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The chemical compound nitric oxide is a gas with chemical formula NO. It is an important signaling molecule in the body of mammals including humans, one of the few gaseous signaling molecules known. It is also a toxic air pollutant produced by automobile engines and power plants.

Nitric oxide (NO) should not be confused with nitrous oxide (N2O), a general anaesthetic, or with nitrogen dioxide (NO2) which is another poisonous air pollutant.

In the body, nitric oxide serves several roles, mainly involving small blood vessels. Nitric oxide is synthesized from L-arginine and oxygen by various nitric oxide synthase (NOS) enzymes. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. This phenomenon is thought to be central to endothelial health. A large percentage of humans are deficient in their manufacture of nitric oxide, placing them at increased risk of cardiovascular disease. This underlies the action of nitroglycerin, amyl nitrate and other nitrate derivatives in the treatment of heart disease: The compounds are converted to nitric oxide (by a process that is not completely understood), which in turn dilates the coronary artery (blood vessels around the heart), thereby increasing its blood supply. A chemical known as asymmetric dimethylarginine can interfere with the production of nitric oxide and is considered a marker of cardiovascular disease.

Macrophages, cells of the immune system, produce nitric oxide in order to kill invading bacteria. Under certain conditions, this can backfire: Fulminant infection (sepsis) causes excess production of nitric oxide by macrophages, leading to vasodilatation (widening of blood vessels), probably one of the main causes of hypotension (low blood pressure) in sepsis.

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Nitric Oxide and its role in Oxidative stress.

Nitric oxide also serves as a neurotransmitter between nerve cells. Unlike most other neurotransmitters that only transmit information from a presynaptic to a postsynaptic neuron, the small nitric oxide molecule can diffuse all over and can thereby act on several nearby neurons, even on those not connected by a synapse. It is conjectured that this process may be involved in memory through the maintenance of long-term potentiation. Nitric oxide is an important non-adrenergic, non-cholinergic (NANC) neurotransmitter in various parts of the gastrointestinal tract. It causes relaxation of the gastrointestinal smooth muscle. In the stomach it increases the capacity of the fundus to store food/fluids.

Production of NO also plays a role in development and maintenance of erection by stimulating PDE5-related intracellular cGMP in the smooth muscle cells surrounding the blood vessels supplying the corpus cavernosum; through relaxation of these muscles, more blood can flow in. This is the biological basis of sildenafil (Viagra)or tadalafil (Cialis), which works to turn off the enzyme that converts cGMP to GMP. The high levels of cGMP that result lead to vasodilation and hence erection. The effects of the recreational drugs known as poppers are also thought to be due to nitric oxide.

The discovery of the biological functions of nitric oxide in the 1980s came as a complete surprise and caused quite a stir. Nitric oxide was named "Molecule of the Year" in 1992 by the journal Science, a Nitric Oxide Society was founded, and a scientific journal devoted entirely to nitric oxide was created. The Nobel Prize in Physiology or Medicine in 1998 was awarded to Ferid Murad, Robert F. Furchgott, and Louis Ignarro for the discovery of the signalling properties of nitric oxide. It is estimated that yearly about 3,000 scientific articles about the biological roles of nitric oxide are published.

NO variation due to ABO blood group

A recent letter to the editor in the journal Lancet had an interesting letter on differences between ABO groups and the responsiveness of respiratory patients to nitric oxide (NO) therapy. Apparently, those types with a B antigen (types B and AB) have less success with this therapy. The authors speculate that this must be the result of a lack of "anti-B antibody" which perhaps assists the NO in working. They speculate that this might result from "some putative, unknown gene associated with the ABO locus on chromosome 9Q34."

Actually, we do know what gene would "putatively" assist in NO function and would be influenced by ABO genetics. It codes for Argininosuccinate synthase, an enzyme unfortunately abbreviated "ASS." ASS recycles arginine from citrulline in the production of NO. The ABO locus is very closely positioned to the ASS locus.

NO is a free radical gas, which can diffuse across membranes rapidly thus acting on neural elements, which are at some distance from the site of production. One of the modes of action of NO is to stimulate soluble guanylate cyclase, leading to an increase in intracellular cyclic GMP in target cells. This can then lead to further effects, depending on the cell.

NO is synthesized from L-arginine by the action of NO synthase (NOS) with the production of L-citrulline. L-Citrulline is then recycled to L-arginine by argininosuccinate synthetase and argininosuccinase.

There is a widespread distribution for NOS within the brain, including in the thalamus and the cerebral cortex, where it is predominantly in neurones, but also in astrocytes.

A diversity of cellular compartments suggests not only that NO may be an active end-product, but that as intermediates may move between compartments. L-arginine and L-citrulline might have a signaling function in their own right. This is speculative, but is supported by the release of arginine upon stimulation of pathways in cerebellar slices and in the thalamus in vivo (Do et al., 1994).

  • McFadzean J, et al Nitric oxide ABO blood group difference in children. Lancet. 1999 Apr 24;353(9162):1414-5. Entrez PubMed

The Nitric Oxide / Arginine System in the Thalamus

The nitric oxide (NO) system has been the subject of much study since the discovery that it plays an important part in neural signalling (Garthwaite, 1993). NO is a free radical gas which can diffuse across membranes rapidly, thus acting on neural elements which are at some distance from the site of production. One of the modes of action of NO is to stimulate soluble guanylate cyclase, leading to an increase in intracellular cyclic GMP in target cells, and this can then lead to further effects, depending on the cell. NO is synthesised from L-arginine by the action of NO synthase (NOS), with the production of L-citrulline. L-Citrulline is then recycled to L-arginine by argininosuccinate synthetase and argininosuccinase. There is a widespread distribution for NOS within the brain, including in the thalamus and the cerebral cortex, predominantly in neurones but also in astrocytes. Some of these neurones are also immunoreactive for citrulline. Studies have also been carried out on the cellular localisation of the NO precursor L-arginine. Immunohistochemical studies indicate that it is located mainly in glial cells in the CNS, but it is also possible that it is located in neuronal elements. A diversity of cellular compartments suggests not only that NO may be an active end-product but that, as intermediates may move between compartments, L-arginine and L-citrulline might have a signalling function in their own right. This is speculative, but is supported by the release of arginine upon stimulation of pathways in cerebellar slices and in the thalamus in vivo (Do etal., 1994).

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