# Nitric oxide

Category: Drugs & Compounds

Nitric oxide is a free radical gas that Ray Peat treated as a fundamental metabolic toxin, analogous in its action to carbon monoxide and cyanide. Peat argued that its primary mechanism of harm is the poisoning of mitochondrial respiration, specifically by blocking the enzyme…

8 passages · 2 authors · 2014–2016 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/nitric-oxide

## Synthesis

**Nitric oxide** is a free radical gas that Ray Peat treated as a fundamental metabolic toxin, analogous in its action to **carbon monoxide** and **cyanide**. [Source 3, 8] Peat argued that its primary mechanism of harm is the poisoning of mitochondrial respiration, specifically by blocking the enzyme *cytochrome c oxidase* and other electron transport components, which shuts down oxidative energy production. [Source 3, 8] This interruption causes electrons to back up, shifting the entire cell into a *reduced chemical state* and creating a condition of reductive stress that promotes the leakage of electrons and further free radical damage. [Source 2, 8] Although the body produces nitric oxide endogenously, Peat emphasized that it was first known as a toxic component of smog, and its internal production should be viewed as a dangerous, primitive adaptation rather than a health-promoting molecule. [Source 1, 8]

The physiological role of nitric oxide is that of an **emergency vasodilator**, deployed when the organism cannot produce sufficient **carbon dioxide** to properly relax blood vessels. [Source 4] Georgi Dinkov has explained that both gases regulate vascular tone by controlling calcium levels in cells, but carbon dioxide is the preferred, non-pathological mechanism, while nitric oxide is a compensatory response to a perceived state of *hypoxia* when oxidative metabolism is failing. [Source 4] Peat documented that this emergency system becomes destructive when chronically activated, as nitric oxide is a central damaging agent in the dopamine system in Parkinson's disease, a killer of insulin-producing beta cells in the pancreas leading to diabetes, and a promoter of cancer growth by stimulating cell division in the absence of sufficient energy. [Source 1, 2, 3] The muscle growth touted by bodybuilders using arginine supplements is, in Peat's view, an inflammatory and hypoxic process akin to putting a tourniquet on a limb, forcing cells to divide because they lack the energy to perform differentiated functions. [Source 5]

Peat traced a distinct chronology in the scientific perception of nitric oxide, noting that from its discovery in the body in the late 1980s until the mid-1990s, research clearly demonstrated its toxicity, including massive documentation of its role in killing pancreatic beta cells. [Source 1, 3] He argued that this understanding was abruptly inverted around 1997 when the patent and marketing for **Viagra** (sildenafil) created a financial incentive to reframe nitric oxide as a wonder molecule associated with virility, leading to a flood of publications touting its protective effects. [Source 1, 3, 8] After the initial wave of publicity subsided, Peat observed that research began to re-acknowledge its role in producing diabetes, heart failure, and the fibrotic degeneration of aging. [Source 6, 8] He noted that the age-related loss of muscle, gain of fat, decreased insulin sensitivity, and collagen deposition in arteriosclerotic arteries are all produced by increased nitric oxide. [Source 6]

The body's natural regulation of nitric oxide is hormonally controlled, with **estrogen** exciting and activating the nitric oxide synthase enzyme, while **progesterone** and related neurosteroids like **pregnenolone** inhibit its production and stabilize the cell. [Source 2] Peat highlighted that nitric oxide impairs the oxidation of glucose, creating a state of *aerobic glycolysis* that mimics cancer metabolism, and that its excitatory effects on the parasympathetic nervous system can paradoxically lead to vascular spasms, variant angina, and transient ischemic attacks. [Source 6, 7] The accumulation of nitric oxide, combined with the reductive stress from blocked respiration, is implicated in the pathology of Alzheimer's disease and other degenerative conditions. [Source 6] Peat suggested that therapeutic intervention involves using substances that block these energy-limiting systems to restore full oxidative energy production. [Source 7]

## People also ask

### How does nitric oxide damage cellular energy production?

Peat argued that nitric oxide poisons mitochondrial respiration by blocking cytochrome c oxidase, which shuts down oxidative energy production and creates a state of reductive stress that promotes further free radical damage.

### Why did Peat consider nitric oxide an inferior vasodilator compared to carbon dioxide?

Peat viewed nitric oxide as an emergency vasodilator deployed during hypoxia when carbon dioxide production fails, making it a compensatory and potentially destructive mechanism rather than the preferred, non-pathological way to regulate blood vessel tone.

### What role did Peat believe estrogen played in nitric oxide production?

Peat noted that estrogen excites and activates the nitric oxide synthase enzyme, while progesterone and related neurosteroids inhibit its production, positioning hormonal balance as a key regulator of nitric oxide levels in the body.

## Related concepts

- [Methylene blue](https://bioenergeticoracle.com/md/concepts/methylene-blue/index.md)
- [Tetracycline](https://bioenergeticoracle.com/md/concepts/tetracycline/index.md)
- [Erectile Dysfunction](https://bioenergeticoracle.com/md/concepts/erectile-dysfunction/index.md)
- [Glycation](https://bioenergeticoracle.com/md/concepts/glycation/index.md)
- [Growth Hormone](https://bioenergeticoracle.com/md/concepts/growth-hormone/index.md)
- [Histamine](https://bioenergeticoracle.com/md/concepts/histamine/index.md)

## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — Digestion and Emotion KMUD January 2015

Ray Peat · Interview · 2015 · https://www.youtube.com/watch?v=nFxqSK5DC8Y

> **Andrew Murray:** So Dr. Peat, you've looked at and interpreted the link, then, between sort of decreased mental performance and poor digestion with the endotoxin formation especially from starch. I'm glad you brought up Nitric Oxide because again when I was looking up some articles this afternoon, I think you need to bring this out as a fairly important point because I think just like sugar, and just like polyunsaturates, both of which...well, sugar was demonized , and polyunsaturated fats were promoted so the liquid oils, the polyunsaturates have now definitely swinging the other way - even medical opinion is of the mindset now that maybe saturated fats are actually much better for the cells, much more stable, and more health promoting than the polyunsaturates, but it's taking a long time. Maybe, I think, sugar perhaps in time will come around again - but, it seems at the moment that nitric oxide is a pretty prevalent supplement - or, rather, the l-arginine that nitric oxide is manufactured from is becoming a fairly supplement, especially in the body building world. I wanted to ask you - given that these things are so freely available, and publications - numerous publications - even so-called scientific journals are coming out with studies that support nitric oxide's importance, and saying that it's extremely important for endothelial health, so the inner lining of the arteries, arterioles, etc. is the endothelia, and nitric oxide is produced within that to prevent things like stroke, angina, and a whole other host of cardiac events that would be considered causative without nitric oxide in terms of the kind of starvation, as it were, because the vasoconstriction that would happen, because nitric oxide is a vasodilator, but yet there's so much evidence contrary to that, and that's what I'd like you to bring out. Why is nitric oxide so dangerous because I know it's been implicated in stroke in people who used Viagra, for example?
>
> **Ray Peat:** Ya, I just recently heard about a doctor who treats cancer patients with intravenous arginine. Just before I heard about him, I had been reading way back to the 1940s, people discovered that arginine stimulate cancer growth, and starvation or reduction of arginine stops cancer growth. Through the 50s and 60s continuing - it's being picked up again just recently - methods to stop the conversion of arginine to nitric oxide, or to reduce the availability of arginine, it's being investigated again as a way to cure cancer. So, there are these two very opposite things going on. One is nitric oxide is being proposed to cure cancer; or suppressing nitric oxide - it's demonstrated to stop the growth of cancer. The first things that I was hearing about nitric oxide, I happened to be interested in endogenous carbon monoxide in the early to mid-80s. It can promote cancer by blocking the respiratory enzymes. And then in the mid and late 80s, people started realizing that something was producing nitric oxide in the body. It was '88 or '89 when the enzyme was demonstrated that we actually have the enzyme that makes this smog-like free radical in our tissues. Because it was already known as a major toxin in smog, immediately people were investigating what it's really doing in the body. From about 1990 up until the middle '90s there are many publications showing that very clearly nitric oxide produced in the pancreas kills insulin-producing beta cells. That was just massively documented up until about '96. Then, the Viagra people, they got a patent and started promoting the idea that somehow nitric oxide is associated with virility. Suddenly the research, by the late '90s, was turning just 180 degrees saying everything that nitric does must be wonderful because it is related to male virility.

### Source 2 — Nitric Oxide

Ray Peat · Interview · 2014 · http://l-i-g-h-t.com/files/herb-doctors-nitric-oxide.mp4

> **Andrew Murray:** OK, so in general the nitric oxide forms are pretty energy wasteful mechanism and also damaging in its free-radical producing effects.
>
> **Ray Peat:** Yeah, this shift of the whole cell away from oxidation starts that whole process that people are still just starting to put together the whole picture of how it fits in to physiology. But it has its effects on the nervous system that people are now seeing that Parkinson's Disease, for example, has the signs that nitric oxide is one of the central damaging components of the dopamine system.
>
> **Andrew Murray:** You're listening to KMUD......So, so far as the damaging effects of nitric oxide are concerned, I think there is three species of nitric oxide and the one I think that's most commonly referenced in PubMed and other scientific literature for its effects, both negative and for that small beneficial effect of its energy burst effect on bacteria etc is the inducible nitric oxide synthase, and that's been implicated in causing an increased severity of disease in quite a few different models, one of which was a Herpes simplex model, encephalitis, which is a brain inflammation in mice, and then I saw other references as well to chronic viral hepatitis in man as definitely being aggravated by nitric oxide and potentially nitric oxide suppression might be a useful treatment for people suffering from chronic hepatitis. What are the most reasonable ways of blocking nitric oxide synthesis in the body or at least managing its production and providing a buffer to it so that you can maintain the little nitric oxide that is beneficial whilst keeping in check any excess.

### Source 3 — Current Trends in Nitric Oxide KMUD 2015

Ray Peat · Interview · 2015 · https://www.youtube.com/watch?v=6TquRcpR8RY

> **Ray Peat:** My dissertation in 1972 focused on estrogen, but I saw that the effects of estrogen where indistinguishable from effects of x-rays and aging and oxygen deprivation. And how that works is, that it changes the oxidative enzyme function (cytochrome c oxidase). And it was known that smog produces nitric oxide. It wasn't known that it occurred naturally in the body until the late 80s. But the effects of nitric oxide in smog were known to inhibit or damage that same respiratory enzyme. And at the time I was studying estrogen, it was known that carbon monoxide and cyanide also block the effect of oxygen in the cell. And so, no-one really thought about what nitric oxide was doing to the cell, except when they were exposed to a lot of smog. As soon as it was discovered that it is produced in the body, a series of publications over the next six or seven years, up until the late 90s, identified the harm that it did in the various tissues. For example, several papers clearly showed how it... ..inflammation or stress increasing nitric oxide, damages the insulin-producing cells in the pancreas. So, it's a major cause of diabetes, regardless of the particular person's history leading to diabetes. Not only damaging the cells in the pancreas, but they were seeing similar damage to every tissue they looked at, which seemed logical since it was a free radical, analogous to cyanide and carbon monoxide in its function in the cell. But then someone noticed that nitric oxide causes vasodilation during arousal and erection. And Viagra came on the scene with tremendous amount of funding for research.

### Source 4 — Nitric Oxide and Methylene Blue [Generative Energy #11]

Danny Roddy · Interview · Nov 1, 2015 · https://www.youtube.com/watch?v=GgeZJoir70w

> **Georgi Dinkov:** I think nitric oxide, some of the views that mainstream medicine has on that are legitimate in that it's produced by the organism, both in health and in disease, and it does have a physiological role. I think where modern medicine tends to go astray in the sense that it tries to elevate the levels of nitric oxide to a point where they become directly contributing to pathology. Nitric oxide, just like glycolysis, can be thought of, and there's a good reason for this parallel, they actually mimic each other very well and they induce each other, so to speak. Nitric oxide can be thought of as an emergency substitute for carbon dioxide. So it's the primary so-called endothelial-derived relaxing factor. In other words, when your body perceives a virtual state of hypoxia, there are cells that are lining your blood vessels that express the enzyme called nitric oxide synthase, and they'll synthesize nitric oxide from the amino acid arginine, which is one of the sources. or from dietary nitrates which you ingest with food such as protein and some vegetables like beets. Basically, these cells will produce nitric oxide and this is an emergent situation where your body does not have enough carbon dioxide to dilate the blood vessels, which is its preferred way. That's how it's usually done in a way that doesn't contribute to pathology. And the mechanism behind it is nitric oxide and carbon dioxide both regulate the amount of calcium in the cells. So the relaxation is basically getting the calcium out of the cell. And the correct way to do it is elevating the levels of carbon dioxide. But in an emergency situation where metabolism is not working properly, because as we know, proper levels of carbon dioxide cannot be maintained if oxidative phosphorylation is working well.

### Source 5 — Herb Doctors: Current Trends On Nitric Oxide

Ray Peat · Interview · Oct 16, 2015 · http://l-i-g-h-t.com/files/herb-doctors-current-trends-on-nitric-oxide.mp4

> **Sarah Murray:** So amongst all the things taunting that nitric oxide are good for, is there any thread of truth to these statements?
>
> **Ray Peat:** Of the things you mentioned, it actually does one of those things, which is to make muscles grow. But that's one of the things that Szent-Györgyi and Otto Warburg understood 50 years ago.
>
> **Andrew Murray:** Is that because of inflammation?
>
> **Ray Peat:** In the absence of oxygen, life can't do anything but grow and divide. So anything that blocks the cytochrome c oxidase, blocking oxidative metabolism, tends to stimulate cell division. Because that's all life can do on the lactic acid producing cycle. And experiments both with nitric oxide supplement, or creating the condition such as cutting off the blood supply to cause muscle tissue to produce its own excess nitric oxide, they found that it stimulated the multiplication of cells in the muscle. The satellite cells surrounding the muscle fiber itself multiply under the influence of nitric oxide, or simply hypoxia leading to lactic acid production.
>
> **Sarah Murray:** So it's a very inflammatory process even though they are describing it as something that is wonderful; you’ll increase your muscles if you take supplements that are precursors for nitric oxide production.

### Source 6 — Nitric oxide, aging, and adaptation — the Procrustean adaptogen

Ray Peat · Newsletter · 2016

> Nitric oxide, by blocking the oxidation of glucose, creates aerobic glycolysis. The amyloid protein that accumulates in Alzheimer's disease promotes aerobic glycolysis. Recent studies have discussed the importance of reductive stress for the development of Alzheimer's disease (Lloret, et al., 2016; Badia, et al., 2013).
>
> When the oxidation of glucose is impaired, with fatty acids being oxidized for energy, there is usually a decrease in the overall metabolic rate, as well as a shift toward a more reductive biochemistry. At an extreme, the reductive energy derived from aerobic glycolysis can be consumed by the synthesis of fat, permitting glycolysis to proceed, and this can lead to cancer cells that oxidize fatty acids for energy, while converting glucose to fats and lactic acid.
>
> With aging, as the metabolic rate decreases, the ratio of glucose to fatty acids oxidized also decreases, yet the abdominal fat increases. In unusually long lived people, these features were more like the younger adults, with higher oxygen consumption and carbon dioxide production, higher respiratory quotient, lower proportion of body fat and lower waist fat (Rizzo, et al., 2005). In postmenopausal women, a lower respiratory quotient is associated with a higher risk of breast cancer (Prentice, et al., 2013). High estrogen (increasing NO, interfering with glucose oxidation) lowers the respiratory quotient, so that observation isn't surprising.
>
> Nitrate and nitrite, which are formed in the body when nitric oxide is oxidized, themselves reduce the metabolic rate (Pawlak-Chaouch, et al., 2016). These are being found increasingly in food and water, where they are thought to contribute to hypothyroidism and cancer (Mitacek, et al., 2008; Wang, et al., 2015; Njeze, et al., 2014).
>
> Some of the obvious changes of aging, such as loss of muscle (Martinez-Moreno, et al., 2007) and gain of fat (Bahadoran, et al., 2015) and decreased sensitivity to insulin (Ropelle, et al., 2013), are produced by increased nitric oxide.

### Source 7 — Nitric oxide, aging, and adaptation — the Procrustean adaptogen

Ray Peat · Newsletter · 2016

> For example, by reducing the body's metabolic rate and oxygen consumption, the heart's work is reduced. Investigations between the 1930s and 1960s (Geumei, et al., 1969) found that nitrite constricts the liver's vascular system, reducing the return of blood to the heart, directly reducing the heart's pumping action.
>
> Nitric oxide has an action on the heart that directly related to the blood vessels. When the parasympathetic nerves act on the heart, slowing and weakening its contractions, they are releasing nitric oxide, which reduces the heart's oxygen consumption as well as its energy production.
>
> The effects of nitric oxide on the heart resemble those produced by shock, and those that occur during heart failure, namely, a weakening of both contraction and relaxation (Kalk, et al., 2008; Jessup, et al., 2011; D'Annuzio, et al., 2012), and a loss of, or inversion of, the "staircase" effect, in which force of contraction normally increases with frequency of contraction.
>
> Stimulation of the parasympathetic nerves to the heart can cause a vascular spasm, resulting in heart pain. The parasympathetic nervous system is more active during the night, and this kind of "variant angina" usually happens at night, rather than during exercise. I suspect that this can be explained in terms of the aerobic glycolysis and pseudohypoxia created by nitric oxide.
>
> The impairment of relaxation of the heart by NO is analogous to the rigor or contraction that occurs in smooth muscle during deprivation of oxygen and/or glucose. Ordinarily, parasympathetic nerves produce relaxation, but in a situation of prolonged or inescapable stress, intensified parasympathetic action and accumulation of nitric oxide, the state of reductive stress, pseudohypoxia, probably leads to the vascular spasms of angina pains, transient ischemic attacks in the brain, and worse.
>
> There are other situations in which nitric oxide has an excitatory effect. For example, it's associated with brain arousal, waking, and rapid eye movement (REM) sleep (Marino and Cudeiro, 2006). The amount of nitric oxide in the exhaled breath rises during the night, with the peak around 7 AM (Mattes, et al., 2002).

### Source 8 — Nitric Oxide

Ray Peat · Interview · 2014 · http://l-i-g-h-t.com/files/herb-doctors-nitric-oxide.mp4

> **Ray Peat:** Speaking of poppers, several of the early theorists of AIDS were blaming it on whatever the chemical is, I guess it's nitric oxide, that's produced from the poppers, some kind of nitric compound anyway, and they were arguing that that in itself was enough to account for the AIDS among the people who were using that as a pleasure drug. But in the 1980s, everyone knew nitric oxide primarily as a toxic component of smog, and so when people started discovering that it was being produced in small amounts in the body, immediately they started looking for the parallels with smog poisoning: lung injury, circulatory disease and so on. And one of the first things they found was that it kills the beta cells in the pancreas that produce insulin, so in early 1940s there was this flurry of papers demonstrating that our internal smog is just as toxic as Los Angeles smog! But then the Viagra patent and publicity came out in the later 1990s and right then suddenly the medical publications all found that it was a glorious, protective and natural or protecting just about every function you could think of, making you smarter, have more endurance and all kinds of good things. But then, after a few years, I guess the investment in publicity started wearing off and people started coming back to the diabetes-producing effects and looking at what it's actually doing biochemically. The basic way it causes harm probably is that it is kind of parallel to the effects of carbon monoxide or cyanide, in being a competitor for oxygen in the mitochondria, the enzymes that produce most of our energy. It, in several ways, knocks out not only the key final respiratory enzyme, cytochrome oxidase, but it poisons the previous electron transporting parts of the mitochondrion too. So, simply turning off the energy supply can account for a lot of its problems.

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