Functional Medicine Approach to Nitric Oxide (NO)

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Any functional medicine physician should be well versed in Nitric Oxide, it is essential for cardiovascular health. I have a podcast on Nitric Oxide for additional information.

Nitric oxide is one of the single most important chemicals in maintaining cardiovascular health.  Nitric oxide is actually a gas, diffuses through the tissues very quickly, and has a very short half-life. Nitric oxide counteracts the negative effects of chemicals such as aldosterone, angiotensin II, and endothelin.  We want to do everything we can to ensure that we have appropriate levels of nitric oxide.

There are 2 pathways through which we can make nitric oxide: eNOS & Nitrate/Nitrate pathways.

Endothelial Nitric Oxide Synthase (eNOS)

L-arginine, an amino acid, is the precursor to Nitric Oxide. eNOS converts L-arginine to Nitric Oxide and L-citrulline. This enzyme is a critical component to Nitric Oxide and its ability to make Nitric Oxide is contingent upon whether or not the enzyme is coupled. The enzyme consists of 2 separate components and they must be couple, or stuck together, in order for it to work.

eNOS catalyzes a 5-electron oxidation of a guanidino nitrogen of L-arginine to N-hydroxy-L-arginine then to citrulline, and Nitric Oxide (NO). As stated, this requires dimerization of eNOS, referred to as coupling, in the presence of BH4.

In the absence of BH4, eNOS is in the uncoupled state and its function alters such that the enzyme produces superoxide anion rather than Nitric Oxide (NO).

Co-Factors for eNOS (to keep it coupled and working) include:

  1. BH4 (tetrahydrobiopterin) – levels of BH4 are determined by BH4 production, oxidation, and recycling of BH2 to BH4. BH4 production is controlled by GTPCH-1 (which is expressed in the endothelium). AMPK prevents GTPCH-1 from being degraded. Therefore, AMPK helps increase levels of BH4. Anything that increases AMPK will help increase BH4.
    • Metformin
    • Curcumin
    • Lipoic Acid
    • Green Tea
    • Others…
  2. Flavin Adenine Dinucleotide (FAD)
  3. Flavin Mononucleotide (FMN)
  4. NADPH
  5. Heme (reduced iron to ferrous state to bind oxygen)
  6. Calmodulin

Nitric Oxide (NO) decreases the oxidation of LDL, platelet aggregation, smooth muscle proliferation, smooth muscle contraction, expression of adhesion molecules, monocyte and platelet adhesion, and endothelin production.

Low Nitric Oxide (NO) has detrimental effects. It decreases glomerular filtration rate (GFR) and increases tubular reabsorption in the kidney. This results in decreased pressure natriuresis which causes sodium retention and, thus, hypertension.


Asymmetric DiMethyl Arginine (ADMA)

ADMA is a competitive inhibitor of eNOS. ADMA is structurally similar to L-arginine and basically blocks the enzyme. It makes it where L-arginine can’t use the enzyme and make Nitric Oxide (NO). The more ADMA you have, the less Nitric Oxide (NO) you can make.

ADMA is produced at a relatively constant rate and it is broken down by an enzyme called DDAH (dimethylarginine dimethylaminohydrolase). 80% of ADMA is cleared by DDAH. Therefore, your level of ADMA is essentially due to the activity of your DDAH.

DDAH is induced or inhibited by a number of factors. If you induce DDAH you increase its ability to break down ADMA. The more active your DDAH the more it can break down ADMA and you’ll have lower ADMA levels (and higher Nitric Oxide levels). If you inhibit DDAH then it can’t break down ADMA and your levels will go up.

ADMA is increased in Diabetes, Chronic Renal Insufficiency, Smokers, Hypertension, Elderly, Atherosclerosis, and Homocysteine.

Things that inhibit DDAH (and ultimately increase ADMA):

  1. Proton Pump Inhibitors (PPIs) such as omeprazole, nexium, etc. PPIs also inhibit endothelial cell lysosomes. Lysosomes are the garbage collectors for the cell. Without them, cellular trash accumulates which poisons the cells. Check out this podcast for more detailed information.
  2. Homocysteine
  3. Insulin
  4. TNF-alpha

How to increase DDAH (and decrease ADMA):

  1. L-Arginine
  2. Decreased LDL, oxLDL, and triglycerides
  3. Decrease blood sugar, HbA1c, Advanced Glycation End-products (AGEs)
  4. Decrease Blood Pressure
  5. Stop smoking!!
  6. Increase Vitamin E (mixed tocopherols)
  7. Stop taking PPIs and using mouthwash
  8. Ensure your Omega-3 Index is at least >8%
  9. Medications that may decrease ADMA (see below)
  10. Decrease TNF alpha
  11. Decreased Insulin
  12. Retinoic Acid – I’ve never seen anyone prescribe this for it

Medications that may decrease ADMA:

  1. Angiotensin Converting Enzyme Inhibitors (ACEi) (benazepril, lisinopril, accupril, etc)
  2. Angiotensin Receptor Blockers (ARBs) (telmisartan,
  3. Direct Renin Inhibitors (DRIs) (aliskiren)
  4. Nebivolol (Bystolic)
  5. Metformin
  6. Statins
  7. Estrogen (for women)
  8. Aspirin (make sure you know your COMT status)
  9. Phosphodiesterase-5 (PDE5) Inhibitors (Vigara, Cialis, Levitra)
  10. Block aldosterone with Spironolactone or Eplerenone

If you have issues with ADMA then you probably need Neo40 which helps increase Nitric Oxide via the alternate pathway (Nitrate/Nitrite) to produce Nitric Oxide. Take 1 tablet (wafer) twice daily (they taste quite good!).

The ratio of ADMA to L-arginine determines whether eNOS converts L-arginine to Nitric Oxide (NO) or it converts O2 (oxygen) to superoxide anion. Superoxide anion is highly oxidative and causes damage. It is part of the “3 finite responses” that contribute to cardiovascular disease and you want it as low as you can get it. Thus, you want a good ratio of ADMA to L-arginine in order to produce the best levels of Nitric Oxide and minimize Superoxide Anion.

SDMA (symmetric dimethyl arginine) is similar to ADMA but it is cleared rapidly by the kidney through the urine. ADMA identifies endothelial dysfunction and CVD risk whereas SDMA identifies renal dysfunction and subsequent renal failure.

Nitrate/Nitrite Pathway

This is another pathway through which Nitric Oxide can be produced.

Dietary Nitrates are converted to nitrites by the bacteria in your mouth. The nitrites are then converted to Nitric Oxide (NO) by stomach acid.

This explains why you shouldn’t use mouthwash. The mouthwash kills the bacteria in your mouth and decreases the amount of nitrates converted to nitrites. There are human clinical trials validating this effect. In fact, there was a young, health, athletic patient with normal blood pressure that was made to be hypertensive in 1 week just by using mouthwash!

Proton Pump Inhibitors (PPIs) cause a big problem with Nitric Oxide (NO). They decrease the amount of stomach acid so you can’t convert the nitrites to Nitric Oxide (NO). To add insult to injury, the PPIs also inhibit DDAH. As mentioned above, less active DDAH leads to higher levels of ADMA and less Nitric Oxide (NO).

A comprehensive Functional Medicine approach to cardiovascular health REQUIRES that all of these issues are optimally addressed!


  1. Current Opinion Lipidology 2014;25:339
  2. Vascular biology in Clinical Practice, Oct. 2000; Mark C Houston, MD
  3. J of Hypertension. 2014;32:306