You are only as old as your endothelium

-- Paul VanHoutte, Mayo Clinic (1983)

Nitric Oxide - Protector of the Endothelium

(Lining of the Arteries)

In 1998, the Nobel Prize was awarded to three Americans (Robert Furchgott, Ferid Murad and Louis Ignarro) for their work in the discovery of Nitric Oxide as a key messenger in the cardiovascular system. They had discovered that several important functions relating to the health of the lining of the arteries were initiated by Nitric Oxide signals. They had also found that Nitric Oxide was produced in the cells that line the arteries (endothelium).

Further study has lead to greater understanding of the role of Nitric Oxide and the diseases created when its function is disturbed. The following diagram shows some of the functions of nitric oxide in preserving proper function of all the arteries in the body.

Firstly, the presence of Nitric Oxide allows arteries to dilate easily (vasodilatation) and provide necessary nutrients to tissues. Without Nitric Oxide arteries constrict and require a higher blood pressure to maintain adequate blood flow to the tissues. In addition, lack of Nitric Oxide results in an increase in the numbers of muscle cells (smooth muscle cell proliferation) which may result in higher blood pressure.

Secondly, Nitric Oxide reduces the stickiness of platelets, the blood elements that initiate blood clots. Without Nitric Oxide, platelets are more sticky and blood clotting occurs more easily. This can result in heart attacks, strokes and blood clots in the legs and pelvis which can migrate to the lungs.

Thirdly, Nitric Oxide reduces the stickiness of monocytes, a type of white blood cell which acts as a scavenger. These cells pick up debris from vessel injury and oxidized LDL cholesterol which is not soluble in blood. When these cells become sticky (adherent) they can stick to the lining of the blood vessel and enter the blood vessel wall. Here they become an important component of plaque which can block arteries.

Fourthly, Nitric Oxide suppresses oxidation of LDL cholesterol. When LDL cholesterol is oxidized it no longer floats in the blood stream, but drops out as a solid substance and is picked up by monocytes. This process can start or add to plaque.

Fifthly, when production of Nitric Oxide is inhibited by high levels of ADMA (see the following pages), production of superoxide radicals increases. This can cause damage to DNA and oxidize LDL cholesterol, once again adding to the production of plaque.

Figure 1: Effects of Nitric Oxide production on important endothelial functions.

In addition to its benefits to the endothelium, Nitric Oxide also stimulates growth hormone production. This tends to favor a body composition with reduced fat and more muscle.

How Is Nitric Oxide Made?

Nitric Oxide is made from an amino acid called L-arginine. Hundreds of amino acids are linked together to form proteins. When we eat proteins, they are broken down into individual amino acids and absorbed into the blood stream. In the body they are used to make new proteins or in the case of l-arginine, they can be used to make other substances.

Figure 2: L-arginine.

Once it is in the blood stream, l-arginine is taken up by an enzyme in the endothelium called Nitric Oxide Synthase (NO Synthase). This enzyme combines the l-arginine with oxygen (O2) producing Nitric Oxide.

Figure 3: Production of Nitric Oxide from l-arginine.

With adequate amounts of L-arginine in the diet combined with normal levels of Nitric Oxide Synthase and oxygen, there should never be a deficiency of Nitric Oxide in the blood vessels, except:

ADMA, the Central Link in Cardiovascular Disease

There is a constant process of protein production and protein destruction occurring in our bodies at any given time. Normally, the kidney is programmed to recognize amino acids and to save them, not allowing them to be excreted in the urine. There are times, however, like when we are ill, when the rate of breakdown of proteins is much higher than the rate of production. Since too many amino acids in the blood stream can make us very ill, the enzymes that break down protein tack on one or more messenger substances which fool the kidney and allow these “old” amino acids to be removed.

This messenger substance is called a “methyl group” It is basically a carbon atom attached to three hydrogen atoms which is substituted for one of the hydrogen atoms attached to the nitrogen atom at the end of the amino acid. With this methyl group in place, the kidney is permitted to get rid of the “old” amino acid.

If the levels of normal amino acids are not too high, the “methylated” amino acids are recycled by special enzymes in the liver which remove the methyl groups.

During the normal breakdown of protein, which occurs in every cell of the body, l-arginine, present in almost all protein, is changed chemically into a substance called ADMA (asymmetric dimethyl arginine). This is accomplished by adding two methyl groups to the end of the l-arginine molecule.

Figure 4: Comparison of l-arginine and its methylated cousin, ADMA.

How Does ADMA Affect Nitric Oxide?

Experimental studies in various laboratories around the globe have shown that ADMA inhibits Nitric Oxide production. The inhibition of Nitric Oxide production has been demonstrated to be concentration-dependent. This means that when the ADMA level increases and l-arginine levels remain the same, the production of Nitric Oxide decreases. The reverse is also true. If l-arginine levels are increased with dietary supplementation, the production of Nitric Oxide is restored and the effect of a high ADMA level is reduced or eliminated.

L-arginine fits into a specific binding site on the Nitric Oxide Synthase enzyme. This is mainly because of its shape (like a peg in the proper hole). Because ADMA is structurally similar to the l-arginine, it is also attracted to the same binding site. When ADMA levels increase, they compete with L-arginine for this binding site on the Nitric Oxide Synthase enzyme.

When ADMA occupies the L-arginine binding site, the methyl groups prevent the release of the nitrogen atom which must combine with oxygen to form Nitric Oxide. As a result, Nitric Oxide cannot be produced. This results in a loss of the protection which Nitric Oxide normally gives to the endothelium.

But there is more bad news!! Not only does the Nitric Oxide not get made, but in its effort to make the reaction happen, the enzyme gives an electron to the oxygen molecule, creating a Superoxide Radical. This highly reactive substance can interact with and change many compounds including DNA (increasing the risk for cancer) and LDL-cholesterol (producing plaque).

Figure 5: Effect of ADMA on Nitric Oxide synthesis. Production of superoxide radical.

The Role of ADMA

In the early 1990s, ADMA was reported to inhibit Nitric Oxide synthesis. Since that time the role of ADMA has studied by many groups of researchers throughout the world. Many researchers today agree that ADMA plays a central role in the production and in the progression of cardiovascular diseases - specifically those marked by formation of plaque in the arteries (atherosclerosis).

Many clinical studies have demonstrated the presence of an independent relationship between blood levels of ADMA and the incidence of major cardiovascular events or death. In Figure 6, several diseases have been highlighted in which elevations of ADMA are present.

Figure 6: Clinical conditions that have been reported to be associated with elevated ADMA concentration and for which there is data available supporting a role for ADMA in the production of the disease.

The measurement of ADMA levels in serum or plasma of a person can provide evidence for risk of cardiovascular disease which goes beyond the information gained by evaluating traditional risk factors (high blood pressure, high cholesterol or triglycerides, diabetes, family history of vascular disease). In fact, the production of ADMA may be the mechanism by which these traditional risk factors exert their destructive potential.

This graph demonstrates the inhibition of Nitric Oxide synthesis as ADMA levels increase. When ADMA levels are below 0.4, the Nitric Oxide production is more than 60% of maximum and persons are at low risk for cardiovascular disease.

When the ADMA concentration is above 0.4, the Nitric Oxide production falls below 60%. At this level, the endothelium loses its protective shield and risk for cardiovascular disease increases.