If you lift weights, you’ve likely experienced the phenomenon known as ‘the pump’.

When working against a significant resistance for repetitions, blood flow locally increases to working muscles, increasing tone and size almost instantly. While getting your swole on can be great for the mirror, it is not just cosmetic - increasing blood flow to hard-working muscles also delivers nutrients to fuel muscle contraction.

Greater blood flow to working muscles also helps to increase cell volume, which, along with mechanical tension generated from lifting heavy weights, comprise a large part of the early ‘go’ signal for muscle adaptation.

The much sought-after “pump” in the gym isn’t just for aesthetics, it’s also an ingredient in the recipe for muscle growth.

The NO-cGMP pathway: anatomy of a pump

While the behind the scenes cell signaling that drives increased blood flow to working muscles can get a bit complicated (more on that later), a simple thought experiment gives a good overview of the process.

Let’s say you have an empty swimming pool in your backyard that you need to fill with water. So you place a small garden hose in the pool and turn on the faucet. Only nothing happens. You discover that there’s a leak in the pool, and the small amount of water delivered through the garden hose leaks out as fast as you can pump it in. Since our ultimate goal is to get that pool filled with water, there are two things we can do to this end: deliver the water faster than it leaks out, or fix the leak! If this makes sense, you now have an overview of a muscle pump: arteries supplying the working muscle dilate, allowing more blood to enter. At the same blood flow is restricted in other less active areas of the body, promoting the local delivery of increased nutrient-rich blood to hard-working muscles.

The pump effect is driven by a molecule known as nitric oxide (NO) that is part of the NO-cGMP pathway. In response to hard work, neurons release NO from nerves and endothelial cells in and around the working muscle. From here, NO makes its way to the smooth muscle cells lining blood vessels, where it binds to guanyl cyclase. This NO-guanyl cyclase interaction results in the production of cGMP. cGMP then goes on to activate downstream signaling that decreases calcium levels in the smooth muscle that lines blood vessels, leading to relaxation and arterial dilation.

While this may sound complicated, the overall concept is straightforward: NO is locally released, which increases cGMP levels, which in turn increases blood flow to working muscles.

Supplementing the pump

There’s a huge market for supplements meant to potentiate the pump by affecting the NO-cGMP pathway. Many contain large amounts of L-arginine, which is combined with oxygen by the nitric oxide synthase (NOS) enzyme to produce NO. This type of supplement is generally taken pre-workout, where a bolus of arginine with the right timing spikes blood arginine levels when it counts, increasing NO production and blood flow to working muscles.

While this looks great on paper, L-arginine supplementation is not perfect. As much as L-arginine exists at the business-end of NO synthesis, getting significant quantities into the bloodstream can be an inefficient process. A significant amount of arginine taken orally will be broken down in the liver before it ever gets into circulation. The second issue is that NO is a highly reactive molecule that is broken down soon after it is formed.

There are two main issues to using L-arginine supplementation to increase NO levels: L-arginine delivery into the bloodstream, and NO and stability.

Use Citrulline to increase blood arginine levels

Because L-citrulline is more readily absorbed than L-arginine, which is rapidly broken down in the liver before it reaches circulation, L-citrulline is a far more efficient way to increase blood arginine levels. One study in heart patients found that 3g of citrulline (as citrulline malate) was equivalent to a 6g dose of arginine, suggesting that citrulline may have twice the potency of arginine itself when it comes in increasing arginine levels in the blood stream.

Doses of citrulline in the 4-8 g range seem to be optimal for boosting pre-workout NO levels, and can be taken as free-form L-citrulline as well as citrulline malate. For the purposes of increasing blood arginine levels, these are probably interchangeable, and the malate form has shown promise in a recent study on lower-body resistance exercise, as seen in Figure 1. Keep in mind though, that 1.8g of citrulline malate is equivalent to only 1g of free-from citrulline, due to the added molecular weight of the malate salt.

The solution to the delivery problem is an easy fix: take citrulline instead. L-citrulline is byproduct of NO synthesis that can be converted back into arginine through the arginine-citrulline cycle.

Increase glutathione levels to stabilize NO in the blood stream

Having solved the delivery issue by taking L-citrulline, we still have a problem to overcome to maximize the potential of NO: it breaks down real fast in the blood stream. If there was a way to extend the life of NO even by a little bit, this could help to augment cGMP production and increase blood flow.

Recent research has suggested that supplementing glutathione alongside citrulline may help to do just that, potentiating NO synthesis. Glutathione is a tripeptide consisting of the amino acids cysteine, glutamic acid, and glycine. It is also major cellular antioxidant that plays a role in detoxification of toxic reactive oxygen molecules such as peroxides. GSH has a connection to NO synthesis, as some cells can’t make NO in the absence of GSH. GSH also increases the activity of NOS, the enzyme that makes NO from arginine.

In a human trial, 200mg/day glutathione (GSH) alongside 2 g/day L-citrulline showed a non-significant trend toward increasing plasma cGMP levels. Although the observed increases in cGMP levels didn’t quite reach statistical significance, citrulline and GSH in combination also increased nitrate and nitrite levels more than citrulline alone. Since nitrate and nitrite also are substrates for NO synthesis, this work suggests that the overall effect of L-citrulline and glutathione supplementation may support NO production to a greater extent than L-citrulline alone.

Taking GSH alongside L-citrulline may help potentiate NO levels more than citrulline alone. While this idea has not been rigorously tested in robust larger-scale trials, the evidence is sufficient to give it a shot.

It is important to emphasize, though, that rock-solid diet, training and nutrition are the foundation for progress in any fitness endeavor. Supplements become important if you're already firing on all cylinders, and even then, natural NO boosters such as beets may be preferred over pills.

With a basic knowledge of the nuts and bolts of NO synthesis, we can at least be better consumers, paying attention to ingredients and amounts rather than advertising hype when evaluating the value of a product. So take this information, apply it, and let us know the results!