NO and exercise performance enhancement

Nitric Oxide (NO) manipulation is supported in the scientific literature as a means of increasing exercise performance through vasodilation, and there are several ingredient choices for enhancing NO in exercising humans – though not all sources are created equal.

For the reformulation of PreRace, we settled on a patented and well-studied version of stabilized arginine that targets on-demand NO production and that has human studies showing improved circulation, exercise benefits, mental performance, and recovery at the dose in PreRace.

You’ve probably already got two big questions: What’s arginine and what’s this mystery ingredient? We’ll come back to answer both shortly, but first, a brief intro to NO.

NO primer – it’s a gas gas gas!

Nitric Oxide (nitrogen monoxide or, simply, NO) is a super simple molecule – the simplest signaling molecule in our bodies: one oxygen atom bonded with one nitrogen atom.

You would think something this chemically simple would be everywhere all the time (like nitrogen and oxygen gasses), but NO has a problem. It’s a free radical gas. And like any other free radical/oxidant, too much is not good for you. It’s also very unstable, lasting only a few seconds at most in your body. Like oxygen, nitrogen, and carbon dioxide, it can freely diffuse in and out of your cells and tissues – if it lasts that long.

NO was discovered in 1620 and has been studied as early as 1720. Around 260 years later, it came to enjoy something of a renaissance when an avalanche of research interest in the 1980s led to NO garnering Science journal’s 1992 Molecule of the Year title, with its main proponents getting Nobel Prizes in 1998.

These studies often refer to the diminutive molecule as EDRF (Endothelium Derived Relaxing Factor), which is a what’s-in-a-name way for scientists to describe its function. For scientists, EDRF is a clear way of communicating that the molecule relaxes blood vessels; for everyone else, NO is a more agreeable solution.

In understanding NO’s role in exercise, though, it is helpful to consider the effect explicitly described by the outdated moniker Endothelium Derived Relaxing Factor. It tells us that NO is an instant signaling molecule that uses specific receptors to trigger second-to-second changes in your blood vessels to relax, improving blood flow, airway tone, and peristalsis (gut motility). It also carries molecular ammo and attack orders to immune cells, and it has a role in long-term memory. Notably (or not), it’s crucial for the little blue pill that affects blood flow in a certain part of the male anatomy. (But that’s a long story.)

NO contest for exercise performance

The impact of NO on endurance athletes is pretty straightforward. Exercise relies on blood flow to feed your muscles so you can perform. NO helps your body increase blood flow, redistribute blood supply, and move blood from splanchnic organs (gut, mostly) to working muscles during exercise, improving blood supply to whatever muscle group you’re relying on as your “engine” for a given activity.

The shorthand version of all of that: NO improves circulation during long-duration exercise; however, those improvements max out quickly, making NO manipulation a perfect pathway to improve exercise performance – and an obvious target for PreRace.

Unlocking the NO system

In our bodies, NO comes from the free form of the amino acid L-arginine and oxygen gas – both of which are always everywhere inside us – that combine together on specific enzymes (Nitric Oxide Synthases or NOSs) to ultimately make NO, L-citrulline, and water. A complex and well-regulated series of steps ensures that only the right amount of NO at the right place and time is generated.

So in theory, giving more arginine should make more NO, right? Wrong. Giving more and more arginine does not effectively raise NO levels, because our bodies practice NO control, super-regulating it to keep NO toxicity from getting out of control. So we needed an arginine work-around. Enter citrulline for the previous iteration of PreRace.


PreRace 1.0 used Citrulline as a NO enhancer, but citrulline (as either the free form amino acid or as citrulline malate) requires large doses to be effective, and it works by roundabout conversion to L-arginine, requiring specific conditions for conversion. Research on citrulline and endurance exercise improvement was hit-and-miss. It was effective, but it required a large dose and was saddled with a not-so-good taste. We wanted a NO enhancer with a smaller dose and better palatability. Enter Nitrosigine® for PreRace 2.0.

Nitrosigine® is arginine (the key to the NO system) complexed with inositol and silicate in a specific, patented manner that produces three advantages over regular arginine. First, it increases arginine availability by getting more into the bloodstream; second, it stabilizes arginine to be more attractive to the synthase enzymes that make NO; and third, it has a long retention time to produce long-duration effects, better aligning with long-distance endurance exercise. The net result is more NO for a longer time period when and where your body wants it – all within normal safety limits.

Nitrosigine® is also premium and proven. It’s a well-studied, low dose, palatable, non-nitrate/nitrite arginine precursor that fits into the intended endogenous, regulated pathways for precision generation of NO. It also does so with resulting nitrate exposures that are orders of magnitude lower than the same process using nitrates. (That’s why Nitrosigine® being non-nitrate is significant – but more on that in a later blog.) It’s a patented and trademarked product from Nutrition21®, a long-time supplier of clinically-tested specific nutrients for supplement use.

Nitrosigine® benefits summary

Let’s cut to the chase – what can taking Nitrosigine® before exercise do for me? Here are the highlights from using a dose of 1,500mg, the amount in a single serving of PreRace:

  1. Increased blood levels of arginine by 30 minutes that remain for up to 6 hours
  2. Decreased blood levels of arginase, the enzyme that gets rid of arginine
  3. Increased blood NO levels
  4. Increased blood levels of kallistatin, a normal endogenous signal to dilate blood vessels
  5. Increased vasodilation and blood flow
  6. Increased blood flow to working muscles
  7. Increased muscle pump (volume)
  8. No significant changes in heart rate or blood pressure
  9. Increased perceived energy levels (non-stimulant)
  10. Increased mental cognitive functions, focus, and mental acuity starting 15 minutes after a dose
  11. Improved recovery after exercise (reduced markers of exercise-induced muscle damage)
Serving Size 1 scoop (4.9g)


Taurine 2000 mg
Inositol-Stabilized Arginine Silicate (Nitrosigine®) 1500 mg
VitaCherry® Sport (Prunus cerasus var. Montmorency)(fruit) 500 mg
Cacao Extract (Theobroma cacao)(seed)(minimum 6% theobromine) 500 mg
Caffeine Anhydrous 200 mg


In First Endurance PreRace 2.0, Nitrosigine® provides an immediate and sustained boost of blood flow to get your muscles going, kickstarting your circulation in about 15 minutes and keeping your blood flow maxxed for several hours. We also like the mental effects from Nitrosigine®, which help keep your head and wit together throughout a race, event, or training.

Since Nitrosigine® improves blood flow, your body will be transporting and delivering critical nutrients and water more efficiently. That applies to the other nutrients in PreRace, but it also covers the broader First Endurance system. EFS, EFS-PRO, Liquid Shot – PreRace makes them all more effective.

In future blog posts, I’ll go into more depth about why we chose Nitrosigine® over other common NO sources, why non-nitrate sources are so important, and how human studies and clinical research demonstrate Nitrosigine®’s benefits. But in the meantime… Start your engines!

June 28, 2022 — Luke Bucci
Tags: research

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