The Dark Side of Nitric Oxide

The importance of the nitric oxide pathway in human physiology came about with the discovery in the 1980s that it was the primary mechanism for dilation of blood vessels, vasodilation. Up until then, nitric oxide was a gaseous pollutant, a by product of industrial activity. Please don’t confuse nitric oxide, with nitrous oxide, or more commonly known as “laughing gas”. They are two very different substances; so for the rest of this post I’m going to use the official abbreviation NO when I refer to nitric oxide so you don’t think about laughing gas.

This was such an important discovery that in 1998 Robert F. Furchgott, Louis J. Ignarro and Ferid Murad were awarded the Nobel Prize in Physiology or Medicine.The citation for their groundbreaking work is one of the best explanations of the importance of NO:

“Nitric oxide (NO) is a gas that transmits signals in the organism. Signal transmission by a gas that is produced by one cell, penetrates through membranes and regulates the function of another cell represents an entirely new principle for signalling in biological systems. The discoverers of NO as a signal molecule are awarded this year’s Nobel Prize.”

In a bit of historical irony, the benefactor of the Nobel Prizes, Alfred Nobel, made his fortune by creating and patenting a method to stabilise the highly volatile chemical nitroglycerin. Later in his life he suffered from a heart condition for which his physician prescribed nitroglycerin. Nobel refused to take nitroglycerin because he had experienced first hand the devastating headaches it caused him to have. Oh, if only we could learn from history…

It was nearly 100 years from the stabilization of nitroglycerin to the discovery of the role NO plays in the physiology of all life on the planet. However, as with most things, the more we learn about it, the more complicated it becomes. The early investigations of NO painted a picture of all it’s benefits, despite Nobel’s intimate knowledge of his life long work on his physiology. As the research progressed, the darker side of NO began to reveal itself. Sure NO results in vasodilation, cell growth and adaptation, but an excess of NO was causing cellular fatigue, damage, and even death.

Today if you talk to a physician, depending on their specialty, they will paint NO as either the saviour or the devil. It just depends on what you are suffering from. For example the NO boosting drugs for erectile dysfunction have improved the lives of millions. On the other hand, in 2006 the testing of the NO boosting supplement L-arginine in victims of heart attack had to be terminated due to the high death rate compared to control subjects.

NO is highly reactive and potentially damaging, and it’s effects are difficult to predict. Research is starting to indicate that that nitric oxide–boosting nutrients may in fact be harmful and that in some ailments NO production should be decreased.

In broad terms, neurologists tend to align themselves with the negative consequences/decrease production school of thought.

Here’s where we need to head Master Yoda’s words:

“Be aware of the dark side. Fear, anger, aggression; the dark side of the force they are. Easily they flow, quick to join you in a fight. If, once you start down the dark path, forever will it dominate your destiny, consume you it will…”

yoda-667955_640If anything is quick to join you in a fight, it’s NO. It is primarily a stress response catalyzed by a group of enzymes known as nitric oxide synthases (NOSs). There are actually three types of NOSs which are produced by, and target different systems in humans:

eNOS– endothelial enzymes are found on the lining of blood vessels and are primarily responsible for vasodilation. The effects are usually short lived with NO production boosted along the scale of seconds to minutes.

iNOS– inducible and is produced by the cells of the immune system. They use NO to help kill invading pathogens, but it is released to the whole body. The period of NO induction can become chronic with excess NO production for up to weeks and months.

nNOS– neuronal are enzymes found in neurons where NO is a neurotransmitter and signaling molecule. The effects are usually short lived with NO production boosted for seconds to minutes.

Regardless of the pathway of induction and the enzymes used to make it, NO is produced. A picture is starting to emerge that it is the inducible NO that has a particularly dark side. The activity of iNOS, and thus its product NO, is greatly increased under the conditions of stress and trauma. It is now thought that the harmful effects of NO is the direct result of that produced through the iNOS pathway. The cells of the immune system can create excess NO for days to weeks to months, that gets dumped into the bloodstream looking for something to do.

NO synthesis pathway, while only recently discovered, is well known. The primary building block is the amino acid arginine. Arginine is a conditional amino acid, one that is needed in times of illness and stress. This is opposed to an essential amino acid which is one nine amino acids you get from food because the body can’t make them from base chemicals or a nonessential amino acid which your body can make even if you don’t eat it. And there you have it my friends, the pathway is fueled by an amino acid that is only needed in times of illness and stress.

Arginine is readily available in a balanced diet. Foods high in arginine include seeds & nuts, cereals & grains, and citrus & grapes. From this list I can see two common migraine triggers; orange juice and pistachio nuts. Most likely they are feeding the migraine beast.

You can always kick start a chemical reaction by adding more fuel. A warm fire is a great example of a chemical reaction involving oxygen. We are all familiar with the mechanisms to stop this chemical reaction:

  1. Remove the fuel – don’t add anymore wood.
  2. Remove oxygen – smother it with ashes.
  3. Remove the heat – heat is catalyzing the reaction so to stop it we throw something to absorb the heat like water.
  4. Stop the chain reaction – scatter the fire.

If we apply the same logical process to excess NO production we might be able to manage migraine frequency and/or severity:

  1. Remove the fuel – limit the uptake of the chemicals that drive the reaction.
  2. Remove the oxygen – not an option because we need that to live.
  3. Remove the heat – which is really remove the catalyst, or stop the enzymes from making NO. However we need NO to live, just not too much of it, so not an option.
  4. Stop the chain reaction – you could (A) take drugs that impede the reaction. Migraine abortive drugs do this by blocking the uptake of NO by blood vessels and stop them from dilating. They do nothing to reduce the excess production of NO which is causing the problem. Alternatively you could (B) not induce the production of NO with lifestyle choices, like not drinking alcohol.

So we are pretty much stuck with number 1; limiting our uptake of the chemicals that drive the reaction. In other words you don’t want to feed the beast by being careful of what you feed yourself.

The beast’s primary food is arginine. But when that’s gone and the pathway has been induced it will just keep on chugging along using other fuels, notably nitrates and nitrites. It’s not the first choice, but beggars can’t be choosers.

Next week I’ll provide you with some digestible information (yeah I did that on purpose) on sources of arginine, nitrates and nitrates in your diet. I’ll also provide you with suggestions on some lifestyle changes you can make to stop feeding the beast. In the meantime, here are three lifestyle changes you can make now:

Stop drinking wine. 23% of an adult’s daily nitrate and nitrite intake comes from wine. Wine not only feeds the beast, but pokes it by causing the liver to create excess NO when detoxifying alcohol.

Reduce high sources of natural nitrates and nitrites from your diet. Celery, rosemary and watermelon are the three highest sources of natural nitrates and nitrites. Simply drinking a watermelon juice daily for two weeks doubled NO in the blood stream compared to control and placebo (apple juice). Together these three form the Unholy Trinity for migraineurs. This is going to be one of the few times that I say this, but they are forbidden. Trust me, you can live without them. This weeks cooking post has some great tips for getting celery out of your diet and keeping the flavour of your dishes.

Eliminate artificial sources of nitrates and nitrites from your diet. I know this has been on the list every week but you really need to step away from the deli counter. Those lunch meats make up 10% of the daily dietary intake of nitrates and nitrites in adults, more in children.

I can hear the collective cry, “what do you mean I can’t drink and I have to take my lunch”. But if you commit to these two things you will cut your nitrate and nitrites by ⅓. That’s a huge amount. Don’t worry, I’ve got your back. If you look to the right you’ll see my Instagram feed, where on Wednesdays I post a packed lunch tip and on Fridays a new recipe for a mocktail. Don’t forget to follow me on Instagram, @headachefreefoodie. Sure, we’re not going to feed the beast, but we are going to enjoy my friends.

As always, whenever making lifestyle changes be sure and consult your healthcare team. Under no circumstances should you stop or start taking medication or supplements without your physicians consent.

Informed by science, cooked by you.

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