Dear blog readers and loyal PEAK customers, today marks the release of the second part of my blog series on blood circulation in our bodies. After explaining the basics of blood circulation and ways to influence blood flow through sports and training in Part 1, “Nitric Oxide (NO) – How Does Our Blood Circulation Work?”, it’s now time to take a closer look at the substance nitric oxide (NO). Many readers will pay particularly close attention toward the end of this post when it comes to whether the amino acid L-arginine actually leads to a significant increase in nitric oxide in bodybuilding. I would therefore like to preemptively note that my remarks refer to the biochemical processes and synthesis pathways. Although practical studies, research, and athletes’ testimonials suggest otherwise, I’d like to use this blog post to examine the potential effects of L-arginine from a theoretical perspective. It’s important to occasionally question the “god-given” praise heaped upon individual substances. I’d like to address this very point in today’s post.

The Effect of Nitric Oxide (NO) on Blood Flow

What Is Nitric Oxide (NO)?

NO is the chemical symbol for nitric oxide. It is the only known substance that functions both as an endogenous free radical and as a signaling molecule (including for signaling vasodilation). Nitric oxide has a complex effect, acting not only at the site of its production but also in surrounding tissues due to its very short half-life of just a few seconds. Due to its size, it is able to diffuse and can also accumulate in membranes. At physiological concentrations, it primarily performs beneficial functions and acts in both a regulatory and protective capacity. At excessive concentrations, it has a pathogenic (disease-causing) effect. There is also a risk that, in the presence of oxygen, it will react more vigorously with ions and radicals, contributing to cell damage and death.

How is nitric oxide formed?

In addition to L-arginine, the formation of nitric oxide requires enzymes known as NO synthases (NOS), oxygen, and other factors. The conversion of L-arginine to nitric oxide occurs in five distinct steps. The urea derivative L-citrulline is produced as a byproduct of nitric oxide synthesis. [caption id="attachment_6977" align="alignleft" width="580" caption="Illustration: Biosynthesis of nitric oxide"][/caption]

What are the properties of nitric oxide?

Nitric oxide is normally a colorless gas. As a radical, it has an unpaired electron but exhibits relatively low reactivity. Nitric oxide reacts with molecular oxygen, oxygen radical anions, peroxy radicals, and metals. Nitric oxide readily forms compounds, particularly with heme proteins (blood proteins). This bonding gives rise to substances (e.g., cytochrome P450 enzymes) whose primary function is to oxidize numerous endogenous and exogenous substances.

Nitric oxide has a half-life of only five seconds, which is why it must be constantly regenerated.

Where is nitric oxide found, and what is its function?

Nitric Oxide in the Vascular System

Nitric Oxide Synthesis via Calcium Ions Nitric oxide is synthesized as needed from the amino acid L-arginine. This synthesis requires the endothelial enzyme NO synthase, which is activated under physiological conditions by an increase in intracellular calcium concentration. The calcium concentration increases through an influx from the extracellular space and the release of calcium ions from intracellular stores. Endogenous mediators such as ADP, ATP, bradykinin, histamine, and serotonin, as well as exogenous mediators (medications), open the corresponding ion channels and enable the influx. Nitric Oxide Synthesis via Shear Force When an object is dragged across a surface, it deforms. This deformation is called shearing, and the force that attempts to return the object to its original shape is called shear force. Shearing and shear forces also occur during blood flow. Our blood flow is normally non-steady-state, meaning that the flow velocity changes over time because the heart pumps in pulses, causing the flow velocity to fluctuate. High flow velocity leads to high shear forces due to the resulting high friction.

High flow velocities and shear forces occur during physical exertion and trigger the release of hormones that cause blood vessels to dilate through the production of nitric oxide (NO).

Thermoregulation The prevailing external temperature also causes our blood vessels to adapt. In the heat, our blood vessels dilate; in the cold, they constrict.

PRACTICAL TIP

It is crucial to warm up the body sufficiently before exercise (warm-up) to ensure vasodilation based on body temperature right from the start. This is especially important during cold seasons!

What happens to the nitric oxide that is produced? The nitric oxide produced diffuses to the target cells, where it binds to a specific receptor (soluble guanylyl cyclase). The cellular targets of nitric oxide include various blood cells (e.g., platelets and granulocytes), as well as the vascular wall (smooth muscle cells and endothelial cells). By inhibiting platelet aggregation and adhesion, and through the relaxation of vascular smooth muscle cells, vasodilation (widening of the blood vessels) occurs. Platelet aggregation refers to the process by which platelets clump together. Platelet adhesion refers to the attachment of platelets to tissue with which they do not normally come into contact within intact blood vessels.

In addition to this short-term response, nitric oxide has long-term anti-atherosclerotic and antiproliferative effects (counteracting tissue proliferation), thereby maintaining vascular health.

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The Importance of Nitric Oxide in the Vascular System Nitric oxide, formed from L-arginine, is the most important regulatory and protective substance for healthy vascular structure. Arteriosclerotic diseases are most quickly identified by a disruption in NO-mediated endothelial function (the inner layer of blood vessels), in which too little nitric oxide is produced. Such a disruption is triggered, among other things, by elevated blood sugar levels, oxidative stress, or hyperhomocysteinemia (elevated homocysteine levels in the blood).

Nitric Oxide in the Nervous System

Nitric oxide acts as a neurotransmitter in the central nervous system. It is involved in memory regulation and learning ability. Nitric oxide is believed to be responsible for migraines and headaches. As a result of NO-mediated oxidative processes, protein modifications, cell destruction, and associated neurological disorders such as Alzheimer’s disease occur. Reactions with superoxide anions lead to neurotoxic processes affecting DNA and lipids. The far-reaching consequences of a stroke (ischemia) are also attributed to excessive NO production in the brain. Furthermore, nitric oxide is associated with Parkinson’s disease, Huntington’s disease (a severe brain disorder), and numerous autoimmune diseases. Is there a risk associated with taking NO boosters? The amino acid L-arginine can be taken orally, absorbed into the bloodstream, and cross the blood-brain barrier to enter the brain. As we have seen, an excessive amount of NO in the brain tends to have negative effects and can even lead to septic shock. Nevertheless, oral intake of L-arginine is less problematic because the levels of the specific NO synthase enzyme (iNOS) in the brain are significantly lower than in peripheral tissues (e.g., in blood vessels). Consequently, much less nitric oxide can be produced from L-arginine, so there is no risk.

Nitric Oxide in the Peripheral Nervous System

In the peripheral nervous system, nitric oxide influences the motility of the gastrointestinal muscles (digestive tract), penile erection, and the regulation of renal blood flow. The medication Cialis (similar to Viagra), for example, works by increasing nitric oxide levels, thereby leading to an erection. Nitric Oxide and Erectile Dysfunction (Erectile Problems) As nitric oxide diffuses into the muscle layer of blood vessels, it activates the enzyme guanylate cyclase located there. This causes the smooth muscle to relax and vascular tone to decrease. Relaxation of the vascular smooth muscle is a prerequisite for an erection in men.

Nitric oxide produced by arginine and NOS thus causes certain muscles to relax, which in turn allows blood to pool in the penis. This results in an erection.

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Nitric Oxide in the Immune System

Nitric oxide is part of the nonspecific immune defense. Signaling molecules of our immune system (inflammatory agents) activate the NOS enzyme. This allows macrophages (phagocytes) and granulocytes (a type of white blood cell) to produce large amounts of nitric oxide. Nitric oxide diffuses into the surrounding tissues, where it can help kill bacteria, fungi, and viruses. Nitric oxide has also been shown to have a growth-inhibiting and tissue-damaging effect on tumor cells. The NO synthase enzyme iNOS, which predominates in the immune system, is produced over the long term in inflammatory and infectious diseases. The nitric oxide released in high concentrations then contributes to the symptoms of these diseases. Thus, nitric oxide contributes, among other things, to the development of arthritis, inflammatory bowel disease, asthma, multiple sclerosis, Alzheimer’s disease, and meningitis. In septic shock, there is strong NOS expression, leading to an excessive production of NO. The result is massive vasodilation throughout the entire vascular system, which is associated with a massive drop in blood pressure. This can lead to multiple organ failure and, consequently, certain death.

Summary

Nitric oxide has a wide range of effects on various parts of our body. It plays a key role in maintaining the health of our blood vessels, helps prevent heart attacks through its anti-atherosclerotic function, and aids in treating erectile dysfunction. However, it also acts as a trigger for migraines. It supports our immune system in fighting viruses and bacteria. In the brain, it supports our learning ability and memory, but is also involved in degenerative brain diseases. Even cancer cells can be combated through its ability to inhibit tissue growth. In the event of a stroke, nitric oxide plays a key role in the destruction of brain tissue. It also triggers symptoms in the course of chronic inflammatory diseases such as rheumatism and is responsible for the onset of swelling, redness, and pain.

We will examine the question of whether and how we can influence nitric oxide synthesis for vasodilation through diet—in addition to exercise—after we have discussed the catalysts of nitric oxide, the NO synthases.

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NO Synthases

Isoforms

The enzyme nitric oxide synthase, or NO synthase (NOS) for short, is responsible for the formation of nitric oxide (NO) from L-arginine. In humans, NOS occurs in three isoforms. They differ in their localization (site of production), amino acid sequence, kinetics, regulation, and functional significance.

• eNOS (NOS3) endothelial NO synthase (related to blood vessels)
• bNOS (NOS1): neuronal NO synthase (involved in the brain)
• iNOS (NOS2): inducible NO synthase (related to the immune system)

eNOS and bNOS

eNOS and bNOS are regulated by their activity. They are constantly present. Although the activity of eNOS in blood vessels also depends on mechanical forces, regulation via intracellular calcium concentration is of paramount importance. Only when sufficient Ca²⁺ ions are present can the active form of the enzyme be formed.

iNOS

Although iNOS is always present in small amounts, its expression (production) is increased as needed. Following iNOS formation, rapid, intense, and long-lasting nitric oxide synthesis occurs. The amount of nitric oxide produced by iNOS can be up to 1,000 times higher than that produced by eNOS, but only if sufficient iNOS is formed. The binding process in iNOS is calcium-independent and therefore hardly regulatable. Bacterial toxins or inflammatory substances (IFN-γ or interleukin-1β) are two examples of iNOS triggers. Nitric oxide produced by iNOS serves the immune defense.

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Summary

We have seen, then, that there are several types of the NOS enzyme. Of particular interest to us bodybuilders is eNOS, which is primarily active in the blood vessels. If we succeed in maximizing eNOS synthesis, we have a good chance of also benefiting from supplementation with NO boosters in terms of increased nitric oxide synthesis. We’ll now examine whether this is possible in the concluding paragraph.

Influencing Blood Flow Through Diet and Supplements

As we have seen, physical exertion (training) has an extremely beneficial effect on nitric oxide synthesis. To a certain extent, we can also increase NO production through diet.

NO Synthase—The Limiting Factor in NO Production in Bodybuilding

A bodybuilder’s diet is typically very high in protein. In addition, we attempt to increase nitric oxide synthesis by taking NO boosters containing the amino acids arginine, citrulline, or other NO-enhancing substances. It actually seems logical that supplying the starting substrate for NO synthesis—namely, L-arginine—would lead to increased production. Unfortunately, this approach proves to be less efficient than expected, for two reasons: 1. Due to the already very high protein intake, one is already consuming sufficient L-arginine for nitric oxide synthesis. In this case, therefore, a single dose of arginine will not provide as much benefit as it would in a situation of deficiency in total protein and L-arginine. Such a deficiency is rare among bodybuilders. 2. Even if we consume arginine in large quantities through food and NO boosters, the actual limiting factor in NO production is the availability of the NOS enzyme required for conversion. The amount of this enzyme in our blood vessels is limited. As we have read, the regulation of eNOS does not occur through increased production but rather through calcium-dependent activation of the enzyme. Therefore, consuming high amounts of arginine does not automatically lead to the production of more NOS enzyme. L-Arginine and L-Citrulline In this context, supplementation with citrulline—which, according to studies, is converted into arginine in the body and can pass through the gastrointestinal tract more easily than L-arginine itself—is also not beneficial. Here, too, the problem of limited NO production due to a limited supply of NOS cannot be solved or circumvented.

So is supplementing with L-arginine pointless for increasing NO production?

Even though we cannot expect a drastic increase in NOS levels when total protein intake is already high, L-arginine, in combination with folic acid, vitamin B6, and vitamin B12, has the ability to enhance the activity of the existing amount of NOS. Through this effect, it is therefore still possible to trigger increased production of nitric oxide and the associated vasodilation, with all its benefits.

Other Ways to Influence Blood Flow

Milk

According to studies, lactokinins (specific whey peptides) in milk increase blood flow by inhibiting an enzyme that normally constricts blood vessels.

Carbohydrates

Carbohydrates consumed before a workout increase NO production in the blood vessel walls through enhanced insulin secretion.

Blood lipids

Maintaining healthy blood lipid levels has a significant impact on blood flow properties and thus also influences blood circulation.

Summary

NO (nitric oxide) is a substance with far-reaching effects on the entire body. In bodybuilding, we particularly benefit from its vasodilatory effect, which helps deliver more nutrients and active substances to the muscles and thus accelerates muscle growth. Through our training, we have a wide range of options for increasing NO production. Diet and supplements also offer the possibility of positively influencing blood flow. Unfortunately, this approach is not quite as effective as most of us would assume. As mentioned in the introduction, my explanations are based on biochemical facts regarding the synthesis pathways of nitric oxide. Since theory and practice do not always align 100%, it is up to each individual to decide use L-arginine to promote blood flow or not. As with many other supplements, there will be significant individual variation in effectiveness from athlete to athlete. Use is based on the “trial and error” approach. I wish all readers great athletic success. Yours, Holger Gugg www.body-coaches.de . . .