Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

Nitric oxide and asymmetric dimethylarginine

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The Wiki entries on nitric oxide and asymmetric dimethylarginine offer a lot of insight.

In the body, nitric oxide serves several roles, mainly involving small blood vessels. Nitric oxide is synthesized from L-arginine and oxygen by various nitric oxide synthase (NOS) enzymes. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. This phenomenon is thought to be central to endothelial health. A large percentage of humans are deficient in their manufacture of nitric oxide, placing them at increased risk of cardiovascular disease. This underlies the action of nitroglycerin, amyl nitrate and other nitrate derivatives in the treatment of heart disease: The compounds are converted to nitric oxide (by a process that is not completely understood), which in turn dilates the coronary artery (blood vessels around the heart), thereby increasing its blood supply. A chemical known as asymmetric dimethylarginine can interfere with the production of nitric oxide and is considered a marker of cardiovascular disease.

Macrophages, cells of the immune system, produce nitric oxide in order to kill invading bacteria. Under certain conditions, this can backfire: Fulminant infection (sepsis) causes excess production of nitric oxide by macrophages, leading to vasodilatation (widening of blood vessels), probably one of the main causes of hypotension (low blood pressure) in sepsis.

Nitric oxide also serves as a neurotransmitter between nerve cells. Unlike most other neurotransmitters that only transmit information from a presynaptic to a postsynaptic neuron, the small nitric oxide molecule can diffuse all over and can thereby act on several nearby neurons, even on those not connected by a synapse. It is conjectured that this process may be involved in memory through the maintenance of long-term potentiation. Nitric oxide is an important non-adrenergic, non-cholinergic (NANC) neurotransmitter in various parts of the gastrointestinal tract. It causes relaxation of the gastrointestinal smooth muscle. In the stomach it increases the capacity of the fundus to store food/fluids. Nitric Oxide

Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide, a key chemical to endothelial and hence cardiovascular health. […]

Asymmetric dimethylarginine is created in protein methylation, a common mechanism of post-translational protein modification. This reaction is catalyzed by an enzyme set called S-adenosylmethionine protein N-methyltransferases (protein methylases I and II).[2] The methyl groups transferred to create ADMA are derived from the methyl group donor S-adenosylmethionine, an intermediate in the metabolism of homocysteine. (Homocysteine is an important blood chemical, because it is also a marker of cardiovascular disease). After synthesis, ADMA migrates into the extracellular space and thence into blood plasma. [..]

ADMA concentrations are substantially elevated by native or oxidized LDL cholesterol.[3] Thus a spiralling effect occurs with high endothelial LDL levels causing greater ADMA values, which in turn inhibit NO production needed to promote vasodilation. The elimination of ADMA occurs through urine excretion and metabolism by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. Asymmetric Dimethylarginine

The “cardiovascular” effect of NO is basically vasodilation. Asymmetric dimethylarginine is being painted as a bad guy for reducing vasodilation in people with heart disease, however, too little is as bad as too much.

I wonder if too much nitric oxide is a problem, particularly as an inhibitor of the enzyme that converts homocysteine to methionine, as per my last post. The fact that ADMA is produced in the presence of SAM (derived from methionine) when methylation is increased, is part of an interesting feedback loop that could be out of sorts.

If levels of nitric oxide are a problem, I wonder if this would explain why nitrate and nitrite additives cause reactions in the food chemical intolerant, by further supplying fuel to the NO fire? Or are nitrates interfering with the production of NO and the opposite is true? This is of course pure speculation. Nitric oxide may just be a symptom of something else. It would also contradict the asthma issue, for which nitric oxide is extremely important in relaxing the bronchi.

Unfortunately for those of us relying on potatoes, one of the highest sources of natural nitrates and nitrites (even higher than the average additive-containing slice of bacon) is potatoes grown in artificially fertilised soil.

Folks with food chemical intolerance tend to have too much vasoconstriction: histamine, serotonin, dopamine, and tyramine all have vasoactive effects and lead to some of the unpleasant effects we experience, from skin flushing and inflammation, to varicose veins and headaches. Tyramine is a vasoconstrictor. Histamine is supposed to have mediatory effects. Perhaps nitric oxide levels are high for the same reason? And this then inhibits methylation?

Serotonin has a perverse effect, it can produce both vasoconstriction and vasodilation, depending on the receptors present. Serotonin migraines seem to be produced firstly by constriction, then the pain occurs on dilation.


Written by alienrobotgirl

19 April, 2006 at 10:39 am

Posted in Methyl Donors

2 Responses

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  1. Brecht

    30 December, 2007 at 5:43 pm

  2. Thanks Brecht, a great link. Yasko tests for a low NO production gene in autism. I was interested to read the comment that low NO production might lead to underconnectivity in the brain leading to low IQ type autism. Very interesting. Just goes to show, some people have too much NO, others have too little.

    Alien Robot Girl

    30 January, 2008 at 3:29 pm

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