inh. )
Thermodynamic properties
ΔH f 0	91.3 kJ / mol
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . Refractive index: Na-D line , 20 ° C

Nitric oxide is a colorless and odorless poisonous gas with the formula N = O. It is a chemical compound made up of the elements nitrogen and oxygen and belongs to the group of nitrogen oxides . NO is a radical .

properties

The nitrogen monoxide has a molar mass of 30.01 g / mol, the melting point is −163.6 ° C, the boiling point is −151.8 ° C. The critical temperature for NO is −93 ° C and the critical pressure is 6.4 MPa. Nitric oxide is sparingly soluble in water. The bond length of the N = O bond is 117 pm. Under the action of oxygen and other oxidizing agents , NO is oxidized very quickly to brown nitrogen dioxide, which disproportionates to nitric acid and nitrous acid in water . Besides iodine , it reacts with halogens to form nitrosyl halides , such as B. nitrosyl chloride . Under the influence of sulfur dioxide , nitrogen oxide is reduced to nitrous oxide .

Due to the rapid conversion into nitrogen dioxide in the air, nitric oxide has an irritating effect on the mucous membranes , and the formation of methemoglobin has a toxic effect. The formation of methaemoglobinaemia is based on a reaction of HbO ₂ with NO itself, whereby nitrate and methaemoglobin are formed, as well as on the reaction with nitrite formed from NO.

${\displaystyle \mathrm {Hb(Fe^{3+}){-}O{-}O^{-}+NO_{2}^{-}+H_{2}O\longrightarrow } }$ ${\displaystyle \mathrm {Hb(Fe^{3+})OH+NO_{3}^{-}+OH^{-}} }$

Manufacturing

In laboratory technology, NO can be obtained by reducing around 65 percent nitric acid with copper . However, the product is relatively impure. Pure nitric oxide is available

• from a solution of potassium nitrite and potassium iodide in water, into which sulfuric acid is dropped:

${\displaystyle \mathrm {2\ KNO_{2}+2\ KI+2\ H_{2}SO_{4}\longrightarrow } }$ ${\displaystyle \mathrm {2\ NO+I_{2}+2\ K_{2}SO_{4}+2\ H_{2}O} }$

Instead of potassium iodide, potassium hexacyanoferrate (II) can also be used:

${\displaystyle \mathrm {KNO_{2}+K_{4}[Fe(CN)_{6}]+H_{2}SO_{4}\longrightarrow } }$ ${\displaystyle \mathrm {NO+K_{3}[Fe(CN)_{6}]+K_{2}SO_{4}+H_{2}O} }$

• from nitrosyl hydrogen sulfate and mercury
• from sodium nitrite and sulfuric acid:

${\displaystyle \mathrm {6\ NaNO_{2}+3\ H_{2}SO_{4}\longrightarrow } }$ ${\displaystyle \mathrm {4\ NO+2\ H_{2}O+3\ Na_{2}SO_{4}+2\ HNO_{3}} }$

• from iron (II) sulfate and a mixture of sodium bromide and sodium nitrite. The end product of this simple reaction contains 98.8% NO and 1.2% N ₂ .

The gas is obtained industrially by catalytic ammonia combustion ( Ostwald process ). In the past, the gas was obtained on an industrial scale by burning nitrogen and oxygen in an electric arc . The processes used ( Birkeland-Eyde process , Schönherr process , Pauling process ) aimed at the shortest possible contact of the gases with the very hot flame arc in order to shift the reaction equilibrium to nitrogen monoxide. Since a lot of electrical energy is required here , the processes are not competitive with the Ostwald process and are no longer used.

use

Technically

Nitric oxide occurs as an intermediate product in the technical production of nitric acid and is used together with nitrogen dioxide to produce nitrites. The purest nitrogen monoxide is used as a test gas for calibrating measuring devices.

Medical

Nitric oxide has an expanding effect on the blood vessels and is synthesized from the amino acid L - arginine in the lungs and in sepsis, among other things , by the endothelial nitric oxide synthase (eNOS) .

Original articles and meta-analyzes as well as systematic reviews confirm the protective effects of NO and its precursor L- arginine in healthy people as well as in patients with cardiovascular diseases such as arteriosclerosis , high blood pressure and circulatory disorders, and recommend ensuring that NO formation is achieved through a targeted supply of sufficient quantities L- arginine.

The gas mixture INOmax from the manufacturer Linde AG was approved in 1999 by the Food and Drug Administration (FDA) in the USA and in 2001 by the European Commission in the EU for the treatment of newborns with lung failure with high blood pressure in the lungs ( hypoxic respiratory insufficiency , " Pulmonary hypertension " ). It is the first medical gas in the world to be approved as a drug and contains 100, 400 or 800  ppm (0.01%, 0.04% or 0.08%) nitric oxide as an active ingredient, the rest being inert nitrogen . INOmax is sold as a compressed gas in aluminum gas bottles. For use, it is added to the air you breathe , the recommended dose is 20 ppm.

Nitric oxide acts very quickly, which means that life-threatening complications can be treated well. In cardiac surgery ( valve disease , heart transplants ), NO can be used to treat increased pulmonary pressure. A therapeutic effect of NO has not been proven for the treatment of ARDS , a severe lung dysfunction that can occur after lung injuries, inflammation and irritant gas burns.

Physiological importance

Nitric oxide is a bioactive molecule that can enter into both redox and additive reactions with other molecules . Due to its small size, it can cross biological membranes in a short time and perform various functions locally, some of which are also destructive for the respective organism. These range from signal transduction in the vascular and nervous system to its use as a protective radical scavenger to its role as a reactive nitrogen species in unspecific immune defense . In plants, too, several processes are controlled by NO signals; only in the case of archaea is it questionable whether nitrogen monoxide has a biological function. On the destructive side, the damage to proteins and DNA should be mentioned, which is associated with chronic inflammatory processes in mammals and the resulting local NO production. Other gas transmitters are carbon monoxide and hydrogen sulfide .

The asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis from L -arginine and results in a decoupling of the eNOS activity with the formation of superoxide anion radicals , which then with NO to form peroxynitrite react. The ratio of L- arginine and ADMA influences the formation of nitric oxide. The NO formation should clearly predominate. The decoupling of eNOS through the increased formation of ADMA (reduced L- arginine / ADMA quotient) leads to nitrosative stress and is an indicator of cardiovascular disease. The synthesis of NO should therefore be ensured by a sufficient supply of L- arginine. Nitric oxide reacts in the blood with oxyhemoglobin to form NO ₃ ^- within seconds ; Nitrogen dioxide is not an intermediate product.

history

At the end of the 1970s, the pharmacologist Ferid Murad first became aware of the physiological effects of nitric oxide (NO). In investigations with organic nitrates - a group of substances that are used for acute chest pain - he discovered that they release NO, which causes the blood vessels to expand ( vasodilation ). The pharmacologist Robert F. Furchgott also studied the effects of drugs on blood vessels. He found out that the innermost vascular layer ( endothelium ) produces an unknown substance (factor), which causes the muscle layer above to relax (relax). Since he could not determine the substance, he named it EDRF (endothelium-derived relaxing factor, the vascular muscle relaxant factor derived from the endothelium). It was not until the 1980s that it was possible to decipher the unknown substance EDRF. Louis J. Ignarro and Robert F. Furchgott independently identified EDRF as nitric oxide.

In 1998 the Nobel Prize in Physiology and Medicine was awarded to the Americans Robert Furchgott, Ferid Murad and Louis J. Ignarro . The researchers succeeded for the first time in demonstrating the great importance of NO for the blood supply to organs and its role as a messenger substance in the organism. With the knowledge about NO, new possibilities in the treatment of vascular diseases and the resulting organ damage are opened up.

biosynthesis

With consumption of NADPH , tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme and the calcium-binding protein (calmodulin, CaM) by NO synthases (NOS) from the amino acid L - Arginine and Oxygen are made. Citrulline and water are produced as by-products . Of the NOS isoforms identified so far , the endothelial NOS (eNOS) and the neuronal NOS (nNOS) are constitutively expressed enzymes. There is also a transcriptionally inducible isoform (iNOS). All isoforms have high sequence homology with cytochrome P450 reductase.

→ Main article : NO synthases

Physiological adaptation

In adaptation to life in the highlands at 4000 meters, Tibetans have ten times as much NO in their blood as lowland residents. The resulting doubling of their blood flow enables them to receive an adequate supply of oxygen.

Web links

Wiktionary: nitric oxide  - explanations of meanings, word origins, synonyms, translations

Individual evidence

1. ↑ Safety data sheet nitrogen monoxide (PDF; 46 kB) from AirLiquide.
2. ↑ ^{a b c d} Entry on nitrogen monoxide in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .
3. ↑ ^{a b c d} Safety data sheet nitrogen monoxide (PDF; 201 kB) at Praxair.
4. ↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Dipole Moments, pp. 9-51.
5. ↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Index of Refraction of Gases, pp. 10-254.
6. ↑ Swiss Accident Insurance Fund (Suva): Limit values ​​- current MAK and BAT values (search for 10102-43-9 or nitrogen monoxide ), accessed on November 2, 2015.
7. ^ British Journal of Anesthesia. Vol. 39, 1967, p. 393.
8. ↑ Naunyn-Schmiedeberg's Archive for Experimental Pathology and Pharmacology. Vol. 181, 1936, p. 145.
9. ↑ Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. Vol. 19 (4), 1975, p. 52.
10. ↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Standard Thermodynamic Properties of Chemical Substances, pp. 5-16.
11. ↑ Patrick Horn: Activity and importance of the erythrocytic NOS in cardiovascular risk factors. ( Memento of December 5, 2015 in the Internet Archive ) (PDF; 1.1 MB).
12. ↑ Martin Ledig, Georg Wittke: Nitrate in foods. In: Science in Class. Chemistry. 5 (42) 23, 1994, pp. 7-12.
13. ↑ G. Brauer (Ed.): Handbook of Preparative Inorganic Chemistry. 2nd Edition. vol. 1, Academic Press 1963, pp. 485-487.
14. ↑ ^{a b} J. Y. Dong, LQ Qin, Z. Zhang, Y. Zhao, J. Wang, F. Arigoni, W. Zhang: Effect of oral L-arginine supplementation on blood pressure: A meta-analysis of randomized, double-blind , placebo-controlled trials. In: At Heart. Volume 162, 2011, pp. 959-965.
15. ^ ^{A b} F. Pizzarelli, R. Maas, P. Dattolo, G. Tripepi, S. Michelassi, G. D'Arrigo, M. Mieth, S. Bandinelli, L. Ferrucci, C. Zoccali: Asymmetric dimethylarginine predicts survival in the elderly. In: Age. Volume 35, No. 6, 2013, pp. 2465-2475.
16. ^ ^{A b} S. M. Bode-Böger, J. Muke, A. Surdacki, G. Brabant, RH Böger, JC Frölich: Oral L-arginine improves endothelial function in healthy individuals older than 70 years. In: Vasc. Med. Volume 8, 2003, pp. 77-81.
17. ↑ ^{a b} K. Jung, O. Petrowicz: L-arginine and folic acid in arteriosclerosis. Results of a prospective, multicenter consumption study. In: Perfusion. Volume 21, 2008, pp. 148-156.
18. ↑ ^{a b} P. Lucotti, L. Monti, E. Setola, G. La Canna, A. Castiglioni, A. Rossodivita, MG Pala, F. Formica, G. Paolini, AL Catapano, E. Bosi, O. Alfieri, P. Piatti: Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass. In: Metabolism. Volume 58, No. 9, 2009, pp. 1270-1276.
19. ↑ ^{a b} Y. Bai, L. Sun, T. Yang, K. Sun, R. Chen J. Hui: Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low : a meta-analysis of randomized controlled trials. In: Am. J. Clin. Nutr. Volume 89, No. 1, 2009, pp. 77-84.
20. ^ ^{A b} J. W. Drover, R. Dhaliwal, L. Weitzel, PE Wischmeyer, JB Ochoa, DK Heyland: Perioperative use of arginine-supplemented diets: a systematic review of the evidence. In: J. Am. Coll. Surg. Volume 212, No. 3, 2011, pp. 385-399.
21. ↑ FDA Approval Letter (English; PDF; 100 kB)
22. ↑ ^{a b} European Public Assessment Report (EPAR) and product information on INOmax ( Memento of March 7, 2009 in the Internet Archive ) on the website of the European Medicines Agency
23. ↑ inomax.com: Information for professionals for the USA (English; PDF; 618 kB).
24. ^ NK Adhikari et al.: Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. In: British Medical Journal. 334 (7597), Apr 14, 2007, p. 779. PMID 17383982
25. ↑ HR Bream-Rouwenhorst et al .: Recent developments in the management of acute respiratory distress syndrome in adults. In: American Journal of Health-System Pharmacy . 65 (1), Jan 1, 2008, pp. 29-36. PMID 18159036 .
26. ↑ MV Beligni, L. Lamattina: Nitric oxide in plants: the history is just beginning. In: Plant, Cell and Environment. 24, 2001, pp. 267-278, doi: 10.1046 / j.1365-3040.2001.00672.x .
27. ^ Anton Hermann, Guzel F. Sitdikova, Thomas M. Weiger: Gasotransmitter: volatile transmitters. Nitric oxide, carbon monoxide and hydrogen sulfide function as messenger substances and are physiologically effective. , In: Doctors Week. Springer, New York October 21, 2010 (PDF; 1.6 MB).
28. ^ Anton Hermann, Guzel F. Sitdikova, Thomas M. Weiger: Gases as cellular signal substances. Gas transmitter. ( Memento from December 3, 2013 in the Internet Archive ) In: Biology in our time. 40, 2010, pp. 185–193, doi: 10.1002 / biuz.201010422 .
29. ↑ ^{a b c} B. Poeggeler: Oxidative stress and L- arginine protects against nitrosative stress. Nitric oxide as an endogenous regulator of nitrosative metabolism. In: Perfusion. Volume 25 (2), 2012, pp. 40-43.
30. ↑ ^{a b c} E. Schulz, T. Gori, T. Münzel: Oxidative stress and endothelial dysfunction in hypertension. In: Hypertens Res. Volume 34 (6), 2011, pp. 665-673, doi: 10.1038 / hr.2011.39 . PMID 21512515 .
31. ↑ ^{a b c} I. Seljeflot, BB Nilsson, AS Westhelm, V. Bratseth, H. Arnesen: The L -arginine-asymmetric dimethylarginine ratio is strongly related to the severity of chronic heart failure. No effects of exercise training. In: J Card Fail. Volume 17 (2), 2011, pp. 135-142, doi: 10.1016 / j.cardfail.2010.09.003 . PMID 21300303
32. ^ Joseph S. Beckman, Willem H. Koppenol: Nitric oxide, superoxide and peroxynitrite: the good, the bad, and the ugly. In: AM. J. Physiol. 271/5, p. C1424 doi.org/10.1152/ajpcell.1996.271.5.C1424
33. ↑ SC Erzurum et al .: Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans. In: PNAS. 104, November 2007, pp. 17593-17598, doi: 10.1073 / pnas.0707462104

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