Nitric oxide

From Wikipedia, the free encyclopedia

Not to be confused with nitrous oxide or nitrogen oxides.
Nitric oxide

Names
IUPAC name
Nitric oxide
Systematic IUPAC name
Oxidonitrogen()[1] (additive)
Other names
Nitrogen monoxide
Nitrogen(II) oxide
Identifiers
CAS Registry Number 10102-43-9
3Dmet B00122
ATC code R07AX01
ChEBI CHEBI:16480
ChEMBL ChEMBL1200689
ChemSpider 127983
DrugBank DB00435
EC number 233-271-0
Gmelin Reference 451
InChI[show]
IUPHAR/BPS 2509
Jmol-3D images Image
KEGG D00074
PubChem 145068
RTECS number QX0525000
SMILES[show]
UNII 31C4KY9ESH
UN number 1660
Properties
Chemical formula NO
Molar mass 30.01 gmol1
Appearance Colourless gas
Density 1.3402 g dm3
Melting point 164 C (263 F; 109 K)
Boiling point 152 C (242 F; 121 K)
0.0098 g/100ml (0 C)
Solubility in water
0.0056 g/100ml (20 C)
Refractive index (nD) 1.0002697
Structure
Molecular shape linear (point group Cv)
Thermochemistry
Std molar
210.76 J K1 mol1
entropy (So298)
Std enthalpy of
91.29 kJ mol1
formation (fHo298)
Pharmacology
Routes of
Inhalation
administration
Pharmacokinetics:
Bioavailability good
Metabolism via pulmonary capillary bed
Biological half-life 26 seconds
Hazards
Safety data sheet External MSDS

EU classification
O T
R-phrases R8, R23, R34, R44
S-phrases (S1), S17, S23, S36/37/39, S45
NFPA 704

0
3
3
 OX
Lethal dose or concentration (LD, LC):
315 ppm (rabbit, 15 min)
LC50 (Median
854 ppm (rat, 4 hr)
concentration)
320 ppm (mouse)[2]
LCLo (Lowest published) 2500 ppm (mouse, 12 min)[2]
Related compounds
Dinitrogen pentoxide
Dinitrogen tetroxide
Dinitrogen trioxide
Related nitrogen oxides Nitrogen dioxide
Nitrous oxide
Nitroxyl (reduced form)
Hydroxylamine (hydrogenated form)
Except where otherwise noted, data are given for materials in their
standard state (at 25 C [77 F], 100 kPa).
verify (what is: / ?)
Infobox references

Nitric oxide (nitrogen oxide,[3] nitrogen monoxide) is a molecular, chemical compound with
chemical formula of NO that is a colorless gas under standard conditions. Nitric oxide is a
free radicali.e., its bonding structure includes an unpaired electron[4]and it is in the class
of heteronuclear diatomic molecules that are of historic theoretical interest (for the insights
they gave in formulating early modern theories of bonding). It is a practically important
intermediate in the chemical industry and day-to-day life, for instance appearing as a by-
product of incomplete combustion of fuels burned in fossil fuel power plants and automobile
engines, and it 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.[5] 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 found to be precursors to nitric oxide more than a century after their
first use in medicine. Low levels of nitric oxide production are important in protecting organs
such as the liver from ischemic damage.

Despite being a simple molecule, NO is an important biological regulator and is therefore a

fundamental component in the fields of neuroscience, physiology, and immunology. It was
proclaimed Molecule of the Year in 1992.[6] Research into its function led to the 1998
Nobel Prize for discovering the role of nitric oxide as a cardiovascular signalling molecule.
Nitric oxide should not be confused with nitrous oxide (N2O), an anaesthetic, or with nitrogen
dioxide (NO2), a brown toxic gas and a major air pollutant, the latter being a product to which
nitric oxide is rapidly oxidised in air.

Contents
1 Reactions
 o 1.1 Preparation

o 1.2 Coordination chemistry

o 1.3 Concentration measurement

2 Production

3 Environmental effects

4 Technical applications

o 4.1 Miscellaneous applications

5 Biological functions

o 5.1 Mechanism of action

6 Medical use

o 6.1 Neonatal use

o 6.2 Pediatric and adult use

o 6.3 Dosage and strength

o 6.4 Contraindications

o 6.5 Pulmonary embolism

o 6.6 Pharmacology

o 6.7 Associated problems

o 6.8 Mechanism of action

6.8.1 Pharmacokinetics

7 References

8 Further reading

9 External links

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 N2O2 is formed when nitric oxide is cooled.

Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or

nitrosohydroxylamine and methyl acetate:[7]

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.[8]

Preparation

In commercial settings, NO is produced by the oxidation of ammonia at 750-900 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
BirkelandEyde 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 article: Metal nitrosyl

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.[9]

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.[10] 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

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:[11] 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 + hv

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).[12][13]

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).[14]

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.[15] 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
Main article: 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 biological messenger, playing a role in
a variety of biological processes.[16] It is a known bioproduct in almost all types of organisms,
ranging from bacteria to plants, fungi, and animal cells.[17]

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.[18]

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.[19] Nitrate-rich vegetables, in particular leafy greens, such as
spinach and arugula, and beetroot, have been shown to increase cardioprotective levels of
nitric oxide with a corresponding reduction in blood pressure in pre-hypertensive persons.[20]
[21]
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.[22] 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.
[23]

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,[24]
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.[25]
A high salt intake was demonstrated to attenuate NO production in patients with essential
hypertension, although bioavailability remains unregulated.[26]

Nitric oxide is also generated by phagocytes (monocytes, macrophages, and neutrophils) as

part of the human immune response.[27] Phagocytes are armed with inducible nitric oxide
synthase (iNOS), which is activated by interferon-gamma (IFN-) as a single signal or by
tumor necrosis factor (TNF) along with a second signal.[28][29][30] On the other hand,
transforming growth factor-beta (TGF-) 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.[31] Nitric oxide is secreted as free radicals in an immune
response and is toxic to bacteria and intracellular parasites, including Leishmania[32] and
malaria;[33][34][35] the mechanism for this includes DNA damage[36][37][38] and degradation of iron
sulfur centers into iron ions and iron-nitrosyl compounds.[39]

In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.
[40]
Because nitric oxide might serve as an inflammometer (meter of inflammation) 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.[41]

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,[42][43][44] (although the existence of animal NOS homologs in plants is
debated),[45] (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.
[46]

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.[47] 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.[48]

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.[49] NO
has been demonstrated to activate NF-B in peripheral blood mononuclear cells, an important
transcription factor in iNOS gene expression in response to inflammation.[50]

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.[51]

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[52][53] 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.[54]

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.[55]

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 NO. Elevated NO 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.[56]

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 arteries, nitric oxide drugs lower arterial pressure and left ventricular filling pressure.[57]

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,[58] 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.[57]

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.[59]

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.[60]

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
1.

"Nitric Oxide (CHEBI:16480)". Chemical Entities of Biological Interest (ChEBI). UK:

European Bioinformatics Institute.
"Nitric oxide". Immediately Dangerous to Life and Health. National Institute for
Occupational Safety and Health (NIOSH).
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): 41741. PMID 10390607.
Culotta, Elizabeth and Koshland, Daniel E. Jr (1992). "NO news is good news".
Science 258 (5090): 18621864. doi:10.1126/science.1361684. PMID 1361684.
Traube, Wilhelm (1898). "Ueber Synthesen stickstoffhaltiger Verbindungen mit Hlfe
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): 113942. 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. 9698. 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: 2742. 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): 123570. doi:10.1021/cr010152s. PMID 11942795.
Kojima H, Nakatsubo N, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, Hirata Y,
Nagano T; Nakatsubo; Kikuchi; Kawahara; Kirino; Nagoshi; Hirata; Nagano (1998).
"Detection and imaging of nitric oxide with novel fluorescent indicators:
diaminofluoresceins". Anal. Chem. 70 (13): 24462453. doi:10.1021/ac9801723.
PMID 9666719.
"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): 1091102. 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): 78490.
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): 207216. 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): 4668. 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 (13): 159. 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): 68998. 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):
2331. 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 (12): 8794. 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): 42907. 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): 3538.
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): 39716. 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): 33915. 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): 10013.
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): 399406. 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): 8794. 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.; Barroso, JB; Carreras, A; Quirs, M; Len, AM; Romero-Puertas, MC;
Esteban, FJ; Valderrama, R; Palma, JM; Sandalio, LM; Gmez, M; Del Ro, LA (2004).
"Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea
plants". Plant Physiology 136 (1): 272233. doi:10.1104/pp.104.042812. PMC 523336.
PMID 15347796.
Corpas, F. J.; Barroso, Juan B.; Carreras, Alfonso; Valderrama, Raquel; Palma, Jos
M.; Len, Ana M.; Sandalio, Luisa M.; Del Ro, Luis A (2006). "Constitutive arginine-
dependent nitric oxide synthase activity in different organs of pea seedlings during plant
development". Planta 224 (2): 24654. doi:10.1007/s00425-005-0205-9. PMID 16397797.
Valderrama, R.; Corpas, Francisco J.; Carreras, Alfonso; Fernndez-Ocaa, Ana;
Chaki, Mounira; Luque, Francisco; Gmez-Rodrguez, Mara V.; Colmenero-Varea, Pilar;
Del Ro, Luis A.; Barroso, Juan B. (2007). "Nitrosative stress in plants". FEBS Lett 581 (3):
45361. 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 proteinone function". New Phytologist 162 (2): 2467.
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): 52733. 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-B activation in rat hepatocytes". J. Hepatol. 30 (6): 11381145. 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; Barrington (2006). Finer, Neil, ed. "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.
Chotigeat U, Khorana M, Kanjanapattanakul W; Khorana; Kanjanapattanakul
(2007). "Inhaled nitric oxide in newborns with severe hypoxic respiratory failure". J Med
Assoc Thai 90 (2): 26671. PMID 17375630.
Hayward, CS; Kelly, RP; MacDonald, PS (1999). "Inhaled nitric oxide in cardiology
practice". Cardiovascular research 43 (3): 62838. 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): 26832695.
doi:10.1056/NEJMra051884. PMID 16371634.
 Summerfield DT, Desai H, Levitov A, Grooms D, Marik PE; Desai; Levitov; Grooms;
Marik (2011). "Inhaled Nitric Oxide as Salvage Therapy in Massive Pulmonaryembolism: A
Case Series". Respir Care 57 (3): 4448. doi:10.4187/respcare.01373. PMID 22005573.
Abrams, J (1996). "Beneficial actions of nitrates in cardiovascular disease". The
American Journal of Cardiology 77 (13): 31C7C. 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
(23): 445449. 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): 35464. doi:10.1056/NEJMoa060442. PMID 16870914.
60. 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): 34353. doi:10.1056/NEJMoa061088. PMID 16870913.

Further reading
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.

External links
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 health and diabetes. PDF

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

Sex, Nitric Oxide, and the Endothelium

Nitric oxide is made by the blood vessels lining, or endothelium. The endothelium is
exquisitely sensitive to the physical and chemical conditions inside our blood vessels. When
the endothelium senses heart-healthy conditions, such as physical activity and low
cholesterol, it releases more nitric oxide. And thats a very good thing. Nitric oxide expands
the blood vessels, increasing blood flow and decreasing plaque growth and blood clotting.

Sex, Nitric Oxide, and an Unhealthy Lifestyle

Conversely, when the endothelium senses high cholesterol, high blood pressure, smoking, or
emotional distress, it releases less nitric oxide, and atherosclerosis (heart disease) accelerates.

Penile erection depends on the release of nitric oxide. Viagra and other drugs like it that
reduce erectile dysfunction work on the next step of the nitric oxide pathway

Attention, Gentlemen!

Penile erection depends on the release of nitric oxide. Viagra and other drugs like it that
reduce erectile dysfunction work on the next step of the nitric oxide pathway. Are impotence
and atherosclerosis closely related? Absolutely. Any lifestyle no-no that decreases nitric
oxide, such as smoking, high blood pressure, and high cholesterol levels, causes both
problems.

Nitroglycerin, which my grandfather took to relieve his chest pain, works by being converted
into nitric oxide. In a sense, nitric oxide is the bodys own nitroglycerin. If you had first
discovered how nitroglycerin and nitric oxide work, as three Americans (Robert Furchgott,
Lewis Ignarro, and Ferid Murad) did, in 1998 you would have won the Nobel Prize for
Medicine. Nitric oxide is that important.

Inflammation: The Long, Slow Burn, and How It Harms Your Body

High blood pressure, high cholesterol, smoking, and obesity cause chronic arterial injury not
only because they decrease nitric oxide release but also because they increase inflammation.

In many situations, inflammation is helpful, if not life-saving: when we are injured, for
instance, or when we have a virus or other infection. The body naturally responds by rushing
white blood cells to the area to begin damage control. Scar tissue is accelerated, which heals
cuts and scrapes. Without inflammation, we could neither survive the simplest sinus infection
nor close the smallest paper cut. In our evolutionary history, a vigorous inflammation
response gave us a survival advantage, because infections and injury were more of a threat.

Foods That Promote Sexual Health

Discover the best foods and lifestyle behaviors for improving sexual health. Natural
Aphrodisiacs - Foods That Promote Sexual Health

Today, with antibiotics readily abundant and fewer wild tigers on the loose, unchecked
inflammation is left to cause many degenerative diseases including atherosclerosis,
Alzheimers, and arthritis.

The only difference between inflammation of the regular sort and the kind that triggers
atherosclerosis is that high cholesterol, high blood pressure, smoking, and obesity are
initiating the inflammation, not infection or trauma. Unlike a brief infection or trauma, these
risk factors are longstanding and therefore lead to chronic inflammation and plaque. Active
plaques begin to resemble small abscesses on the inside of arteries. These active plaques are
thought to be sites of future heart attacks.

Your Arteries Know How You Live!

Consider just a few factors about the link between the lifestyle changes we
recommend and your heart health:
We strongly recommend canola oil over the current popular favorite, olive
oil, for dressing your salads and cooking. Why? Because olive oil actually
lowers your bodys release of nitric oxide and canola oil doesnt. Moreover,
canola oil reduces inflammation much more than olive oil. Yes, really!
Exercise not only gives your heart a workout and burns off yesterdays
pasta; it also pumps your nitric oxide and reduces inflammation.

Watching a scary movie reduces nitric oxide in your arteries, but funny
movies increase it. Like Santa Claus, your arteries know whether youve
been naughty or nice.

More Facts About Sex and Your Health

The Power of Touch

Being touched by others is an essential human need. Babies who are not held do not develop
and grow as they should. In a sense, we do not change as we become adults. Touch relaxes
and bonds people in a way that no conversation can. From hand holding to cuddling and
caressing, touch creates an intense sense of well-being in most people.
Couples Retreat
Rediscover romance during your next stay at Pritikin. Couples Retreat Package

Testosterone and Sex

Learn about the risk and benefits of testosterone therapy. Testosterone and Sex

The ultimate touchsexual activityis more than a means of reproduction. Sexual activity
releases stress and can mend even the bitterest argument with a partner or spouse. Touch and
sexual relations stimulate the brain to release the hormone oxytocin, which is one of the
hormones that bind people together (it is also associated with nursing). Oxytocin speeds
wound healing and may decrease the risk of some cancers. Endorphins are also released
during sex, as with exercise.

Sexual Activity and Calorie Burning

Sexual activity burns 100 to 200 calories, or the equivalent of walking one to two miles.
Now, I know what you are thinking: Do I have to walk if I have an active sex life? The
answer is yes. We want you to enjoy both long walks and committed and responsible sexual
activities!

Sex and Your Heart

Does sexual activity reduce heart disease? Studies say yes. In one 10-year study, men who
had sex two or more times per week experienced half as many heart attacks as did those who
had sex less than once per month. In another study, college students who engaged in sexual
activity once or twice per week had higher immunity to infection than those who abstained.

Excerpted from the book The Pritikin Edge: 10 Essential Ingredients for a Long and
Delicious Life by Robert A. Vogel, M.D., and The Pritikin Organization, LLC (Simon &
Schuster). Reprinted by permission of Simon & Schuster, Inc.