Ohhh NO, not Nitric Oxide.
If only we were cars, it wouldn’t matter so much what kind of toxic sludge built up within, when using energy and moving around. Just grab some engine degreaser and a hose, and all will be well. But as living, breathing organisms, it does matter.
Yes stress is unavoidable, and metabolic responses to stress aren’t always optimal. But over time, how metabolism is able (or unable) to deal with stress, can produce things that have a cumulative effect, interfering with overall health and performance. Nitric oxide (NO) is one of those things, and you can’t simply flush it out.
Just imagine you had two different ways to run your automobile. One way got the most out of the fuel you supplied, helping the engine to run as close to optimal as possible. The other way used fuel inefficiently, and released substances, making the situation worse, eventually even preventing the engine from running at all. Which way would you choose?
Maybe a car analogy is a bit too simple, but these two kinds of metabolic scenarios are real. And the subject of NO, is right at the heart of cellular energy system function. In excess, it causes havoc.
So what leads to nitric oxide (NO) issues? Like other defensive stress substances, NO has a basic role to play. Locally and momentarily, it can be helpful. Systemically and chronically, that’s a whole different situation. The ability to produce energy in the face of rising stress, is the fundamental thing keeping the balance.
But the problem is, NO is produced in response to interference with cellular energy production. And then it blocks the key respiratory enzyme (cytochrome c oxidase) in the mitochondria, preventing the use of oxygen by the cell. And what does that do? It interferes with energy production. Can you see the problem?
“…low systemic O2 uptake in hypothyroidism may depend on NO-dependent inhibition on redox activities, mainly on cytochrome oxidase…the differences in cytochrome oxidase specific activity between control and hypothyroid groups are consistent with the notion that, in hypothyroidism, about a two-third decrease of cytochrome oxidase activity depends on NO effects…” (MARI ́A CECILIA CARRERAS, et al., 2001)
“…Higher concentrations of NO and its derivatives (peroxynitrite, nitrogen dioxide or nitrosothiols) can cause irreversible inhibition of the respiratory chain, uncoupling, permeability transition, and/or cell death.” (Brown GC, 2001)
When stress is high, and it messes with energy metabolism, over time, you produce more of the stress substances that rise when energy production is inhibited, and then you have more stress, which can further inhibit energy production. It can turn into a downward spiraling vicious circle.
So basically there’s two kinds of systems. There’s the thyroid backed, carbon dioxide producing, oxidative energy metabolism. And then there’s the lactic acid producing, stress metabolism.
Things that encourage thyroid/oxidative energy metabolism, protect against stress and excess NO, and things that promote NO, suppress thyroid. Choices made, in relation to what goes inside the engine, impact upon how much of a NO issue you have. If you have a ‘NO issue’, you have a metabolic stress issue. And metabolic stress issues, lead to metabolic symptoms and diseases.
“…we found that hypothyroidism…resulted in impaired learning and memory…In addition, we found an increase in NO metabolites in the hippocampus, suggesting that the impairment of memory in hypothyroidism may be due to increases in…NO.” (Hosseini M, et al., 2010)
“…we reported upregulation and adverse functional effects of…iNOS…in hypothyroidism. We found that hypothyroidism up-regulates…iNOS…and enhanced inhibition of cardiomyocyte contraction and relaxation…which promote cardiac dysfunction in the setting of thyroid-hormone deficiency.” (Qun Shao, et al., 2016)
It’s an interconnected system, and some food choices cause more harm than others. Excessive exposure to the polyunsaturated fats (PUFAs) and their break down products, can turn minor localized metabolic issues, into systemic thyroid energy system damage, promoting chronic inflammation, and digestive dysfunction. Nitric oxide excess is driven by, and helps drive these issues.
“Malondialdehyde [MDA] is the end product of lipid peroxidation and is considered as a good marker of free radical-mediated damage and oxidative stress. It is the principal and most studied product of polyunsaturated fatty acid peroxidation…Increase in…MDA…occurs in inflammatory states…NO [nitric oxide] activates a chain of reaction of lipid peroxidation events triggering an increase in…MDA.” (VP Jayasekharan, et al., 2014)
When too much of the PUFAs are consumed, over time they accumulate in tissue. And then whenever there is stress, and that stress isn’t met with sufficient energy, the PUFAs are released out of storage into circulation, as free fatty acids.
Increased exposure to by products of the highly unstable PUFAs, and rising NO levels, go together, and both directly prevent optimal energy production. When energy production is interfered with, digestion is inhibited and bacterial issues become a problem in the intestines, increasing endotoxin release. Low energy, endotoxin, PUFAs and NO, have a big role in sepsis.
“Sepsis and multiple organ failure remain leading causes of death in intensive care patients…the degree of mitochondrial dysfunction is related to the eventual outcome…Associated mechanisms include damage to mitochondria…by nitric oxide…” (Azevedo LC, 2010)
“…data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes… we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion…and low ATP levels.” (Brealey D, Singer M, 2003)
Suppressed thyroid energy metabolism and high stress, allows for bacterial endotoxin to pass through into the main system, and endotoxin directly interferes with energy metabolism, causes inflammation, and increases NO wherever it lands.
“Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), induce…(i)NOS synthesis that produces massive amounts of NO…NO activates cyclooxygenase and lipoxygenase, leading to the production of…prostaglandin E2 (PGE2) and leukotrienes…the massive release of NO, PGE2, and leukotrienes produces toxic effects.” (McCann SM, et al., 1998)
Increased circulation of endotoxin and the inflammatory by products of the PUFAs (including prostaglandins), interferes with liver function, causes systemic levels of estrogen and serotonin to rise, and both estrogen and serotonin suppress cellular energy metabolism and increase stress, causing NO to rise. NO also promotes prostaglandin production. These combinations can lead to serious issues.
“Endotoxemia remains the main cause of death in intensive care units. It has a mortality rate in the US of 50–60%…The release of multiple endogenous mediators plays a causative role in initiating an uncontrolled inflammatory response…One of those mediators has been identified as NO…” (Viktor Brovkovych, et al., 2001)
“E2 [estrogen] significantly increased NO2 levels irrespective of its concentration in both cell lines by 35 % and 42 %…The addition of an E2 antagonist…prevented the E2-induced increases in NO2 levels…This study indicates that E2 induces NO level… ” (Nevzati E, et al., 2015)
“Another mechanism by which NO might promote carcinogenesis is probably by modulating the production of prostaglandins. NO increases…prostaglandin E2…compounds formed with the contribution of NO…may lead to cancer progression…” (Wioletta Ratajczak-Wrona, et al., 2013)
All of the inflammatory stress substances, can over excite and irritate cells, increasing lactic acid production, lowering CO2 levels, inhibiting the use of sugar and oxygen. This all promotes more NO, and encourages the ‘cancer metabolism’, interfering with the ability of cells to do anything other than divide and multiply.
It’s no coincidence that chronic bacterial issues and inflammation, and ongoing exposure to estrogen, serotonin, lactic acid, and the break down products of the PUFAs, drives cancer, because cancer has been shown to be a low CO2, high NO, insufficient energy production, metabolic illness.
“Infection…was…related to up-regulation of iNOS expression at the site of infection and increased NO production…Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes…administration of an iNOS inhibitor prevented NO production and abrogated the epithelial pathology and inhibited the onset of cancer.” (S. E. Erdman, et al., 2009)
“…NO has a central role in the metabolism of OVCA [ovarian cancer] cells by…inhibiting mitochondrial respiration, which can in turn force OVCA cells to maintain high glycolytic rates…enhancing proliferation…” (Caneba CA, et al., 2014)
“Chronic inflammation can lead to the production of NO, which in turn has the potential to mediate DNA damage directly…Biopsy samples of human breast cancer show the presence of greater expression of iNOS in a high-grade tumor, which tends to be more invasive…” (S. Syed Sultan Beevi, et al., 2004)
Nitric oxide also increases growth hormone, and growth hormone causes a greater release of PUFAs out of storage. Growth hormone (GH) interferes with intestinal barrier function, increasing exposure to endotoxin and serotonin. GH promotes estrogen, and GH raises NO levels significantly. GH, in combination with these things, drives inflammatory disease, particularly cancer.
“…findings indicate a 10-fold increase in iNOS expression in…cells treated with GH [growth hormone]…GH is at least as effective as LPS in inducing iNOS…GH may act in a cytokine-like manner to stimulate iNOS.” (SONIA Q. DOI, et al., 2000)
“…it is clear that growth hormone plays a significant role in the development, progression, and metastasis of breast cancer by influencing tumor angiogenesis, stemness, and chemoresistance.” (Ramadevi Subramani, et al., 2017)
Measuring NO isn’t easy. One way is to look at activity of enzymes which generate nitric oxide (NO) from the amino acid L-arginine. The iNOS enzyme is promoted by PUFAs and endotoxin and other inflammatory stress substances (including GH), and it is associated with the progression of cancer, and inflammatory disease in general. iNOS is the enzyme known to raise NO systemically and in the largest quantities, but high and systemic NO is a problem however it is raised. Like with estrogen, blood levels of NO do not accurately reflect tissue levels. If energy production is low, and stress and inflammation is rising, it’s safe to say NO production will be high.
“…unlike eNOS and nNOS, iNOS has not been found to be constitutively present in the normal, younger adult heart, but can be induced by pro-inflammatory substances such as inflammatory cytokines, lipopolysaccharide [endotoxin], and mechanical stress…” (Qun Shao, et al., 2016)
“Chronic inflammation can drive cancer. NO is…regarded as a key inflammation mediator. Until recently, iNOS has received most of the attention because it can be induced by a variety of inflammatory cytokines and can produce micromolar levels of NO, which damage DNA and modify protein structure/function…Evidence is accumulating that low (but above basal/pathologic) levels of NO from eNOS can be procarcinogenic.” (Lei Ying and Lorne J. Hofseth, 2007)
Looking at NO more honestly, fits with a logical understanding of biology, and helps explain many metabolic symptoms. Small temporary increases in NO (like with cortisol, endotoxin, estrogen, lactic acid and serotonin), can help deal with a local stress, or energy insufficiency.
The stress substances do have a role to play, and exist in a well functioning system, but that doesn’t mean you want to increase levels, to help fix metabolic issues. It is metabolic issues that makes stress substances like NO rise too high, and as stress rises, NO rises, causing an accelerated worsening of metabolic issues.
“Acute exposure to cortisol…significantly increased levels of ROS/RNS and DNA damage and…damage…was…attenuated in the presence of an iNOS inhibitor. An increase in…iNOS in response to…stress was observed in vivo and in cortisol-treated cells…a particularly relevant finding in breast cancer as…iNOS has been found to increase in line with tumour grade and progression…” (Flaherty RL, et al., 2017)
“Postprandial increase of 5-hydroxytryptamine (5-HT) has been implicated in irritable bowel syndrome (IBS). There is evidence that nitric oxide (NO) may act as a mediator of 5-HT-evoked secretions in the colon.” (Yazar A, et al., 2005)
“…estradiol rapidly increases NO production in acutely dissociated BECs [bronchial epithelial cells] from female patients…The clinical relevance of our study lies in diseases such as asthma, which are more prevalent in women… inflammation-induced alterations in NO [e.g., due to enhanced epithelial iNOS] may also be relevant…” (Townsend EA, et al., 2011)
There is a long list of inflammatory metabolic illnesses, other than cancer, shown to be some combination of high cortisol, high estrogen, high serotonin, high lactic acid, high histamine, high growth hormone, high stress, thyroid dysfunctional conditions.
This includes IBS, diabetes, heart disease, MS, Alzheimer’s, PTSD, chronic fatigue syndrome, fibromyalgia, schizophrenia, migraine, asthma, liver disease, herpes and other viral illnesses, arthritis, osteoperosis, Parkinson’s and more. They are all connected to high NO.
“NO was low in healthy control subjects…and variations over time were small. In IBS patients NO was slightly increased…whereas patients with active IBD or collagenous colitis had greatly increased NO levels…” (Reinders CI, et al., 2005)
“Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders.” (Heales SJ, et al., 1999)
“The elevated nitric oxide/peroxynitrite theory of CFS, MCS, PTSD and FM is the only available theory explaining the association among these four disease states and it also explains their symptom overlap and their apparent common pattern of induction, with a short-term stress being followed by a chronic pathology.” (Pall ML, 2001)
“Nitric oxide (NO) has been implicated to play a role in the pathogenesis of depressive disorders…The mean value of plasma NO levels in the BPAD group…was significantly higher than that of controls…” (Savaş HA, et al., 2002)
“Nitric oxide (NO) plays an important role in the pathological process of demyelinating diseases…NO can impair oligodendrocyte energy metabolism… In the progression of MS, NO can mainly mediate demyelination, axonal degeneration and cell death.” (Lan M, et al., 2018)
“Elevated free radical generations in inflamed joints and impaired antioxidant system have been implicated in RA [Rheumatoid arthritis]…levels of serum MDA [Malondialdehyde…breakdown product of PUFA] and NO significantly increased…in RA patients when compared to healthy controls.” (Jambale Triveni A, et al., 2014)
“NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia…” (Nasyrova RF, et al., 2015)
In fact NO is promoted by every kind of excess stress, and it is central to the development and spread of every metabolic stress disease. And NO also inhibits every disease protective process.
NO interferes with insulin production and promotes insulin resistance. NO thickens and hardens blood vessels and arteries, and damages heart function, and NO prevents the use of oxygen and breaks DNA strands. NO interferes with testosterone and progesterone production, and promotes estrogen, serotonin, lactic acid, endotoxin and histamine excess. Maybe it isn’t so healthy after all?
“Endotoxin or lipopolysaccharide (LPS) injection is a potent stimulator of inducible nitric oxide synthase (iNOS)…data demonstrate an important role for iNOS in LPS-induced insulin resistance, evidenced by the attenuation of LPS-induced hyperglycemia…” (Sugita H, et al., 2002)
“Endotoxin (i.e. LPS) administration induces a robust inflammatory response with accompanying cardiovascular dysfunction and insulin resistance. Overabundance of nitric oxide (NO) contributes to the vascular dysfunction.” (Lawrence M. House II, et al., 2015)
“TNBC is an extremely aggressive and lethal form of cancer…Patients with TNBC show higher risk of metastasis and tumor relapse…iNOS predicts for worse survival in patients with…breast cancer and has been suggested to increase tumor aggressiveness…The anti-tumor activity of iNOS inhibitors…in oral, glioblastoma, and breast cancer…is consistent with our findings.” (Granados-Principal S, et al., 2015)
“Human lung squamous cell carcinoma (SCC) is highly associated with increased pulmonary macrophage infiltration…lung SCC-associated macrophages specifically express elevated inducible nitric oxide synthase (NOS2)…macrophage NOS2 increases pulmonary inflammatory responses and macrophage survival and impairs macrophage lipid metabolism, thereby promoting lung SCC formation.” (Xin Wang, et al., 2018)
I’m not a doctor or scientist, but on this basis, it looks like it makes sense to protect against the ‘NO metabolism’, by working to improve sugar utilization and energy production. By increasing CO2 levels, limiting lactic acid, and promoting oxidative energy metabolism. By lowering exposure to free fatty acids (especially the PUFAs), and other inflammatory stress promoting things.
“…strong correlations between blood and tissue levels of NO…and MDA…serum NO and plasma MDA, and…tissue NO and tissue MDA…also a significant relationship between all well-known prognostic indicators of PCa [prostate cancer] and blood and tissue NO and MDA levels…” (Dillioglugil MO, et al., 2012)
Excessive accumulation of iron in the tissue also damages energy production and promotes inflammatory disease, including cancer, Alzheimer’s and Parkinson’s disease. Iron dysregulation and the inflammatory effects of endotoxin and the PUFAs, exacerbate each other, and high NO has been shown to promote iron deposition.
…our findings mechanistically sequence elevated NO as causatively upstream of nigral iron elevation in PD [Parkinson’s disease]…findings indicate that NO scavengers…which have shown benefit in multiple PD models…may also act to lower toxic iron accumulation.” (Ayton S, Lei P, et al., 2015)
All of this makes you wonder how anybody can say that NO is a health promoting substance. Problem is, once you tell it the way it is, and you say NO to nitric oxide, the whole ‘sugar causes disease’ and ‘heart healthy PUFAs’ story etc., also has to take a hit.
It’s easy to misinterpret rising NO as beneficial, because in a sense it does rise at first to protect against harm, and because an excess is often misinterpreted as a deficiency. But when you see what high NO does in the context of the high stress, low energy, low oxygen, chronic inflammation, endotoxin, estrogen, serotonin and lactic acid ‘milieu’, it becomes more difficult to pretend it’s still helping.
A diet avoiding the PUFAs, with sufficient protein and other nutrients from milk and cheese and gelatinous meat, and plenty of sugar from sweet fruits, fruit juice, white sugar and honey, is one possible way to lower inflammation, improve digestion, increase energy production, and protect against excessive exposure to NO and the stress promoting things that go along with it.
Some other things that are known to protect against NO and inflammatory disease include niacinamide, aspirin, progesterone, MB, vitamin K, antibiotics like minocycline, doxycycline and tetracycline, red light, and other anti-stress pro-metabolic things.
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Cell Death Discovery volume 4, Article number: 46 (2018). Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis. Xin Wang, Zane Gray, Jami Willette-Brown, Feng Zhu, Gongping Shi, Qun Jiang, Na-Young Song, Liang Dong & Yinling Hu.
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Int J Cardiol. 2016 Feb 1;204:229-41. Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism. Shao Q, Cheng HJ, Callahan MF, Kitzman DW, Li WM, Cheng CP.
J Biol Chem. 2017 Jun 2;292(22):9432-9438. Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism. San Martín A, Arce-Molina R, Galaz A, Pérez-Guerra G, Barros LF.
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Scientific Reports volume 7, Article number: 9265 (2017). iNOS promotes hypothalamic insulin resistance associated with deregulation of energy balance and obesity in rodents. Carlos Kiyoshi Katashima, Vagner Ramon Rodrigues Silva, Luciene Lenhare, Rodrigo Miguel Marin & José Barreto Campello Carvalheira.