Biological functions of nitric oxide
Encyclopedia
The gas nitric oxide
plays a wide variety of roles in biological organisms.
s (NOSs) synthesize the metastable free radical nitric oxide (NO). There are three isoforms of the NOS enzyme: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) - each with separate functions. The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium-dependent and produce low levels of this gas as a cell signaling molecule. The inducible isoform (NOS-2) is calcium independent and produces large amounts of gas which can be cytotoxic. NOS oxidizes the guanidine group of L-arginine in a process that consumes five electrons and results in the formation of NO with stoichiometric formation of L-citrulline. The process involves the oxidation of NADPH and the reduction of molecular oxygen. The transformation occurs at a catalytic site adjacent to a specific binding site of L-arginine.
and increasing blood flow. NO is also a neurotransmitter and has been associated with neuronal activity and various functions like avoidance learning. NO also partially mediates macrophage cytotoxicity against microbes and tumor cells. Besides mediating normal functions, NO is implicated in pathophysiologic states as diverse as septic shock, hypertension, stroke, and neurodegenerative diseases. Currently, exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate enough for normal biological functions. So, recent developments of novel NO donors, NO releasing devices as well as innovative improvements to current NO donors have been investigated.
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 play a key role in renal control of extracellular fluid homeostasis and is essential for the regulation of blood flow and blood pressure. NO also plays a role in erection
of the penis
.
, 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.
. 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).
. 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.
s, 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.
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 neuron
s, 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 enzymatic breakdown or cellular reuptake. NO is also highly reactive with other free radicals, lipids, and proteins.
NO-cGMP
cascade is involved in learning and 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.
Nitric oxide also acts on cardiac muscle
to decrease contractility and heart rate
. NO contributes to the regulation of cardiac contractility. Emerging evidence suggests that coronary artery disease (CAD) is related to defects in generation or action of NO.
Reduced levels of exhaled NO
have been associated with exposure to traffic related air pollution.
The bacterium Deinococcus radiodurans
can withstand extreme levels of radioactivity and other stresses. In 2009 it was reported that nitric oxide plays an important role in the bacteria's recovery from radiation exposure: the gas is required for division and proliferation after DNA damage has been repaired. A gene was described that increases nitric oxide production after UV radiation, and in the absence of this gene the bacteria were still able to repair DNA damage but wouldn't grow.
.
, "poppers" (isobutyl nitrite or similar) and other nitrite 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. These drugs, however, are predominantly venodilators, dilating peripheral veins and hence reducing venous return and preload to the heart. This reduces the oxygen requirement of the myocardium and subsequently lessens the anginal pain felt with myocardial ischemia.
(N
O
).
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. Salvador Moncada
also identified EDRF as NO molecule, but did not share the Nobel Prize primarily due to the Nobel policy of honoring only three discoverers. It is estimated that yearly about 3,000 scientific articles are published on the biological roles of nitric oxide.
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
plays a wide variety of roles in biological organisms.
Nitric oxide synthesis
Nitric oxide synthaseNitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
s (NOSs) synthesize the metastable free radical nitric oxide (NO). There are three isoforms of the NOS enzyme: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) - each with separate functions. The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium-dependent and produce low levels of this gas as a cell signaling molecule. The inducible isoform (NOS-2) is calcium independent and produces large amounts of gas which can be cytotoxic. NOS oxidizes the guanidine group of L-arginine in a process that consumes five electrons and results in the formation of NO with stoichiometric formation of L-citrulline. The process involves the oxidation of NADPH and the reduction of molecular oxygen. The transformation occurs at a catalytic site adjacent to a specific binding site of L-arginine.
Function
NO is an important regulator and mediator of numerous processes in the nervous, immune and cardiovascular systems. These include vascular smooth muscle relaxation, resulting in arterial vasodilationVasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
and increasing blood flow. NO is also a neurotransmitter and has been associated with neuronal activity and various functions like avoidance learning. NO also partially mediates macrophage cytotoxicity against microbes and tumor cells. Besides mediating normal functions, NO is implicated in pathophysiologic states as diverse as septic shock, hypertension, stroke, and neurodegenerative diseases. Currently, exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate enough for normal biological functions. So, recent developments of novel NO donors, NO releasing devices as well as innovative improvements to current NO donors have been investigated.
Vasodilation
Nitric Oxide (NO) is of critical importance as a mediator of vasodilationVasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
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 play a key role in renal control of extracellular fluid homeostasis and is essential for the regulation of blood flow and blood pressure. NO also plays a role in erection
Erection
Penile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
of the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
.
Induction
Platelet derived factors, shear stressShear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...
, acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, and cytokines stimulate the production of NO by endothelial nitric oxide synthase (eNOS). eNOS synthesizes NO from the terminal guanidine
Guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...
-nitrogen of L-arginine and oxygen and yields citrulline
Citrulline
The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.It has the idealized formula H2NCNH3CHCO2H...
as a byproduct. NO production by eNOS is dependent on calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
-calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
and other cofactors.
Phosphorylation
NO, a highly reactive free radical, diffuses into the smooth muscle cells of the blood vessel and interacts with soluble guanylate cyclaseGuanylate cyclase
-Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:...
. Nitric oxide stimulates the soluble guanylate cyclase to generate the second messenger cyclic GMP (3’,5’ guanosine monophosphate) from guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(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
Sensitization
Sensitization is an example of non-associative learning in which the progressive amplification of a response follows repeated administrations of a stimulus. An everyday example of this mechanism is the repeated tonic stimulation of peripheral nerves that will occur if a person rubs his arm...
, hyperpolarize cell through potassium channels, actin filament and myosin dynamic alterations that result in smooth muscle relaxation. (see smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
article).
Erection
The vasodilatatory effect of NO, in turn, also plays a role in development and maintenance of erectionErection
Penile erection is a physiological phenomenon where the penis becomes enlarged and firm. Penile erection is the result of a complex interaction of psychological, neural, vascular and endocrine factors, and is usually, though not exclusively, associated with sexual arousal...
. Vasodilation of blood vessels supplying the corpus cavernosum
Corpus cavernosum
Corpus cavernosum may refer to:* corpus cavernosum clitoridis* corpus cavernosum penis* "corpus cavernosum urethrae" was used for corpus spongiosum in older texts* corpus cavernosum conchae...
results in more blood flowing in and hence erection. This is the biological basis of sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra), which works to inhibit the enzyme phosphodiesterase PDE5 that lowers the cGMP concentration by converting it back to GMP.
Immune system
MacrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, certain cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, produce nitric oxide in order to kill invading bacteria. In this case, the nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
is inducible NOS.
Under certain conditions, this can backfire: Fulminant infection (sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
) causes excess production of nitric oxide by macrophages, leading to vasodilatation (widening of blood vessels), probably one of the main causes of hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(low blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
) 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 neurotransmitterNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
between nerve cells, part of its general role in redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
. Unlike most other neurotransmitters that only transmit information from a presynaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
to a postsynaptic neuron, the small, uncharged, and fat-soluble nitric oxide molecule can diffuse
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
widely and readily enters cells. Thus, it can act on several nearby neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, 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 enzymatic breakdown or cellular reuptake. NO is also highly reactive with other free radicals, lipids, and proteins.
NO-cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
cascade is involved in learning and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
through the maintenance of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(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.
Other functions
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.Nitric oxide also acts on cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
to decrease contractility and heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
. NO contributes to the regulation of cardiac contractility. Emerging evidence suggests that coronary artery disease (CAD) is related to defects in generation or action of NO.
Reduced levels of exhaled NO
Exhaled nitric oxide
In medicine, exhaled nitric oxide can be measured in a breath test for asthma or other conditions characterized by airway inflammation. Nitric oxide is a gaseous molecule produced by certain cell types in an inflammatory response. The fraction of exhaled NO is a promising biomarker for the...
have been associated with exposure to traffic related air pollution.
The bacterium Deinococcus radiodurans
Deinococcus radiodurans
Deinococcus radiodurans is an extremophilic bacterium, one of the most radioresistant organisms known. It can survive cold, dehydration, vacuum, and acid, and is therefore known as a polyextremophile and has been listed as the world's toughest bacterium in The Guinness Book Of World Records.-Name...
can withstand extreme levels of radioactivity and other stresses. In 2009 it was reported that nitric oxide plays an important role in the bacteria's recovery from radiation exposure: the gas is required for division and proliferation after DNA damage has been repaired. A gene was described that increases nitric oxide production after UV radiation, and in the absence of this gene the bacteria were still able to repair DNA damage but wouldn't grow.
Pathology
People with diabetes usually have lower levels of Nitric Oxide than patients without diabetes. 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 amputationAmputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
.
Pharmaceutical analogs
Nitroglycerin, amyl nitriteAmyl nitrite
Amyl nitrite is the chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrito functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group...
, "poppers" (isobutyl nitrite or similar) and other nitrite derivatives are used in the treatment of heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
: 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. These drugs, however, are predominantly venodilators, dilating peripheral veins and hence reducing venous return and preload to the heart. This reduces the oxygen requirement of the myocardium and subsequently lessens the anginal pain felt with myocardial ischemia.
Effects on plants
Generally nitric oxide has an adverse impact on plant metabolism. Nitric oxide can enter the stomates of most vascular species, and can have effects ranging from leaf blemishing to stunting of growth to necrosis.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 oxideNitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
).
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
Science (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
, a Nitric Oxide Society was founded, and a scientific journal devoted entirely to nitric oxide was established. The Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1998 was awarded to Ferid Murad
Ferid Murad
Ferid Murad is an Albanian-American physician and pharmacologist, and a co-winner of the 1998 Nobel Prize in Physiology or Medicine. He is also an honorary member of the Academy of Sciences and Arts of Kosovo.- Life :...
, Robert F. Furchgott
Robert F. Furchgott
Robert Francis Furchgott was a Nobel Prize-winning American biochemist.Furchgott was born in Charleston, SC, to Arthur Furchgott and Pena Sorentrue Furchgott...
, and Louis Ignarro
Louis Ignarro
Louis J. Ignarro is an American pharmacologist. He was corecipient of the 1998 Nobel Prize in Physiology or Medicine with Robert F...
for the discovery of the signalling properties of nitric oxide. Salvador Moncada
Salvador Moncada
Sir Salvador Enrique Moncada, FRS, FRCP, FRCS is a Honduran-British physician and pharmacologist. He is the husband of Princess Marie-Esméralda of Belgium, who is a member of the Belgian Royal Family.-Background:...
also identified EDRF as NO molecule, but did not share the Nobel Prize primarily due to the Nobel policy of honoring only three discoverers. It is estimated that yearly about 3,000 scientific articles are published on the biological roles of nitric oxide.