Published December 22 2014
Nitric oxide is a cellular signaling molecule which has many important roles in the body. Not only is it important for maintaining normal blood pressure, but it also is important for neurotransmission, the health of the mitochondria, it plays a role in platelet function, and it can modulate the immune system, which therefore can be a factor for those people with autoimmune thyroid conditions. The information in this article admittedly might be advanced for some people, but later in this article I’ve listed a brief summary which hopefully will clarify the important points.
Just so there is no confusion, nitric oxide is different from nitrous oxide, which is also known as “laughing gas”. There are at least two known physiological pathways in which nitric oxide (NO) synthesis occurs, which is NO synthase (NOS) dependent and NOS independent (1) [1]. The amino acid L-arginine is responsible for the synthesis of nitric oxide, as it is oxidized to nitric oxide by the action of the NOS enzymes (1) [1]. L-citrulline has been indicated to be a secondary NO donor in the NOS-dependent pathway, and the reason for this is because it can be converted to L-arginine (1) [1].
There are three different forms of nitric oxide:
1. Neuronal nitric oxide synthase (nNOS). This type of nitric oxide is important for optimal brain health, and helps to stimulate neurogenesis (2) [2], which is the formation of cells of the nervous system.
2. Endothelial nitric oxide synthase (eNOS). This type of nitric oxide is found in the lining of the blood vessels, and it has numerous biological properties which help to maintain vascular homeostasis, including modulating the tone of the blood vessels, supporting blood flow, and it protects the vessel from injury (3) [3]. Certain conditions result in a decrease in eNOS such as high blood pressure, high cholesterol, smoking, diabetes, and heart failure (3) [3].
3. Inducible nitric oxide synthase (iNOS). Once this type of nitric oxide is activated it leads to tissue destruction and inflammation, and therefore contributes to pathological conditions (4) [4]. So whereas neuronal and endothelial nitric oxide synthase are beneficial, inducible nitric oxide synthase can be harmful to your health. Keep in mind that low levels of iNOS aren’t necessarily a bad thing, especially when someone has an infection. On the other hand, since iNOS promotes inflammation, too much of this type of nitric oxide isn’t a good thing for someone who has an autoimmune thyroid condition. So just as is the case with everything else, it comes down to balance, as you want to have a proper balance of nNOS, eNOS, and iNOS.
So the question you should have at this point is “how can I increase the levels of nNOS and eNOS, while reducing the levels of iNOS?” This is an important question to answer, especially for those with an autoimmune thyroid condition, and it’s something I’ll discuss towards the end of this article.
The Relationship Between Nitric Oxide and Thyroid and Autoimmune Thyroid Conditions
A few studies have shown a relationship between thyroid hormone status and nitric oxide. One study in rats looked at the effects of hypothyroidism and hyperthyroidism and nitric oxide (5) [5]. The study showed that the hyperthyroid state was associated with increased formation of nitric oxide, but there was a reduced capacity for responding to nitric oxide when compared to the hypothyroid state. The same study showed that both eNOS and nNOS protein expression were modulated in hypothyroidism and hyperthyroidism in a manner consistent with NOS activity. Another rat study showed that thyroid hormones affect the level and activity of nNOS (6) [6]. Another study showed that the nitric oxide pathway might play a crucial role in the pathophysiology of thyroid dysfunctions (7) [7]. This was yet another rat study, and it admittedly would be nice to see some human studies.
I briefly mentioned earlier how nitric oxide plays a role in modulating the immune system, which can be important for those people with Graves’ Disease and Hashimoto’s Thyroiditis. First of all, nitric oxide plays a role in eradicating pathogens, as what happens is that activated macrophages inhibit pathogen replication by releasing a variety of molecules, which include nitric oxide (8) [8]. However, other immune system cells produce and respond to nitric oxide, and in addition to helping to eradicate pathogens, nitric oxide also regulates the functional activity, as well as the growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils, and natural killer cells (8) [8]. Since certain pathogens can trigger autoimmunity, nitric oxide can potentially help to prevent autoimmunity through the eradication of pathogens.
However, nitric oxide also affects the Th1/Th2 balance (9) [9] (10) [10], and this is directly related to autoimmunity. In fact, nitric oxide has both pro-inflammatory and anti-inflammatory roles. Under normal physiological conditions nitric oxide will have more of an anti-inflammatory role. I’ve spoken about Th1 and Th2 dominance in my blog post entitled “The Role of Cytokines In Autoimmune Thyroid Conditions [11]“, and one study showed that low levels of nitric oxide may favor Th2 dominance, and high nitric oxide may augment Th1 responses (11) [12].
A Brief Summary of The Role of Nitric Oxide
Since some of this information is somewhat advanced I’m guessing that some people might be a little bit confused, and so I’d like to briefly summarize the role of nitric oxide. Once again, nitric oxide has numerous functions, but with regards to thyroid health, it’s important to understand that thyroid hormones can affect the formation of nitric oxide. HOW? With regards to the immune system, nitric oxide plays a role in eradicating pathogens, and it also influences the Th1/Th2 balance, which relates to autoimmunity. If nitric oxide is too high or too low then this not only can decrease the body’s ability to eradicate pathogens, but it can shift someone to a Th1 or Th2 dominant state, which in turn can increase the risk of developing an autoimmune condition such as Graves’ Disease or Hashimoto’s Thyroiditis.
How Can Nitric Oxide Levels Be Balanced For Optimal Immune System Function?
Okay, so let’s get back to the question I asked earlier, which is “how can you increase the levels of nNOS and eNOS, while reducing the levels of iNOS?” Since arginine is a precursor to nitric oxide some people will supplement with this, and while this can increase the levels of nNOS and eNOS, it can also increase the levels of iNOS. Dr. Datis Kharrazian, author of the excellent book “Why Do I Still Have Thyroid Symptoms When My Lab Tests Are Normal?”, has written an article on nitric oxide [13], and in this article he talks about how recycling glutathione and taking certain nutrients to modulate nitric oxide can help. According to Dr. Kharrazian these include adenosine, huperzine A, vinpocetine, alpha Glycerylphosphorylcholine (Alpha GPC), xanthinol niacinate, Acetyl-l-carnitine.
The research does show that increasing glutathione levels can offer protection against potential damage caused by nitric oxide (12) [14] (13) [15] (14) [16]. And so this is yet another reason why it’s important to do things to increase glutathione levels. With regards to the other nutrients mentioned by Dr. Kharrazian, you might wonder if you need to take all of these to balance the “good” and the “bad” nitric oxide levels. Well, the way most of these nutrients help is by increasing activity of the neurotransmitter acetylcholine, and this in turn can increase eNOS and nNOS levels while decreasing iNOS levels. While taking all of these nutrients can be beneficial, in most cases it isn’t necessary. Often times doing things to increase glutathione levels alone will be sufficient to balance the nitric oxide levels. With that being said, if someone is having problems suppressing the autoimmune response, then they might want to take some of these other nutrients. Based on the research I’ve done I’d start with acetly-l-carnitine and hyperzine A, or there are also formulations which include all of the ingredients Dr. Kharrazian discussed in his article.
In summary, nitric oxide plays an important role in maintaining normal blood pressure, neurotransmission, mitochondrial health, platelet function, and it also can modulate the immune system. The three different forms of nitric oxide include neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS). Most people with autoimmune thyroid conditions have higher levels of iNOS, which is pro-inflammatory, and therefore they need to decrease the levels of iNOS, while increasing the levels of nNOs and eNOS. Increasing glutathione levels alone might help with this, although certain nutrients might also be necessary to take in some cases, including huperzine A, vinpocetine, alpha Glycerylphosphorylcholine (Alpha GPC), xanthinol niacinate, and acetyl-l-carnitine.