Nitric Oxide (NO)

Nitric oxide is a gas. It is highly reactive; that is, it participates in many chemical reactions. (It is one of the nitrogen oxides ("NO_x") in automobile exhaust and plays a major role in the formation of photochemical smog [Link].)

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.

Blood Flow

NO 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 NO. 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.

NO also inhibits the aggregation of platelets and thus keeps inappropriate clotting from interfering with blood flow.

Kidney Function

Release of NO around the glomeruli of the kidneys increases blood flow through them thus increasing the rate of filtration and urine formation.

Penile Erection

The erection of the penis during sexual excitation is mediated by NO 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.

• sildenafil (Viagra®)
• vardenafil (Levitra®)
• tadalafil (Cialis®)

Recent evidence suggests that NO'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

Peristalsis

Birth

Nitroglycerine has helped some women who were at risk of giving birth prematurely to carry their baby to full term.

NO 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.

NO may also block exocytosis in other types of cells such as macrophages and cytotoxic T lymphocytes (CTL).

Effects on Secretion

NO 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.

NO and the Nervous System

NO and the Autonomic Nervous System

NO and the Medulla Oblongata

Hemoglobin transports NO at the same time it carries oxygen [Link to discussion]. When it unloads oxygen in the tissues, it also unloads NO.

In severe deoxygenation, NO-sensitive cells in the medulla oblongata respond to this release by increasing the rate and depth of breathing.

NO and the Brain

In laboratory animals (mice and rats), NO is released by neurons in the CA1 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.

NO and Fertilization

• blocking the entry of additional sperm and
• orienting the pronuclei for fusion.

Killing Pathogens

NO 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 NO.

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 NO 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.)

NO and Longevity

• show signs of premature aging;
• have a shortened life span;
• fail to benefit from the life-extending effect of a calorie-restricted (CR) diet. [Link]

Mechanisms of NO Action

• a metal ion in the protein or
• one of its S atoms (e.g., on cysteine).

Three prescription drugs

• sildenafil (Viagra®)
• vardenafil (Levitra®)
• tadalafil (Cialis®)

Fireflies Use NO To Turn On their Flashes

Plants Also Use NO

• It is a weapon against invading pathogens. Infection of the plant triggers the formation of a NOS that, like the animal versions, makes NO from arginine. Release of NO by the infected cell induces a number of defense responses.
• Once a pollen tube has entered the ovule [Link], a burst of NO blocks the entry of other pollen tubes thus ensuring that polyploidy does not occur.
• NO inhibits flowering.
• NO promotes recovery from etiolation.
• and others.