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 āthe pumpā 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 āthe pumpā, 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.
How Does Nitric Oxide Affect the Immune System?
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).
How Does Nitric Oxide Affect the Brain?
Within the brain, nitric oxide regulates blood flowĀ (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,Ā the excitatory amino acid glutamate, the most abundant CNS neurotransmitter, is an initiator of the reaction that forms nitric oxide.Ā 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 anĀ excitatoryĀ neurotransmitter. However, itĀ 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.Ā
What are the Three Forms of Nitric Oxide Synthase?
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.
I Want to Enhance Nitric Oxide Function, What Supplement Do I Use?
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 ā 2 L-Citrulline + 2 nitric oxide + 4 H 2O + 3 NADP+
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.
Consider an L-Citrulline Supplement
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.
What about taking an Agmatine or AAKG Supplement?
Besides supplementing with citrulline malate, there have also been efforts made to improve the bioavailability of L-Arginine. The first step involves complexing L-Arginine with Alpha Ketoglutarate, a molecule integral to the urea cycle. Theoretically this should increase the efficiency of L-Arginine as a nitric oxide booster, whilst also promoting healthy mitochondrial function. Anecdotally, AAKG is praised as a nitric oxide booster, but scientific evidence supporting its efficacy remains limited. The second way to increase L-Arginine bioavailability, is to decarboxylate it. Agmatine, derived from decarboxylated L-Arginine, surpasses enhanced bioavailability, acting as a neurotransmitter and not a substrate for NOS.
Instead agmatine turns NOS on and off. More specifically, it blocks iNOS and nNOS whilst promoting the activity of eNOS. Preserving eNOS activity avoids inflammation from iNOS and nNOS overactivation, promoting the desired vasodilation. Agmatine sulfate, favored for its strong ‘pump’ sensation, enhances blood flow into muscles during exercise more than other boosters.
How to Choose the Best Nitric Oxide Supplement
So which one do you choose? Preferences dictate choice; all threeāAAKG, citrulline malate, and agmatine sulfateāare highly effective nitric oxide boosters. For those seeking only vasodilatory effects in a small capsule, agmatine sulfate emerges as the optimal choice. Some may find cognitive effects like mood enhancement and focus undesirable when seeking a pure nitric oxide booster. In such a scenario, citrulline malate proves excellent, effectively boosting nitric oxide and buffering ammonia to combat fatigue.
Citrulline malate’s only drawback is its sourness, requiring large doses for effectiveness. In a homemade preworkout blend, AAKG adds a sour tang, masking bitter flavors, especially when combined with our flavor packs. For those averse to sour flavors, AAKG supplements offer a tasteless alternative, making them a great choice. 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 energy producer.
Should I Stack L-Citrulline, Agmatine and AAKG?
Various combination of all three can be used as well. Combining agmatine with AAKG or citrulline malate may enhance nitric oxide production via eNOS, potentially increasing its amount. Agmatine diverts nitric oxide production from iNOS and nNOS while enhancing output from eNOS, which aligns with our goals. Our recommendation would be to combine agmatine sulfate with citrulline malate. Combining AAKG with agmatine is an option, though we don’t find it necessary since both raise plasma arginine levels.
Also read our blog on DHA (docosahexaenoic acid)
