Nitric Oxide The Right Way
By Anthony Roberts
Nitric Oxide (NO) is one of the flavor-of-the-month bodybuilding supplements that we see burning up message boards and killing entire forests with their advertisements in muscle magazines. Ask a bodybuilder what it does, and they’ll tell you that it “increases blood flow” and gives a “killer pump” – but what does that mean? Originally the hot product for a pump was arginine, but even 20g/day of Arginine for 28 days has been shown not to increase blood flow or increase vasodilation (Chin-Dusting, PMID: 8797150), despite it being a precursor of Nitric Oxide. This is because the expression and activity of arginases (the enzyme he was referring to) are positively related to external arginine supplementation. Hence, the more Arginine is consumed, the more is destroyed, ultimately resulting in impaired NO production (Dioguardi, PMID: 21625171).
For a less abstract example of how this works, we see increased arginase activity expressed in hypertension, and a direct relationship to reduced NO production. Which brings me to the next point: If your Nitric Oxide supplement contains arginine, it’s more likely to lower NO than raise it.
In fact, it’s almost sure to lower NO. All of those companies who put arginine in their NO products? They’re stupid. But that doesn’t stop NO products from dominating the marketplace:
But what about the pump? The pump isn’t an indicator of prerequisite for muscle growth and the idea that increasing blood flow to the muscle will increase hypertrophy has been soundly rejected by sports scientists:
A quick look through the National Strength and Conditioning Association textbook reveals that their sections on hypertrophy never mentions the increase in blood flow as being a pathway towards hypertrophy or strength, and honestly, if it weren’t for the advertisements for NO-type products, this wouldn’t even be an issue. Most people know intuitively that a better pump doesn’t translate to better gains – if it did, we’d all be doing sets of 25 reps with minimal rest between them (a practice that we know is inferior for building muscle and strength).And the quicker you get a pump, the more rapidly your endurance degenerates. Again, think about your own personal experiences here: Could you run farther after a set of 6 reps or 60 reps?
So even if a NO supplement actually did increase blood flow to the muscles, it’s doubtful that this effect in and of itself would lead to muscle growth. So, other than the alleged increase in blood flow that NO produces in the muscle, and the t-shirt-swelling-painful-pump-blah blah blah advertising hype that we’ve all seen, what does NO actually do? Nitric oxide regulates blood pressure and blood flow to various organs as well as playing a key role in the immune response and neuronal signaling. In the muscle, the first and most noteworthy effect of Nitric Oxide is in its ability to increase glucose uptake – in fact, this point is irrefutable: Nitric Oxide when produced during muscular contractions plays a positive role in the uptake of glucose by muscles.
However, it decreases the contractile ability of muscles by promoting relaxation via the cyclic guanosine monophosphate (cGMP) pathway. It likely reduces the muscle’s ability to forcefully contract by making it more difficult for cells to replenish Adenosine Triphosphate (ATP), the immediate source of muscular energy. NO donors decrease myofibrillar ATPase (Galler et al. PMID: 9178621) as well as creatine kinase activity (Gross et al., PMID: 8643623) the former of which catalyzes ATP into ADP, and the latter of which converts it back. More NO equals less ATP. It can also deenergize mitochondria(Schweizer and Richter, PMID: 7945356), which I’m sure you remember from high school biology as the “cell’s powerhouse.”
And less ATP means you’re going to have a lowered ability to forcefully contract your muscles. This isn’t just wild speculation, and although there is a lot of conflicting data, it appears that Nitric Oxide can directly impair the muscle’s ability to contract:
“NO or NO-derivatives inhibit force production by modulating excitation-contraction coupling.” (Reid et al., PMID: 11253787)
” single fibres of rat skeletal muscle were exposed to physiologically relevant NO concentrations by adding NO donor molecules into the bath solution. Donor application caused a decline both in the contractile properties and in the myofibrillar adenosine triphosphatase (ATPase) activity. These results reveal a novel molecular mechanism of NO action: a direct inhibition of the force-generating proteins in skeletal muscle. (Galler et al. PMID: 9178621)
“Deenergization is observed when mitochondria utilize respiratory substrates such as pyruvate plus malate, succinate, or ascorbate plus tetramethylphenylenediamine, but not when mitochondria are energized wit ATP. These findings reveal a direct action of NO on the mitochondrial respiratory chain and suggest that NO exerts some of its physiological and pathological effects by deenergizing mitochondria.” (Schweizer and Richter, PMID: 7945356)
“NO synthase activity in muscles correlated with type II fibre density…. Contractile function was augmented by blockers of NO synthase, extracellular NO chelation, and guanylyl cyclase inhibition; it was depressed by NO donors.” (Kobzik et al. PMID: 7527495)
“…the effects of NO are direct, due to nitrosation or metal nitrosylation of target proteins: depression of isometric force, shortening velocity of loaded or unloaded contractions, glycolysis and mitochondrial respiration….”(Marechal & Gailly PMID: 10442090)
So at least in the short term, it appears that an NO boosting preworkout drink is going to produce exactly what we don’t want for a workout – decreased muscular contraction. And we know that it’s not going to make you bigger or stronger because of “the pump.”
I can hear the resistance to this last statement now: You used an NO supplement and were stronger during your training session. But chances are high that your “NO supplement” also contained creatine, beta-alanine, caffeine, and a bunch of other stuff that cancels out the negative effects of NO on muscle contraction. Take a look at the best selling NO product(s) and you’ll see that they’re crammed with other stuff. In fact, they’re crammed with everything but NO stimulators – a 2010 study noted that even though they’re called “Nitric Oxide Supplements,” many of them don’t actually show an increase in markers of NO production, hemodynamic variables, or pump (as measured by muscle size immediately after training (Bloomer et al., PMID: 20459623).
Ok, so Nitric Oxide isn’t such a hot idea for a preworkout supplement (*if we even assumed that we could find one that actually elevated NO levels). Does that mean Nitric Oxide is completely useless? Actually no…it could turn out to be one of the more potent anabolics on the market. The problem is that everyone (literally 100% of the vendors on Bodybuilding.com, at least, ) is selling it in a preworkout drink instead of a post-workout drink. Go ahead and check, I’ll wait …(admittedly I’ve observed that a few companies have included supposed NO boosters in post workout formulas, it’s interesting to note that the same companies also have it as a preworkout ingredient as well, and even recommend stacking them).
So I think it may turn out that elevating NO levels is only useful after a workout, and never before. Because while it will hinder your ability to contract your muscles, it turns out that Nitric Oxide mediates satellite cell activation (the cells that you need to recruit to form new muscle) and supports myogenic (muscle generating) cell release after an injury (similar to what we see from the breaking down of tissue that occurs in weight training). On the other hand, inhibition of NO will delay the hypertrophy of satellite cells in damaged muscle (Anderson, PMID: 10793157). Since we know that it’s purported “pump increasing” ability is neither necessary nor sufficient to cause muscle growth, this theory presents us with an alternative mechanism of action for it to exert an anabolic effect. Postworkout. Not pre. Not intra.
In addition, endogenous nitric oxide production is required for myoblast fusion which is necessary for the growth of new muscle tissue. The action of NO can also induce expression of follistatin (Pisconti, et al. PMID: 16401724). Follistatin causes the growth of new muscle tissue through several direct and indirect mechanisms: the inhibition of myostatin and activin, the proliferation of satellite cells, and the increase of muscle protein along with the expression of myogenic DNA and mRNA (Gilson, et al. PMID: 19435857).
Since NO is very short lived in the muscle, it’s unlikely that taking a such a supplement prior to working out would prove to have any post-workout benefits…while it would almost definitely have a negative effect on the workout itself. But the research does indicate that the introduction of NO to damaged muscle cells shows a “washing over” effect…in other words, it seems to hit them almost immediately and begin to recruit new cells for repair and rebuilding. So obviously a true NO supplement will be a loser in terms of a preworkout formula, but with regards to a postworkout supplement, it may just be that it will enhance your body’s ability to repair itself, thereby leading to increased muscle gains.
I think the entire NO industry has it wrong…but don’t worry…it’s fixed now. It can work, but not with the ingredients most companies are putting in their formulas, and not with the preworkout dosing protocol most people are following. Just find a supplement that actually raises NO levels, and make sure you only take it after a workout.