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Nitric oxide

Author: Dr Sharnika Abeyakirthi, Dermatologist, Columbo, Sri Lanka, 2009. Revised October 2020.


What is nitric oxide?

Nitric oxide is a small gaseous molecule also known as nitrogen monoxide, with the chemical formula NO.

Nitric oxide molecule is synthesised from molecular nitrogen and oxygen at very high temperatures of >10000C. This occurs naturally in the environment during lightning.

In the laboratory nitric oxide can be produced by reduction of nitric acid or nitrous acid. Nitric oxide has a melting point of -163.6°C (109.6 K) and a boiling point of -151.7°C (121.4 K).

Nitric oxide is called a free radical because it contains single unpaired electrons in its molecule. Hence it is reactive, and has a half-life of only a few seconds.

It is considered as an air pollutant responsible for the depletion of the ozone layer. Nitric oxide reacts with oxygen (O2) and ozone (O3) to form nitrogen dioxide (NO2), a brown fume and an environmental pollutant. Nitric oxide generated from automobile engines, industries and power plants is the cause of acid rain and smog.

However, this toxic environmental pollutant has also been shown to be a very important signalling molecule in living organisms including the human body.

What is the role of nitric oxide in the body?

Some of the known functions of nitric oxide are listed in the table below.

Cardiovascular system
  • Controls vascular tone.
  • Relaxes vascular smooth muscles and reduces blood pressure.
  • Dilates vessels and relieves the pain of angina.
  • Inhibits the aggregation of platelets within the vessels and prevents thrombotic events.
Nervous system
  • Acts as a neurotransmitter, including in the autonomic nervous system.
  • Increases cerebral blood flow and oxygenation to the brain.
  • One of the important mediators in penile erection during sexual arousal.
  • Dilates pulmonary vessels.
  • Beneficial in Adult Respiratory Distress Syndrome, Pulmonary hypertension and Chronic Obstructive Airway Disease.
  • Produced in abnormal amounts in inflammatory lung conditions.
  • Concentration of NO in exhaled air is a marker of airway inflammation.
Gastrointestinal tract
  • Regulates the relaxation of smooth muscles.
  • Controls peristalsis and the function of sphincters.
Renal system
  • Due to its vasodilatory effect, increases blood flow to the kidney.
  • Increases the glomerular filtration rate and the production of urine.
Immune system
  • Modulates T cell-mediated immune response.

What is the role of nitric oxide in the skin?

Nitric oxide controls cutaneous microcirculation. Nitric oxide:

  • Modulates the vasodilator response of the skin to local warming and ultraviolet-B (UVB)
  • Mediates cutaneous oedema and inflammation
  • Is involved in skin pigmentation through ultraviolet induced melanogenesis
  • May contribute to impaired barrier function
  • Promotes wound healing by cellular proliferation and angiogenesis.

Nitric oxide has shown antimicrobial properties against micro-organisms.

  • BacteriaStaphylococcus aureus
  • Dermatophytes – Trichophyton rubrum, Trichophyton mentagrophytes
  • Yeasts – Candida albicans

Nitric oxide also plays an important role in T-cell mediated diseases of the skin, and it has both pro and anti-apoptotic properties depending on its concentration, cell type, and availability of other substrates.

How is nitric oxide produced in the human body?

Humans produce nitric oxide by several mechanisms.

  • From the amino acid L-arginine by the enzyme nitric oxide synthase (NOS)
  • From inorganic nitrates in green leafy vegetables, fruits, cereals, and cured meat

Nitric oxide synthase has 3 isoforms:

  • Neuronal NOS – nNOS or NOS I
  • Inducible NOS – iNOS or NOS II
  • Endothelial NOS – eNOS or NOS III

Neuronal NOS and endothelial NOS are constitutive enzymes. Their levels are relatively steady in the human body. They are found in endothelial cells, neurones, skeletal muscles, epithelial cells and many other tissues.

NOS II is inducible and stimulated by specific cytokines. Most cells in the human body synthesise iNOS in response to inflammatory conditions.

How does the skin produce nitric oxide?

As all 3 isoforms of NOS are present either in the epidermal cells, dermal cells or both, skin can produce nitric oxide by an enzyme dependent mechanism.

Human skin can release nitric oxide in an enzyme independent manner by UVA photolysis of nitric oxide stores.

Nitric oxide is also produced by reduction of sweat nitrate by skin commensal bacteria, in particular Staphylococci.

How is nitric oxide stored in the human body?

Nitric oxide does not usually exist in its free form in the body due to its unstable nature but reacts with other molecules to form more stable products.

  • In the blood, nitric oxide has a very short half-life and rapidly oxidises to nitrite. It is then further oxidised with oxyhaemoglobin to produce nitrate. Nitric oxide also reacts directly with oxyhaemoglobin to produce methhaemoglobin and nitrate.
  • Reactions with cysteine residues in proteins lead to formation of nitrosylated products. Because of its high affinity to sulfhydryl groups (thiols), S-nitrosothiols (RSNOs) are the most common nitrosylated product in plasma.

Nitrate is the main storage form of nitric oxide. It is very stable when compared with other storage forms such as nitrites and RSNOs, which are important carriers and donor molecules of nitric oxide.

How can you test for nitric oxide?

There are no tests for nitric oxide itself, as it is too unstable. Instead, nitrates, nitrites and nitrosylated compounds may be measured using the following tests.

  • Griess assay
  • Saville assay
  • Electron paramagnetic resonance (EPR) spectroscopy
  • Chemiluminescence method

Nitric oxide deficiency

Deficiency of nitric oxide is suspected to have a role in several disorders.

  • Essential hypertension (high blood pressure)
  • Congenital abnormalities, including achalasia cardia, hypertrophic pyloric stenosis, and Hirschsprung disease
  • Chronic kidney disease

In the skin, insufficient nitric oxide may result in psoriasis by promoting cell proliferation and reducing differentiation of skin cells.

  • Reduced eNOS levels in the endothelial cells that line the blood vessels in the skin is believed to contribute to systemic sclerosis and morphoea (localised scleroderma).

Excessive nitric oxide

Consuming food rich in nitrates and nitrites increases the level of nitric oxide and its storage form. Just as deficiency of nitric oxide can lead to disease, too much can also cause disease.

Nitric oxide is released from the cerebral vasculature, brain tissue and nerve endings.

  • It may cause headache in migraine.
  • It may damage brain cells leading to neurodegenerative diseases like Parkinson disease, Alzheimer disease, Huntington disease and amyotrophic lateral sclerosis.

Nitric oxide produced by β cells in the pancreas may damage the cells (apoptosis) causing type 1 diabetes.

In the skin, ultraviolet irradiation may lead to excessive nitric oxide production by enzyme-dependent and independent mechanisms. Nitric oxide has a role in the promotion and growth of melanoma via multiple mechanisms.

The treatment potential of nitric oxide

Due to its antimicrobial properties, a nitric oxide-releasing gel formulation, berdazimer sodium (SB206, SB207, Novan), is under evaluation to treat dermatophyte fungal infections such as tinea pedis and viral skin infections  including genital warts and molluscum contagiosum



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