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Nitric Oxide (NO), What is Nitric Oxide?
Nitric oxide is a gas. It is highly reactive; that is, it participates in many chemical reactions. (It is one of the nitrogen oxides ("NOx") in automobile exhaust and plays a major role in the formation of photochemical smog.)
But NO also has many physiological functions.
They share these features:
• NO is synthesized within cells by an enzyme NO synthase (NOS).
• The human (and mouse) genome contains 3 different genes encoding NO synthases.
◦ nNOS (or NOS-1): found in neurons (hence the "n").
◦ eNOS (or NOS-3): found in the endothelial (hence the "e") cells that line the lumen of blood vessels.
◦ iNOS (or NOS-2): found in macrophages. (the "i" stands for "inducible"). Whereas the levels of nNOS and eNOS are relatively steady, expression of iNOS genes awaits an appropriate stimulus (e.g., invasion by a pathogen).
• All types of NOS produce NO from arginine with the aid of molecular oxygen and NADPH.
• NO diffuses freely across cell membranes.
• There are so many other molecules with which it can interact, that it is quickly consumed close to where it is synthesized.
• Thus NO acts in a paracrine or even autocrine fashion — affecting only cells near its point of synthesis.
This page examines some of the functions of NO.
Nitric Oxide relaxes the smooth muscle in the walls of the arterioles. At each systole, the endothelial cells that line the blood vessels release a puff of Nitric Oxide. This diffuses into the underlying smooth muscle cells causing them to relax and thus permit the surge of blood to pass through easily. Mice whose genes for the NO synthase found in endothelial cells (eNOS) has been “knocked out” suffer from hypertension.
Nitroglycerine, which is often prescribed to reduce the pain of angina, does so by generating nitric oxide, which relaxes the walls of the coronary arteries and arterioles.
Three of the pioneers in working out the biological roles of Nitric Oxide shared a Nobel Prize in 1998 for their discoveries. The award to one of them, Ferid Murad, honored his discovery that nitroglycerine works by releasing NO. This seems particularly appropriate because Alfred Nobel's fortune came from his invention of making dynamite from nitroglycerine!
Nitric Oxide also inhibits the aggregation of platelets and thus keeps inappropriate clotting from interfering with blood flow.
Release of Nitric Oxide around the glomeruli of the kidneys increases blood flow through them thus increasing the rate of filtration and urine formation.
The erection of the penis during sexual excitation is mediated by Nitric Oxide released from nerve endings close to the blood vessels of the penis. Relaxation of these vessels causes blood to pool in the blood sinuses producing an erection.
Three popular prescription drugs
• sildenafil (Viagra®)
• vardenafil (Levitra®)
• tadalafil (Cialis®)
enhance this effect by the mechanism described below.
Recent evidence suggests that Nitric Oxide's job in reproduction is not finished with producing an erection. At the moment of contact, release of NO by the acrosome of the sperm activates the egg to complete meiosis II and the other steps of fertilization.
Other Actions on Smooth Muscle
The wavelike motions of the gastrointestinal tract are aided by the relaxing effect of Nitric Oxide on the smooth muscle in its walls.
Nitric Oxide also inhibits the contractility of the smooth muscle wall of the uterus. As the moment of birth approaches, the production of NO decreases.
Nitroglycerine has helped some women who were at risk of giving birth prematurely to carry their baby to full term.
Nitric Oxide and Inflammation
The NO produced by eNOS (NOS-3) inhibits inflammation in blood vessels. It does this by blocking the exocytosis of mediators of inflammation from the endothelial cells.
Nitric Oxide may also block exocytosis in other types of cells such as macrophages and cytotoxic T lymphocytes (CTL).
Effects on Secretion
Nitric Oxide affects secretion from several endocrine glands.
For examples, it stimulates
• the release of Gonadotropin-releasing hormone (GnRH) from the hypothalamus;
• the release of pancreatic amylase from the exocrine portion of the pancreas;
• the release of adrenaline from the adrenal medulla.
Nitric Oxide and the Nervous System
Nitric Oxide and the Autonomic Nervous System
Some motor neurons of the parasympathetic branch of the autonomic nervous system release Nitric Oxide as their neurotransmitter. The actions of Nitric Oxide on penile erection and peristalsis are probably mediated by these nerves.
Nitric Oxide and the Medulla Oblongata
Hemoglobin transports NO at the same time it carries oxygen. When it unloads oxygen in the tissues, it also unloads Nitric Oxide.
In severe deoxygenation, NO-sensitive cells in the medulla oblongata respond to this release by increasing the rate and depth of breathing.
Nitric Oxide and the Brain
In laboratory animals (mice and rats), NO is released by neurons in the CAI region of the hippocampus and stimulates the NMDA receptors there that are responsible for long-term potentiation (LTP) — a type of memory (and learning).
The ease with which NO diffuses away from the synapse where it is generated enables it to affect nearby synapses. So what may have begun as a localized action becomes magnified.
Laboratory rats treated with inhibitors of NOS synthesis fail to develop and/or retain learned responses such as the conditioned response.
Mice whose genes for nNOS have been knocked out are healthy but display abnormal behavior, e.g., they kill other males and try to mate with nonreceptive females.
Nitric Oxide and Fertilization
The acrosome at the tip of sperm heads activates its NO synthase when it enters the egg. The resulting release of NO in the egg is essential (at least in sea urchins) for triggering the next steps in the process :
• blocking the entry of additional sperm and
• orienting the pronuclei for fusion.
Nitric Oxide aids in the killing of engulfed pathogens (e.g., bacteria) within the lysosomes of macrophages.
Mice whose genes for the NO synthase found in macrophages (iNOS) have been knocked out are more susceptible to infections by intracellular bacteria like Listeria monocytogenes.
Th1 cells, the ones responsible for an inflammatory response against invaders, secrete Nitric Oxide.
Harmless bacteria, living as commensals at the rear of our throat, convert nitrates in our food into nitrites. When these reach the stomach, the acidic gastric juice (ph~1.4) generates Nitric Oxide from them. This NO kills almost all the bacteria that have been swallowed in our food.
(Since the dawn of recorded human history, nitrites have been used to preserve meat from bacterial spoilage.)
Nitric Oxide and Longevity
Mice whose genes for eNos have been knocked out
• show signs of premature aging;
• have a shortened life span;
• fail to benefit from the life-extending effect of a calorie-restricted (CR) diet.
Mechanisms of Nitric Oxide Action
The signaling functions of NO begin with its binding to protein receptors on or in the cell. The binding sites can be either:
• a metal ion in the protein or
• one of its S atoms (e.g., on cysteine).
In either case, binding triggers an allosteric change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein target for NO seems to be guanylyl cyclase, the enzyme that generates the second messenger cyclic GMP (cGMP).
Three prescription drugs
• sildenafil (Viagra®)
• vardenafil (Levitra®)
• tadalafil (Cialis®)
enhance the effects of Nitric Oxide by inhibiting the enzyme that normally breaks down cGMP.
Fireflies Use Nitric Oxide To Turn On their Flashes
Plants Also Use Nitric Oxide
NO has been implicated in many plant activities.
• It is a weapon against invading pathogens. Infection of the plant triggers the formation of a NOS that, like the animal versions, makes Nitric Oxide from arginine. Release of NO by the infected cell induces a number of defense responses.
• A gradient of Nitric Oxide may also guide the pollen tube to its destination in the ovule. The popular prescription drug sildenafil citrate (Viagra®) enhances the effect of NO on pollination (just as it does on penile erection).
• Nitric Oxide inhibits flowering.
• Nitric Oxide promotes recovery from etiolation.
"The discovery of Nitric Oxide is one of the most important in the history of cardiovascular medicine" ~ President of the American Heart Association
"Nitric Oxide is the body's way of protecting against cardiovascular disease" ~ UCLA Department of Molecular and Medical Pharmacology
"Any risk factor for cardiovascular disease is associated with loss of Nitric Oxide." ~ Mayo Clinic Research
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