Endothelium-derived relaxing factor

This article is about the biological functions of nitric oxide. For the chemical compound in a general sense, see Nitric oxide.

Endothelium-derived relaxing factor (EDRF) is nitric oxide produced and released by the endothelium that results in smooth muscle relaxation. It is released 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 cyclases (sGC), increasing the cyclic guanosine monophosphate (cGMP) concentration and activating the protein kinase G, 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 actually produces a number of endothelial derived relaxing factors such as prostacyclin (PGI2), and Endothelium-derived hyperpolarizing factor. Heme proteins from blood can also stimulate the inducible isoform of Heme oxygenase (HO-1 also known as heat shock protein 32) which produces Carbon monoxide that can relax smooth muscle. These are distinct compounds by a number of physicochemical and pharmacological criteria. The endothelium also produces a number of vasoconstricting agents and there is a balance of constricting and relaxing signals.

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.

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Synthesis

Nitric oxide is synthesized by nitric oxide synthase (NOS). There are three isoforms of the NOS enzyme: endothelial (eNOS), neuronal (nNOS), and inducable (iNOS) - each with separate functions. The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium dependent and produce low levels of gas as a cell signalling molecule. The inducible isoform (NOS-2) is calcium independent and produces large amounts of gas which can be cytotoxic.

Function

The endothelium (inner lining) of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation of the artery and increasing blood flow.

NO is used in the immune system by macrophages to kill pathogens.

It is a neurotransmitter in the nervous system and has been associated with neuronal activity and various functions like avoidance learning.

Vasodilation

Nitric Oxide (NO) is of critical importance as a mediator of vasodilation in blood vessels. It is induced by several factors, and once synthesized by eNOS it results in phosphorylation of several proteins that cause smooth muscle relaxation. The vasodilatory actions of nitric oxide plays a key role in renal control of extracellular fluid homeostasis. This also plays a role in erection of the penis.

Induction

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.

Phosphorylation

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, hyperpolarize cell through potassium channels, actin filament and myosin dynamic alterations that result in smooth muscle relaxation. (see smooth muscle article). [1].

Erection

The vasodilatatory effect of NO, in turn, also plays a role in development and maintenance of erection. Vasodilation of blood vessels supplying the corpus cavernosum results in more blood flowing in and hence erection. This is the biological basis of sildenafil (Viagra®), which works to inhibit the enzyme phosphodiesterase PDE5 that lowers the cGMP concentration by converting it back to GMP.

Immune system

Macrophages, certain cells of the immune system, produce nitric oxide in order to kill invading bacteria. In this case, the nitric oxide synthase is inducible NOS.

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. The inducible isoform of nitric oxide synthase is expressed and produces cytotoxic levels of nitric oxide.

Neurotransmission

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, uncharged, and fat-soluble nitric oxide molecule can diffuse widely and readily enters cells. Thus, it can act on several nearby neurons, even on those not connected by a synapse. At the same time, the short half-life of NO means that such action will be restricted to a limited area, without the necessity for enymatic breakdown or cellular reuptake. NO is also highly reactive with other free radicals, lipids, and proteins.

It is conjectured that this process may be involved in memory through the maintenance of long-term potentiation (LTP). 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.

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 sterilization 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.

Other functions

Nitric oxide also acts on cardiac muscle to decrease contractility and heart rate.

Pathology

People with diabetes usually have lower levels of Nitric Oxide than patients without diabetes^[1]. Diminished supply of Nitric Oxide can lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can lead to decreased blood flow to the extremities, causing the diabetic patient to be more likely to develop Neuropathy, non-healing ulcers, and be at a greater risk for lower limb amputation.

Pharmaceutical analogs

Nitroglycerin, amyl nitrate, "poppers" (isobutyl nitrite or similar) and other nitrate derivatives are used 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.

Discovery

Endothelium-derived relaxing factor was originally the name given to several proposed factors causing vasodilation. The major endothelial derived relaxing factor was later discovered to be nitric oxide (NO).

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. Another notable contributor to NO research is Salvador Moncada who also identified EDRF as NO molecule but 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.