Endothelium-derived relaxing factor

From Wikipedia, the free encyclopedia

To meet Wikipedia's quality standards, this article or section may require cleanup.
Please discuss this issue on the talk page, or replace this tag with a more specific message. Editing help is available.
This article has been tagged since August 2006.

For the chemical compound nitric oxide (nitrogen monooxide, NO), see nitric oxide.

Endothelium-derived relaxing factor (EDRF) was the tentative name of what was later discovered to be nitric oxide (N O). It is released by the vascular endothelium in response to a variety of chemical and physical stimuli. It causes the smooth muscle in the vessel wall to relax by activating the soluble guanylate cylclases (sGC), increasing the cyclic guanosin monophosphate (cGMP)concentration and activating the cGMP-dependent Protein kinase G (cGKI), resulting in vasodilation. It is also the active substance absorbed into the blood stream by people using nitroglycerin tablets or spray under their tongue, by patch, pill or intravenous infusion of nitroglycerin.

Endothelium also produces prostacyclin (PGI2), Endothelium-derived Hyperpolarizing factor, and Heme oxygenase which produces carbon monoxide. These are distinct from EDRF by a number of physicochemical and pharmacological criteria.

EDRF was discovered and characterized by Robert F. Furchgott, a winner of the Nobel Prize in Medicine in 1998 with his co-researchers Louis J. Ignarro and Ferid Murad.

[edit] Function

The endothelium (inner lining) of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow; bodybuilders use this to achieve a more "ripped", vascular look. 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. Nitric oxide also plays a role in erection of the penis. The effects of the recreational drugs known as poppers are also thought to be due to nitric oxide.

Nitric Oxide (NO) is of critical importance as a mediator of vasorelaxation in blood vessels. Platelet derived factors, shear stress, angiotensin II, acetylcholine, and cytokines stimulate the production of NO by endothelial nitric oxide synthase (eNOS). eNOS synthesizes NO from the terminal guanidine-nitrogen of L-arginine and oxygen and yields citrulline as a byproduct. NO production by eNOS is dependent on calcium-calmodulin and other cofactors. NO, a highly reactive free radical, then diffuses into the smooth muscle cells of the blood vessel and interacts with soluble guanylate cyclase. Nitric oxide stimulates the soluble guanylate cyclase to generate the second messenger cyclic GMP (3’,5’ guanosine monophosphate)from guanosine triphosphate (GTP). The soluble cGMP activates cyclic nucleotide dependent protein kinase G (PKG or cGKI). PKG is a kinase that phosphorylates a number of proteins that regulate calcium concentrations, calcium sensitization, actin filament and myosin dynamic alterations that result in smooth muscle relaxation.(see smooth muscle article) Macrophages, certain 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.

Nitric oxide also serves as a neurotransmitter between nerve cells, part of its general role in Redox signaling. 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 the production of 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®), which works to inhibit the enzyme phosphodiesterase PDE5 that lowers the cGMP concentration by converting it to GMP. The high levels of cGMP and subsequent activation of protein kinase G leads to vasodilation and hence erection. Dietary nitrate is also an important source of nitric oxide in mammals. Green, leafy vegetables and some root vegetables (such as beetroot) have high concentrations of nitrate. When eaten and absorbed into the bloodstream nitrate is concentrated in saliva (about 10 fold) and is reduced to nitrite on the surface of the tongue by a biofilm of commensal facultative anaerobic bacteria. This nitrite is swallowed and reacts with acid and reducing substances in the stomach (such as ascorbate) to produce high concentrations of nitric oxide. The purpose of this mechanism to create NO is thought to be both sterilisation of swallowed food, to prevent food poisoning and to maintain gastric mucosal blood flow. A similar mechanism is thought to protect the skin from fungal infections, where nitrate in sweat is reduced to nitrite by skin commensal organisms and then to NO on the slightly acidic skin surface.

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 established. 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 widely recognised as a travesty of justice that Salvador Moncada who actually identified EDRF as NO molecule did not share the Nobel Prize. It is estimated that yearly about 3,000 scientific articles are published on the biological roles of nitric oxide.