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nitric oxide

nitric oxide Two strands of research in the late 1970s led to a revolution in biology. Robert Furchgott was unravelling a paradox concerning the well-known neurotransmitter acetylcholine: when injected intravenously it lowers blood pressure, showing that the body's blood vessels are relaxing, but when applied directly to blood vessels in isolation, outside the body, acetylcholine normally makes them contract. Furchgott showed that the response of blood vessels depended critically on the innermost layer of cells lining the vessel — the endothelium. When the endothelium was present, acetylcholine relaxed blood vessels, but when it was removed they contracted. Acetylcholine was shown to cause the release of a diffusible factor from endothelium, and it was this endothelium-derived relaxing factor (EDRF) — its nature then unknown — which relaxed the blood vessels.

Meanwhile, Ferid Murad was investigating how blood vessels are relaxed by the nitrovasodilators (e.g. glyceryl trinitrate, amyl nitrite) used in the treatment of angina. He found that these compounds increase the levels of cyclic GMP (known to promote relaxation) inside the smooth muscle cells of the vessels, probably by generating the substance nitric oxide (more correctly called nitrogen monoxide; NO).

It was soon shown that EDRF also increases the levels of cyclic GMP in smooth muscle, and the two lines of research converged when it was found that various agents, including haemoglobin and the dye methylene blue, inhibit the action both of EDRF and of the nitrovasodilators. By 1987, Furchgott and Louis Ignarro were suggesting that EDRF and NO were one and the same. This was confirmed by Salvador Moncada, who showed that NO is synthesized from the dietary amino acid L-arginine.

It then became evident that the endothelium of blood vessels was not the only site where NO is made. The enzyme nitric oxide synthase (NOS), which uses L-arginine, oxygen, and cofactors to make NO, exists in three forms: neuronal NOS (nNOS), from nerve cells; inducible NOS (iNOS), in inflammatory and other cells when the body's defence mechanisms are activated; and endothelial NOS (eNOS). nNOS and eNOS are ‘constitutive’ enzymes — that is, they are always present in their cells — and they are activated by increases in the intracellular concentration of calcium ions. iNOS is produced in many cells in response to bacterial infection and other circumstances (such as rheumatoid arthritis) when the immune system is activated; it is not regulated by calcium.

Nitric oxide is a tiny molecule. It is a gas, but dissolves in the fluids in and around cells. It is a free radical (sometimes denoted •NO to show that it has an unpaired electron, which makes it react very readily with other molecules). In particular, NO reacts with the radical anion, superoxide (•O2-), to form peroxynitrite (ONOO-), which can damage cellular DNA and hence cause cell death. Thus, excess NO can cause damage to cells. In some situations this is valuable: for instance, cells of the immune system use NO to kill invading bacteria. However, it can also be dangerous. After a stroke, for example, the nerve cells that have been deprived of oxygen fail to control their intracellular calcium; this rises and triggers a massive synthesis of NO by nNOS activation, leading to peroxynitrite production and the death of surrounding neurons. Peroxynitrite also oxidizes low density lipoproteins (LDL), which carry cholesterol in the blood, and oxidized LDL promotes atherosclerosis of blood vessels.

In septicaemia (blood poisoning), bacteria circulate in large numbers in the blood, and, in response, much NO is produced by many types of cells, including the muscle cells of the blood vessels this causes the blood vessels to relax. This leads to a severe fall in blood pressure, septic shock, which is difficult to reverse with agents such as adrenaline and dopamine, which normally increase blood pressure by constricting blood vessels. Septicaemia causes many deaths each year, and inhibition of NO synthesis appeared to be a promising treatment. But early attempts using inhibitors of NOS were largely unsuccessful. However, these were not selective for the relevant type (iNOS) and simultaneous inhibition of eNOS was deleterious to organ function. The increase in iNOS activity in inflammation can be inhibited by glucocorticoids (e.g. prednisolone, corticosterone), which explains part of their anti-inflammatory action, but they have no effect on the level of enzyme once it has been made. Thus the search is on for selective iNOS inhibitors which will leave nNOS and eNOS uninhibited.

NO has a good side and a bad side. While excess NO in septicaemia, inflammation, and stroke causes severe damage, localized production of small quantities of NO is essential for normal body function. Endothelial NOS maintains blood vessel function, and inhibition of this enzyme increases blood pressure. Indeed, hypertension is associated with decreased effectiveness of endothelial NO mechanisms. In blood vessels NO also regulates multiplication of muscle cells. Coronary artery bypass surgery sometimes fails because of narrowing of the newly replaced vessels; this is caused by thickening of their walls through muscle cell proliferation — thought to be due to decreased local production of NO as a result of endothelial damage during the surgery.

NO acts as a neurotransmitter in nerves involved in controlling a number of ‘vegetative’ functions, including operation of the sphincters in the gut and erection of the penis. Viagra (Sildenafil) works by prolonging the actions of NO released from penile nerves. In the brain, NO could even be involved in the formation of memory. ‘Long-term potentiation’ — the increase in strength of synapses in the hippocampus, as a result of strong stimulation which is thought to underlie certain forms of memory — is blocked by drugs that inhibit NO synthesis.

This small inorganic molecule, which was probably best known to the general public as a pollutant in car exhausts, became the biological molecule of the 1990s. Its importance was recognized by the award of a Nobel Prize to Furchgott, Ignarro, and Murad in 1998 ‘for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system’.

C. Robin Hiley


See also blood vessels.

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nitric oxide

nitric oxide or nitrogen monoxide, a colorless gas formed by the combustion of nitrogen and oxygen as given by the reaction: energy + N2 + O2 → 2NO; m.p. -163.6°C; b.p. -151.8°C. Nitric oxide readily combines with oxygen or air to form nitrogen dioxide (NO2), which can again be separated by ultraviolet light to produce nitric oxide and highly reactive oxygen atoms. These oxygen atoms combine with hydrocarbons producing noxious compounds that irritate the membranes of living organisms and destroy vegetation. Large amounts of nitric oxide are created by internal-combustion engines and manufacturing processes. Its quantity is greatly reduced by passing the oxide gas through a catalyst, thereby converting it back to its constituent nitrogen and oxygen gases.

In the environment, nitric oxide is a precursor of smog and acid rain. Nitric oxide in minute amounts serves as a source of energy in certain bacteria. In the body, it serves as a chemical messenger with a wide range of functions. It acts as a neurotransmitter and is necessary for penile erection. It affects blood pressure and is produced by macrophages in the immune system to help defend against infection and cancer. Despite its usefulness, nitric oxide can have a toxic effect on body cells and has been implicated in Huntington's disease and Alzheimer's disease.

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nitric oxide

/add to existingnitric oxide (nitrogen monoxide) A gaseous mediator in mammals and other vertebrates, especially in the cardiovascular and nervous systems. It is produced in tissues from molecular oxygen and the amino acid arginine by the enzyme nitric oxide synthase and diffuses to neighbouring cells, where it stimulates formation of the intracellular messenger cyclic GMP. The effects of nitric oxide include relaxation of smooth muscle and dilation of blood vessels. It also inhibits platelet aggregation and adhesion, may act as a neurotransmitter in some tissues, and may influence neuronal development. Certain cells of the immune system also produce nitric oxide, which is converted to the cytotoxic peroxynitrite anion (O–O–N=O). This has nonspecific activity against tumour cells and pathogens, including protozoan and metazoan parasites.

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nitric oxide

nitric oxide n. an important gaseous mediator that is involved in the manifestations of sepsis and septic shock. Formula: NO.

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Nitric Oxide

Nitric Oxide

OVERVIEW

Nitric oxide (NYE-trik OK-side) is a sweet-smelling, colorless gas that can be liquefied to make a bluish liquid and frozen to produce a bluish-white snow-like solid. It is one of five oxides of nitrogen, the others being nitrous oxide (N2O), nitric oxide (NO), dinitrogen trioxide N2O3), and nitrogen dioxide (NO2). Nitric oxide was first discovered in 1620 by Flemish physician and alchemist Jan Baptista van Helmont (1580–1635 or 1644).

Nitric oxide is used in the production of nitric acid, ammonia, and other nitrogen-containing compounds. It is also formed as a byproduct of the combustion of coal and petroleum products. As such, it is a major contributor to air pollution.

KEY FACTS

OTHER NAMES:

Nitrogen monoxide

FORMULA:

NO

ELEMENTS:

Nitrogen, oxygen

COMPOUND TYPE:

Nonmetallic oxide (inorganic)

STATE:

Gas

MOLECULAR WEIGHT:

36.01 g/mol

MELTING POINT:

−163.6°C (−262.5°F)

BOILING POINT:

−151.74°C (−241.13°F)

SOLUBILITY:

Slightly soluble in water

HOW IT IS MADE

Nitrogen and oxygen are the two most abundant gases in the atmosphere. Since both elements are relatively inactive, they do not combine with each other under normal circumstances. However, the energy provided by lightning strikes causes the reaction of the two elements, producing nitric oxide.

N2 + O2 → 2NO

Another source of the energy needed for this reaction is the combustion of coal and oil products used for human activities. For example, the combustion of gasoline in an internal combustion engine produces temperatures in excess of 2,000°C (3600°F). These temperatures are sufficient to bring about the reaction between nitrogen and oxygen in a vehicle engine, resulting in the formation of nitric oxide as one product of gasoline combustion. That nitric oxide then passes into the atmosphere and becomes a major component of air pollution.

COMMON USES AND POTENTIAL HAZARDS

The most important industrial use of nitric oxide is in the preparation of other nitrogen-containing compounds, especially nitrogen dioxide (NO2), nitric acid (HNO3), and nitrosyl chloride (NOCl). It also finds some application in the bleaching of rayon (a synthetic, or artificially created, fabric) and as a polymerization inhibitor with certain compounds such as propylene and methyl ether. Such compounds have a tendency to react with each other to form large, complex molecules known as polymers.

Nitric oxide is considered an environmental pollutant. It oxidizes readily to form nitrogen dioxide, which, in turn, reacts with moisture in the air to form nitric acid, a component of acid rain. Acid rain is thought to be responsible for a number of environmental problems, including damage to buildings, destruction of trees, and the death of aquatic life. The nitrogen dioxide produced from nitric oxide is also a primary component of photochemical smog, a hazardous haze created by a mixture of pollutants in the presence of sunlight.

Even though it is toxic in the environment, nitric oxide plays several important roles in the human body. Nitric oxide is involved in the process by which messages are transmitted from one nerve cell to the next. It also regulates blood flow by triggering the smooth muscles surrounding blood vessels to relax. This action increases blood flow and lowers blood pressure. Nitric oxide also prevents the formation of blood clots, which can break off and travel to the heart or brain, increasing the risk of heart attack or stroke.

During sexual arousal, nitric oxide increases blood flow to the penis, leading to an erection in a man. The drug Viagra stimulates erections by enhancing the flow of nitric oxide in the penis.

Interesting Facts

  • In 1992, Science magazine named nitric oxide "Molecule of the Year" after scientists discovered that it had several important functions in the body.
  • Ferid Murad (1936–), Robert Furchgott (1916–), and Louis Ignarro (1941–) shared the 1998 Nobel Prize in Physiology or Medicine for their discovery of the role played by nitric oxide in the body's nervous system.

Finally, nitric oxide plays a role in memory and learning. A deficiency of the compound appears to be related to the development of learning problems. On the other hand, an excess of nitric oxide has been implicated in the development of certain diseases, such as Huntington's chorea, an inherited disorder characterized by unusual body movements and memory loss, and Alzheimer's disease, a progressive disorder that results in memory loss.

When used to treat a medical condition, nitric oxide is usually administered in the form of a solid or liquid medicine that decomposes in the body, releasing the compound. For example, the drug nitroglycerin is used to treat heart problems. When it enters the bloodstream, nitroglycerin begins to break down, releasing nitric oxide. The nitric oxide causes smooth muscle cells in the heart to relax, relieving the symptoms of angina, chest pain caused by an inadequate flow of blood to the heart. Other types of drugs produce nitric oxide to inhibit the buildup of fatty deposits in blood vessels, which can lead to heart attack and stroke. Patients with pulmonary hypertension, a condition in which the vessels that supply blood to the lungs are constricted, preventing normal oxygen flow, are sometimes given an inhaler with a mixture of nitric oxide and air to open blood vessels to the lungs.

In spite of its many benefits, nitric oxide may also be a health hazard. If inhaled in excessive amounts, it may replace oxygen in the lungs, leading to asphyxia, suffocation resulting from an insufficient supply of oxygen. Research suggests that exposure to low concentrations of the gas over long periods of time may result in lung disease, emphysema, and chronic bronchitis.

Words to Know

POLYMERIZATION
The process of creating a polymer, a compound consisting of very large molecules made of one or two small repeated units called monomers.

FOR FURTHER INFORMATION

Butler, A. R., and R. Nicholson. Life, Death and Nitric Oxide. London: Royal Society of Chemistry, 2003.

"Gas Data." Air Liquide. http://www.airliquide.com/en/business/products/gases/gasdata/index.asp?GasID=44 (accessed on October 20, 2005).

"Nitric Oxide." Reproductive and Cardiovascular Disease Research Group. http://www.sgul.ac.uk/depts/immunology/∼dash/no/ (accessed on October 20, 2005).

"Nitrogen Oxides." International Programme on Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc188.htm#SubSectionNumber:2.1.1 (accessed on October 20, 2005).

Stanley, Peter. "Nitric Oxide." Biological Sciences Review (April 2002): 18-20.

See AlsoNitric Acid; Nitrogen Dioxide

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