Nitric Oxide

Nitric oxide
Identifiers
CAS number 10102-43-9 Y
PubChem 145068
ChemSpider 127983 Y
UNII 31C4KY9ESH Y
EC number 233-271-0
UN number 1660
DrugBank DB00435
KEGG D00074 Y
ChEBI CHEBI:16480 Y
ChEMBL CHEMBL1200689 N
RTECS number QX0525000
ATC code R07AX01
Gmelin Reference 451
3DMet B00122
Jmol-3D images Image 1
Properties
Molecular formula NO
Molar mass 30.01 g mol−1
Appearance Colourless gas
Density 1.3402 g dm−3
Melting point −164 °C, 109 K, -263 °F
Boiling point −152 °C, 121 K, -242 °F
Solubility in water 74 cm3 dm−3
Refractive index (nD) 1.0002697
Structure
Molecular shape linear (point group Cv)
Thermochemistry
Std enthalpy of
formation
ΔfHo298
90.29 kJ mol−1
Standard molar
entropy
So298
210.76 J K−1 mol−1
Pharmacology
Bioavailability good
Routes of
administration
Inhalation
Metabolism via pulmonary capillary bed
Elimination
half-life
2–6 seconds
Hazards
MSDS External MSDS
EU classification Oxidising agent O Toxic T
R-phrases R8, R23, R34, R44
S-phrases (S1), S17, S23, S36/37/39, S45
NFPA 704
NFPA 704.svg
0
3
3
OX
Related compounds
Related nitrogen oxides Dinitrogen pentoxideDinitrogen tetroxide
Dinitrogen trioxide
Nitrogen dioxide
Nitrous oxide
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Nitric oxide, or nitrogen oxide,[2] also known as nitrogen monoxide, is a molecule with chemical formula NO. It is a free radical[3] 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.[4] 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.[5]

Contents

Reactions

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.
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.[7]

Preparation

Nitric oxide production.

Commercially, 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 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

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

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.[8]

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.[9] 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.

Measurement of nitric oxide concentration

Nitric oxide (white) in conifer cells, visualized using DAF-2 DA (diaminofluorescein diacetate)

Nitric oxide concentration can be determined using a simple chemiluminescent reaction involving ozone:[10] 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).[11][12]

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

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 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.

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.[13] 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.

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.

Biological functions

NO is one of the few gaseous signaling 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.[14] It is a known bioproduct in almost all type of organisms, ranging from bacteria to plants, fungi, and animal cells.[15]

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 (within a single cell) signaling molecule.[16]

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,[17] 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. Similarly, 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.[18] A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.[19]

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.[20] 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 secreted as an immune response is as free radicals and is toxic to bacteria; the mechanism for this includes DNA damage[21][22][23] and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.[24]

In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.[25] 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.[26]

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,[27][28][29] (although the existence of animal NOS homologs in plants is debated),[30] (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.[31]

An important biological 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.

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.[32] 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.[33]

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 and thereby stopping the crossbridge cycle leading to relaxation of the smooth muscle cell. [34]

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[35][36] 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.[37]

Pediatric and adult use

Currently in the United States nitric oxide use is not approved for any population other than neonates.

Dosage and strength

Currently in the United States nitric oxide is a gas available only in 100 ppm and 800 ppm concentrations. 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.[38]

Pharmacology

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.[39]

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. 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.[39]

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; 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.[40]

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.[41]

Pharmacokinetics

Nitric oxide is absorbed systemically after inhalation. Most of it move 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

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Further reading

External links

This article uses material from the Wikipedia article Nitric Oxide, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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