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Posted on March 07, 2018
Nitric oxide is a very interesting neurotransmitter within the body that mainly functions as a blood flow optimizer. What sets it apart from most of the neurotransmitters in our body is that it is a gas. This gives it a few distinct advantages, such as being able to diffuse through membranes rapidly, but it also has a few unique traits, such as a very short duration of action. The main purpose of nitric oxide in the body is to relax blood vessels, allowing for increased blood flow, which promotes blood flow through the body while also increasing blood flow to the brain. This makes nitric oxide boosters very popular among athletes. By promoting better blood supply to the muscles, we can ensure that things like lactic acid are moved out of the muscle, and that various nutrients are moved into the muscle. This will allow for slight gains in strength acutely, but more importantly, it will lead to increases in muscle recovery. In addition to this, extra blood flow can be quite the confidence booster, as it will make the muscles look much bigger post-exercise due to ‘the pump’ which is something Arnold Schwarzenegger made very popular in the documentary "pumping iron." Due to this, nitric oxide supplements are also often referred to as muscle pump supplements.
Nitric oxide function goes far beyond helping enhance ‘the pump’, as it serves many other purposes throughout the body and even throughout the brain. The most obvious benefit, again has to do with blood supply. By relaxing blood vessels, nitric oxide can also help promote healthy blood pressure. Nitric oxide, by working on nitric oxide neurons, can also relax other smooth muscles; which can support digestive health.
Nitric Oxide Structure
Nitric oxide is also a major supporter of the immune system and plays an intricate role in the bodies inflammatory response. The phagocytes in our body are armed with large quantities of nitric oxide and upon activation, the phagocytes release the nitric oxide onto bacteria. The nitric oxide in this case, is released into an environment that is highly saturated with the oxidant superoxide. Nitric oxide interacts with super oxide to create the strong oxidant peroxynitrite which kills the bacteria. In fact, in recent decades nitric oxide has been recognized as one of the most versatile players in the immune system. Nitric oxide is produced by three different NO synthases (NOS), the principal enzyme involved is the inducible type-2 isoform of nitric oxide synthase (NOS-2).
Within the brain, nitric oxide regulates blood flow (just like in the body). Beyond this, it interacts with the glutamate system, and thereby plays a major role in memory and learning. By interacting with glutamate systems, it can also cause excitotoxicity when it becomes dysregulated. So, it is no surprise that nitric oxide is strictly regulated. In fact, the excitatory amino acid glutamate, the most abundant CNS neurotransmitter, is an initiator of the reaction that forms nitric oxide. Nitric oxide binds to guanylyl cyclase, the cyclic guanosine-monophosphate (cGMP)-producing enzyme which is a soluble NO receptor, and through cGMP-mediated signaling cascades it expresses its modulating effects either as a post- or a pre-synaptic retrograde messenger. This is how nitric oxide can act as an excitatory neurotransmitter. However, it also acts on inhibitory gamma-aminobutyric acid (GABA)-ergic synaptic transmission. As such, nitric oxide can fill the role of an excitatory or inhibitory neurotransmitter in the brain.
The regulation of nitric oxide is managed by three different enzymes, called the nitric oxide synthases. The three forms are inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). The phagocytes that we talked about earlier, mainly express iNOS which is capable of producing and releasing large bursts of nitric oxide, which may support immune response, but can also be counterproductive when there is no direct immune threat. Within the nervous system, nNOS is widely expressed and is responsible for producing nitric oxide in neurons. This leads to enhanced neuroplasticity, central regulation of blood pressure and relaxation of smooth muscle cells. Finally, eNOS is the most commonly expressed form of NOS and is expressed widely in blood vessels. Usually, when we think about enhancing nitric oxide function, we are focusing on eNOS as it produces vasodilation without many other effects.
The easiest route to support nitric oxide function is to increase the amount of substrate available for NOS to produce nitric oxide. The reaction that takes place in NOS to produce nitric oxide is as follows:
2 L-Arginine + 3 NADPH + 3 H+ + 4 O2 ⇌ 2 L-Citrulline + 2 nitric oxide + 4 H 2O + 3 NADP+
Nitric Oxide Synthase
As you can see, the main substrate is L-Arginine, so we will want to increase the amount of L-Arginine available to NOS. There is one issue with this, and that is that L-Arginine has poor bioavailability; so it is actually fairly hard to get a meaningful increase in L-Arginine plasma levels by just simply consuming L-Arginine. Luckily for us, L-Arginine is one of three amino acids that play a role in the urea cycle; a cycle which converts toxic ammonia into the relatively non-toxic urea. The other two amino acids that play a key role in the urea cycle are L-Ornithine and L-Citrulline. The basis of the urea cycle, is that ammonia is converted to carbamoyl phosphate which then enters the urea cycle. The carbamoyl phosphate is then converted to L-Citrulline, which then converts to an intermediary molecule called arginosuccinate before converting to L-Arginine. The L-Arginine is then converted to urea and L-Ornithine.
Urea Cycle Diagram
By supplementing with the highly bioavailable citrulline malate we can provide the urea cycle with excess L-Citrulline which will get converted to L-Arginine. This leads to a significant rise in plasma L-Arginine levels, which will then get converted by NOS to nitric oxide. Based on this, citrulline malate is currently the most highly regarded nitric oxide booster, as it leads to a very significant rise in nitric oxide. In addition to this, L-Citrulline speeds up the urea cycle which leads to more ammonia buffering.
Besides supplementing with citrulline malate, there have also been efforts made to improve the bioavailability of L-Arginine. The first of which, is to complex the L-Arginine with Alpha Ketoglutarate, a molecule that is involved in the urea cycle. Theoretically this should increase the efficiency of L-Arginine as a nitric oxide booster, whilst also promoting healthy mitochondrial function. Anecdotally, arginine alpha ketoglutarate (AAKG) is a great nitric oxide booster, however, there is very little concrete scientific evidence for AAKG. The second way to increase L-Arginine bioavailability, is to decarboxylate it. Decarboxylated L-Arginine is known as agmatine, which goes a step further than just enhanced bioavailability, since agmatine functions as a neurotransmitter and actually does not act as a substrate for NOS. Instead agmatine turns NOS on and off. More specifically, it blocks iNOS and nNOS whilst promoting the activity of eNOS. This has several advantages, as over activation of iNOS and nNOS can lead to inflammation and the eNOS activity is preserved which produces the vasodilation we are after. Agmatine sulfate is a favorite among those seeking a "pump" as it appears to produce one of the strongest sensation of blood rushing into the muscle during exercise when compared to the other nitric oxide boosters.
So which one do you choose? This really depends on your preferences at the end of the day, as all three are very efficacious nitric oxide boosters. If you would like to just take a small capsule and experience the vasodilatory effects, then agmatine sulfate is the best option. However, some people find that it has cognitive effects (mood boosting, calming and focus enhancement) that are not desirable in just a pure nitric oxide booster. If this is the case, then citrulline malate is a fantastic choice, as it will both be a very efficacious nitric oxide booster whilst also being an ammonia buffer which can stave off fatigue. The only issue with citrulline malate is that it is fairly sour and large doses of it need to be taken. In a homemade preworkout blend, it goes really well, by adding a sour tang that can cover up bitter flavors, especially when it is combined with one of our flavor packs. For those who would rather not deal with the sour flavor, an AAKG supplement is a great choice as it is completely tasteless. AAKG also has the potential added benefit of producing ATP by enhancing mitochondrial function. This is based on the fact that the alpha ketoglutarate in AAKG is used within mitochondria as an antioxidant and energy producer.
Various combination of all three can be used as well. By taking agmatine in combination with either AAKG or citrulline malate, we can potentially enhance the amount of nitric oxide that is produced via eNOS. This is based on the fact that agmatine diverts nitric oxide production away from iNOS and nNOS whilst enhancing nitric oxide output from eNOS, which at the end of the day we are after. Our recommendation would be to combine agmatine sulfate with citrulline malate. AAKG could also be combined with agmatine, however, we do not see much of a reason to combine both AAKG and citrulline malate as both simply enhance plasma arginine levels.
Learn more about L-Citrulline Malate, Agmatine Sulfate and AAKG by clicking the product jars below.