Nitric Oxide Replacement Therapy

Testosterone is the most important molecule in your body, right?  Well, I would argue that it's probably a tie between T and NO (nitric oxide) actually.  Nitric oxide is critical for the brain and functions as a neurotransmitter: it plays a powerful role in the immune system;  and, of course, it plays a cardioprotective role and makes erections possible.  That's a pretty hard hand to beat, eh?

So just where do you get your (arterial) nitric oxide?  And how can you increase it? 

1. The standard pathway for arterial NO is from the endothelium, the lining of the arteries. This pathway is usually very seriously damaged from the Western lifestyle, causing arteriosclerosis, accompanied by the hardening of the arteries.

2. A secondary pathway is to consume higher nitrate foods - arugula, beets, spinach, etc. - which then are converted to nitrite by the bacteria in your mouth. After passing into the GI tract, nitrite is then converted to nitric oxide. Assuming that you're not NO-depleted, this will make it back into your saliva as nitrites and recycled to form more nitric oxide. Hence, saliva is a critical step in this bioconversion process to form nitric oxide.

The older you get, the more prominent role #2 plays in your daily nitric oxide production. In fact, I call this strategy Nitric Oxide Replacement Therapy, defined as boosting nitric oxide through consumption. We're all familiar with the TRT (Testosterone Replacement Therapy) that many middle-aged guys need. Well, I would make the case that men 35+ almost always need NO Replacement Therapy in the form of nitrate. (Citrulline can help as well:  see my link on The Benefits of Citrulline.)

Nitric Oxide Replacement Therapy Steps

  1. Choose a diet with lots of plant material.  My favorites are what I call Low Fat Paleo, which is actually based on many primal cultures and is plant-based. Other great choices are the Mediterranean Diet, a vegetarian diet and the DASH Diet. (For additional information, see my book, The Peak Erectile Strength Diet.)
  2. Consume high nitrate foods every 4-5 hours in the day. These foods include arugula, spinach, lettuce, carrots and, of course, beets or beetroot juice.
  3. Use mouthwash sparingly; it will eliminate the nitrate-to-nitrite conversion process in your mouth.
  4. Monitor your progress using the Berkeley Test Saliva Nitric Oxide Test Strips - see discussion below - and a home blood pressure cuff. Do not buy a wrist cuff: these are notoriously inaccurate.
  5. CAUTION: If you are on any medications or have any medical conditions, discuss with your doctor first. Even food and juices can have a clinical effect and interact with some medications.

Nitric Oxide Replacement Therapy Monitoring

But how do you measure the above strategy? How do you know if those nitrates you are eating are actually creating nitric oxide? Well, one way we can fairly accurately measure this is through the new nitric oxide test strips that have hit Amazon - see Berkeley Nitric Oxide Test Strips (50 Count) for example - and the market in general. These strips measure nitric oxide indirectly, however, saliva is an obligatory step in the bioconversion for the body to form nitric oxide and nitrite is a well established biomarker or surrogate for nitric oxide; nitrite serves as both a precursor for nitric oxide through the chemical reduction and a byproduct of nitric oxide via oxidation, which, in turn, can be recycled to form nitric oxide.

I was fortunate to have a recent interview with Berkeley Test's representatives and they explained the real power of these strips, which I have included below.

NOTE: For other ways to boost NO through food and also my Review of the Berkeley Nitric Oxide Test Strips

Q. Why should a man buy your current test strips when it's not truly measuring endothelial NO?

A. The reality is that you can't necessarily control the degree of endothelial NO gene expression or endothelial NO production, especially as you age, but you are able to compensate with a diet rich in vegetables with high nitric oxide potency. Hence, the strips are "enabling" -- they provoke you to change your dietary lifestyle to ensure your nitric oxide levels are elevated.

From a practical standpoint, the strips empower you to identify, which foods are rich in nitric oxide potency, but they also help in the timing to achieve optimal levels with a nitric oxide potent diet. For example, optimal nitric oxide levels to enhance performance are typically found 2-3 hrs after eating nitric oxide potent natural beet juice derived from winter beets resulting in an elevation to Target-Threshold levels shown with Berkeley s saliva nitric oxide test strips.

To achieve Threshold levels with Berkeley Test strips through natural whole foods diets, such as DASH, reinforce the recommended multi-servings of leafy greens that exhibit the benefits of these diets.

Hence, the strips are helpful in screening what foods are producing the greatest NO response. And for those foods which exhibit nitric oxide potency, Berkeley Test strips provides insight as to when levels are optimal. A number of clinical studies have reported on the effects of nitric oxide foods and diets elevating saliva levels in context of lowering blood pressure (see Scientific Articles, The Science Behind Nitric Oxide and Nitric Oxide potent foods at Berkeley Test).

Q. So these test strips are not really measuring arterial nitric oxide levels? Thus, a young man with good endothelial nitric oxide production may be misrepresented by the strips, i.e. his arterial nitric oxide may be good even though he has not eaten much in the way of nitrates?

A. The strips are reflective of nitric oxide bioavailability and bioactivity that is reflective of both nitric oxide produced by the endothelial cells and dietary sources, i.e., nitrate-rich vegetables.

Regarding the dietary source, ie, nitric oxide-potent beets and spinach, the bio-conversion of nitrate to nitrite in saliva to make nitric oxide is an obligatory and necessary step for arterial pressure changes: in brief, if saliva is interrupted, blood pressure is elevated.

For example, Webb s work (Hypertension 51:784, 2008) elegantly reinforced the obligatory role of saliva in humans. They showed that ingestion of beet juice by healthy volunteers markedly reduced blood pressure (BP) and by disrupting saliva, either by spitting or interrupting the conversion of dietary nitrate to nitrite in the mouth, the reduction of blood pressure was abated; by blocking the saliva from recirculating, it prevented a rise in plasma levels, and blocked a decrease in blood pressure and abolished the inhibitor effects on platelets aggregation confirming both arterial pressure changes and cardio-protective effects were attributable to the conversion in the mouth. So, our mothers were right: eat your vegetables and do not spit. (Wink et al, Hypertension 51:617, 2008.) Sobko et al (Nitric Oxide 22:136, 2010 ) shows that Japanese traditional diets abundant in leafy greens elevated both plasma and saliva levels with a corresponding BP decrease, or the recent clinical correlate between saliva and blood pressure lowering with nitric oxide-potent spinach. Here, the consumption of spinach lowered systolic blood pressure and increased large artery compliance acutely in healthy men and women with a corresponding 8-fold increase in salivary levels (Liua et al, Nitric Oxide 35: 123, 2013 ).

Ahluwalia s reports in 2012 and 2013 re-enforces the concept among pre-hypertensives (Nitric Oxide 26:197, 2012). They showed in a cross over protocol of 14 volunteers who ingested inorganic nitrates, plasma and saliva level increased 3 hrs post ingestion with a significant reduction of BP. A follow on study (Kapil et al, Biology Medicine 55:93, 2013), showed that nitrite/nitrate is extracted from blood by the salivary gland, accumulates in saliva, and it is then reduced to nitric oxide to have a direct BP lowering effect. And when interrupting saliva levels in volunteers that already had elevated levels, a rise in systolic and diastolic BP resulted. In their most recent paper (Ghosh et al, Hypertension 61, 2013), they found that pre-hypertensives may be more sensitive to the BP lowering effects of the dietary nitrate-nitrite-nitric oxide pathway; it is a fascinating paper that sets the stage for an inexpensive antihypertensive strategy with beet juice.

As you well know this field is rapidly evolving. If we look to how other biomarkers evolved, such as serum cholesterol or blood pressure, new clinical correlates causes the scientific community to reassess how to interpret the information. For example, just this past year, new guidance was provided regarding BP measurements.

In like fashion, we envision saliva testing for nitric oxide status will evolve; eventually, we would like to see descriptive terms, i.e., low or depleted, move to quantitative ranges that provides guidance as to a physiological outcome, i.e. arterial pressure or endothelial dysfunction. This is something we are interested in providing some day, however, that will be driven by more clinical evaluations and correlates. So, this discussion will continue to evolve and will be on going.

Today, Berkeley Test strips are reflective of nitric oxide bioavailability and bioactivity that is reflective of both nitric oxide produced by the endothelial cells and dietary sources, i.e., nitrate-rich vegetables.