Nitric Oxide and Peroxynitrites

Nitric oxide was named “Molecule of the Year” in 1992 and 6 years later this work lead to the award of a Nobel Prize—so this stuff carries some clout. And it should. Nitric oxide affects function throughout the body and without it, we would not be alive.

What does nitric oxide do?

Nitric oxide (NO) is a powerful signaling molecule that influences function of virtually every bodily organ.  A signaling molecule works by fitting into receptors on cell walls to trigger a biochemical reaction.

Supports immune function

NO is an antimicrobial and antiviral—including DNA and RNA viruses which is super important right now due to Coronavirus. It supports wound healing and for some with a Th1 with autoimmune condition, it may help balance the Th1/Th2 balance toward a Th2 response.

NO inhibits most pro-inflammatory mediators and promotes anti-inflammatory messengers.

Helps prevents cardiovascular disease

NO acts as a vasodilator which means it causes blood vessels to expand. This in turn reduces blood pressure, increases nutrient delivery to the muscles and organs, and helps remove waste products.

It plays an important role in platelet modulation, reduces arterial plaque, lowers cholesterol, and prevents the formation of blood clots.

Supports brain function

NO helps with cognitive function, aids in storage and retrieval of long-term memory, and optimizes neuronal communication and processing.

Nitric oxide modulates neurotransmitters such as norepinephrine, serotonin, dopamine, and glutamate .

Supports reproductive function

NO plays a role in fertility by increasing ovarian response to hormones in women and increasing sperm count and motility in men. It supports circulation helping with erectile function.


Increases energy by stimulating mitochondria, enhances pulmonary function, regulates insulin and helps reduce diabetes complications, aids in detoxification, supports kidney disease, and more.

How is nitric oxide produced?

Nitric oxide is made with the amino acid L-arginine, various cofactors, methylation, and the nitric oxide synthase (NOS) enzyme.

This enzyme exists in three different forms. Each plays their part in the many functions listed above.

NOS 1 or nNOS

Participates in brain function.

NOS 2 or iNOS

This is also called inducible NO for a reason since there has to be something abnormal (a wound, tissue damage, hypoxia, infection, etc.) to create it. Once triggered, it is made extraordinarily high concentrations or bursts, mostly in part to kill pathogens.

NOS 3 or eNOS

eNOS maintains the diameter of blood vessel to optimize delivery of blood to tissues–skin, muscle, nerves, and bone, etc.

In addition, it causes angiogenesis–the growth of new blood vessels. This is especially important in healing an ulcer or wound in order to increase circulation.

What affects nitric oxide production?


Nitric oxide levels begin to decline sometime before or around age 30 and drop sharply. By age 45, NO levels can be half of what they were when we were young.

“ Clinical studies provide evidence that insufficient NO production is associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and severity of atherosclerosis, and also has a profound predictive value for disease progression including cardiovascular and Alzheimer’s disease…. it can be concluded that enzymatic production of NO declines steadily with increasing age in healthy human subjects. Implementing strategies to diagnose and treat NO insufficiency may provide enormous benefit to the geriatric patient.”

Environmental factors

According to Dr. Datis Kharrazian, PhD, the presence of NO can be either protective or destructive.

Protective Mode

In this mode, it promotes circulation, immune activation, and brain function.

↓ iNOS

↑ eNOS

↑ nNOS

  • Dampens tissue inflammation and destruction
  • Supports in tissue healing
  • Modulates autoimmunity to dampen activation
  • Increases blood flow to brain, hands, feet, and sexual organs
  • Enhances brain endurance
Destructive Mode

When endothelial tissue is damaged by age, an unhealthy lifestyle, illness, a toxic environment, or genetic susceptibility , healthy NOS production is impaired and iNOS takes over. In this mode..

↑ iNOS

↓ eNOS

↓ nNOS

  • Promotes tissue destruction
  • Promotes inflammation
  • Allows for greater chance of autoimmune expression
  • Decreases blood flow to brain, hands, feet and sexual organs
  • Decreases brain endurance, function and focus
  • Leads to poor recovery from autoimmune attacks


High blood sugar can lead to a decrease in the production of nitric oxide (NO), which “affects all major components of innate immunity and impairs the ability of the host to combat infection”. 


Genetics play an important role in the production and usage of nitric oxide. SNPs are common in many of the genes listed below…(Bob Miller CTN).

  • MTHFR A1298C for creation of BH4
  • QDPR and DHFR for recycling of BH4
  • NOS Enzymes (NOS1, NOS2, NOS3)
  • Adequate NADPH–cofactor
  • Adequate Urea Cycle to clear ammonia that may deplete BH4
  • Adequate SOD (SOD1, SOD2, SOD3)

Are there any issues that affect the NOS enzyme?

Uncoupling the NOS enzyme

As scientific as it sounds, NOS uncoupling is just the failure of the NOS enzyme to do its job. Instead of converting arginine into NO, the outcome is a potent free radical called superoxide. Free radicals damage DNA, cells, tissues, organs, etc.

Superoxides can also be created by inflammation, glutamates,  histamine, mitochondria dysfunction, NOX–anything that might upregulate free radical production.

High iNOS

Additionally, high levels of iNOS can combine with superoxide to produce peroxynitrite or as its scientific formula indicates, the “ O NOO” free radical. ONOO is even more destructive than superoxide.

BH4 issues

BH4 is a cofactor in the production of NO. With the help of the NOS enzyme, BH4 becomes BH2 and NO. BH2 is turned back into BH4 and the cycle continues.

Why is this so important? The NOS enzyme not only facilitates making NO. but is also involved in removing ammonia from the body. If ammonia levels are high, BH4 doesn’t get recycled–leading to low NO levels and free radical production.

Methylation is a BH4 recycling cofactor and issues can also lead to NOS uncoupling.

Unfortunately, NOS uncoupling and BH4 conversion issues can be a self-perpetuating cycle that results in impaired NO and increased oxidative stress—leading to cellular damage and loss of function.

Other causes

NO levels can be impacted by a diet either low in arginine or nitrogen sources.  

In addition, high levels of oxidized glutathione or increased levels of iNOS .

Environmental agents such as BPA is known to uncouple NOS3 and create peroxynitrites.

What is peroxynitrite?

ONOO is a powerful oxidizing agent. This is not always a bad thing.

Because the rate of peroxynitrite formation rises 100-fold for each 10-fold increase in superoxide and NO production, the production of superoxide offers a way to redirect NO from being a signaling molecule into a powerful defensive innate immunity mode.

High levels can go as far as even signaling cell death to help protect the host.

How does peroxynitrite affect my health?

The brain is especially sensitive to peroxynitrite which can trigger microglial activation (the nervous system’s “personal immune system”), increase NMDA receptor stimulation, cause excessive glutamate production, and eventually brain degeneration.  

Peroxynitrite easily reacts with lipids and DNA, leading to major destruction and degenerative disease such as:

  • Stroke
  • Myocardial infarction
  • Chronic heart issues
  • Diabetes
  • Circulatory shock
  • Chronic inflammatory diseases
  • Cancer
  • Neurodegenerative disorders
  • Anxiety, etc.

Peroxyniitrite has been found to play a direct role in:

  • Asthma
  • Alzheimer’s
  • Fibromyalgia
  • Ulcerative colitis
  • Low serotonin and dopamine
  • Atherosclerosis
  • Lung disease
  • Arthritis
  • Autoimmune such as Celiac, MS and Raynaud’s
  • Parkinson disease
  • Migraines
  • Bipolar disease
  • and more

How can I support proper nitric oxide levels?


A diet including nitrate foods such as may help. These would include but are not limited to:

  • Celery
  • Cress
  • Chervil
  • Lettuce
  • Beetroot
  • Spinach
  • Arugula
  • Etc.

We should avoid foods high in sodium nitrates that are commonly used as a preservative and color enhancer found in bacon, cold cuts, hot dogs, etc.  Antioxidants like vitamin C taken with these foods may help neutralize these compounds.

Some of the foods above are also high in oxalates so caution to those sensitive.

High antioxidant foods such as polyphenols may help limit free radical damage.

Addressing limiting factors

Addressing underlying sources of superoxide production is absolutely essential.  Addressing gut issues may help facilitate the absorption of amino acids, and cofactors,. Methylation support may be necessary.


There are various supplements on the market that can help enhance NO. But again care must be taken that high levels of prooxidants such as superoxide are not present to avoid creating peroxynitrites.


  • Vitamin C also help to enhance eNOS as well as limit nitric oxide uncoupling.
  • Glutathione can enhance protective NO activity as well as increase total antioxidant capacity.
  • Hydroxocobalamin (B12) may help to reduce high iNOS
  • Optimal concentrations of L-arginine and/or BH4 are required for reducing formation of NO.  BH4 supplementation is not common and expensive, instead methylation support should be considered.
  • Antioxidants such as vitamin E, Vitamin C, melatonin, etc., may help prevent the formation of peroxynitrite. 
  • Free radical support such as SOD and NAD(H)may be warranted.
  • Additional iNOS inhibitors can help reduce inflammation and free radical production.

Since cause is different for everyone, it is best to work with your provider.


Exercises such as Nitric Oxide Burst exercises may help increase eNOS levels.

Can you test for nitric oxide?

There are at home test kits that help you potentially indirectly determine NO levels by testing nitrate levels. 

You can test for potential genetic weakness in NOS production and genes that upregulate superoxide and downregulate methylation.

Amino acids levels can also be tested using a blood spot test.

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