Nitric Oxide, Peroxynitrite, and the Impairment of Mitochondrial Replication in CFS

[Deltrus]

Hello Hip!

I've been on agmatine for ~5 months. It gives high mangitude eNOS increases and also slightly inhibits iNOS and nNOS. It is a very strange drug with many effects. I take it because it gives better bowel function, less vasoconstriction, and a slight feeling of being more peaceful.

• agmatine can positively modulate signalling through the NMDA receptor (via putrescine), α2 adrenergic receptors, and serotonergic receptors (5-HT1A/1B) at low concentrations, while inhibiting binding at the polyamine binding site (that putrescine acts via binding to), competitively inhibiting the α2 adrenergic receptors, and being antagonistic with 5-HT1A/1B signalling at higher concentrations.

The α2 adrenergic receptor activity is responsible for increases in eNOS.

Actually, on further reading that very lengthy article, the effects of agmatine on iNOS/nNOS are only in higher doses.

The NO system is actually incredibly complex. This is probably because it has a very short half life from when it is created and thus has many small interactions rather than overarching and simple interactions.

From the examine arginine article, it says that eNOS is also very plentiful in brain tissue just like nNOS, despite the "neuronal" in the nNOS name.

So far I seem to like very low doses of agmatine (125 mg) rather than higher ones (1-2g). There seems to be good and bad effects that get increased at higher doses. I almost never see people go near 125 mg but I think it is better. There are several bell curves with this drug on different mechanisms.

Bad effects of higher doses:
- Increased brain fog over time? This has been my observation but it might be unrelated.
- Lack of energy?

Good effects of higher doses:
- More antidepressant effect
- More clarity acutely

But still the low dose agmatine seems to give a good increase in eNOS and doesn't have as many crazy interactions and complexities. I like the chemical but I'm going to stay low dose just because I don't know wtf it is doing.

 

[Hip]

Hi @Deltrus

I have tried daily doses of up to 500 mg of agmatine for short periods of a few days, but I cannot say I noticed anything. Perhaps I should try agmatine for longer periods. Or try lower doses, like the 125 mg dose you use.

From the examine arginine article, it says that eNOS is also very plentiful in brain tissue just like nNOS, despite the "neuronal" in the nNOS name.

Sure, because you will find eNOS wherever there are blood vessels.

The NO that comes from nNOS is used as a neurotransmitter, ie, to communicate information between neurons.

 

[ahmo]

They found that humming increased nitric oxide levels fifteenfold, compared to quiet exhalations without sound.

Hip, I've been engaged with this thread over the last couple weeks. (mind you, i'm just completing page 4) I now lay my most pressing symptoms/limitations at the feet of NO/ONOO. (interesting saying, that: to lay at the feet of. Or, in the lap of...I guess in a way it rings true: approaching for revelation or blessing)

Even though my comprehension of it is still very superficial, I now subscribe to Martin Pall's theory as the explanation for what appears to be my new normal. I'd spent some time trying to differentiate whether my symptoms could be understood as ammonia or whether peroxy was the more accurate label. The symptoms seemed the same, and strategies to relieve them was also the same. To this end, I engaged in a deep Candida/SIBO purge. I wanted to eliminate potential sources of ammonia production. By now I've regained my equilibrium from that 2.5 month experience, and I continue to need mega amounts of antioxidants to be comfortable in my own skin.

Happily I've switched from olive leaf tea, as on Pall's recommended list, and switched to the cheaper and easier to source green tea. + a few other herbs. + supps. + something like 1 kg carrots a day: this seems to work immediately. It's been a stretch to meet my body's requests for carrots. And I've found, like dbkita and LaurieL that my body wants nuts/seeds. Happily, having eliminated them as autoimmune stimulators some months ago, I'm now able to eat something like 5T a day.

Why I'm writing in this instant is that I just said, This cannot go on. Surely this is the point where I need to engage some inner resources. Instead of looking for another list of antioxidants, I came back to this thread, and knew I'd seen meditation and humming mentioned. So I'm really posting to thank you for this really useful conversation you started and which, happily, deltrus kicked back into life.

 

[Hip]

@ahmo
Martin Pall's theory and Dave Whitlock's theory (which is detailed in this thread) take opposing views: Whitlock proposes that ME/CFS is caused by a low basal level of NO, whereas Pall thinks there is too much NO (and peroxynitrite) in ME/CFS patients.

The ability of humming to raise NO only applies to the sinuses and nasal cavities, unfortunately. Still, it might be worth trying humming if you have chronic nasal congestion or sinusitis, as NO is a potent anti-microbial, and so should fight nasal and sinus infections.

 

[PeterPositive]

To this end, I engaged in a deep Candida/SIBO purge. I wanted to eliminate potential sources of ammonia production.

What is exactly a SIBO purge? Can you share the details?

thanks

 

[ahmo]

@Hip Yes, I understand that their theories are opposite. I've not followed the line of increasing, or decreasing, NO, but rather of managing peroxy. Interesting that the humming is of local significance. I found it really useful, an alternative to focussing on my breath, to alter my inner state and help dampen my stress response. Before I found your comment, I thought it had been Wayne who'd mentioned humming. His use of Hu suggests this can be a powerful strategy.

@PeterPositive I made a blog post re my reasoning, research, and choices. I found it pretty intense, but I find that I'm needing less of several supps since completion. I've also been able to add back in tiny amounts of histamine and autoimmune stimulating foods. My impression is that the protyolytic enzyme component has been as valuable as the anti-fungal/microbials.

http://forums.phoenixrising.me/inde...campaign-the-answer-to-my-ammonia-quest.1701/

 

[Hip]

I've not followed the line of increasing, or decreasing, NO, but rather of managing peroxy.

You might find the list of peroxynitrite scavengers in this post of interest.

 

[JPV]

Whitlock's theory then focuses on the mechanism behind this insufficient mitochondrial biogenesis: namely, (in Whitlock's view) the low basal levels of nitric oxide existing at the same time as high nitric oxide output from the immune system (from iNOS), and how this combination of circumstances forces basal NO levels to get lower and lower, by the "ratchet" system he describes.

@Hip, Ok, I purchased, and just received, Whitlock's AO+ Mist and will be experimenting with it over the next few weeks.

I've read some of his blog posts and interviews but I'm still having a hard time wrapping my head around some of the seemingly paradoxical aspects of high and low NO.

It's been mentioned on this thread, and elsewhere, that those with ME/CFS tend to have very high NO. Is there some counterintuitive reason that boosting NO, in his proposed manner, would somehow regulate high NO? Are we talking about different forms of NO or diametrically opposed distribution in different parts of the body?

I'm also not really clear on what is meant by "basal" NO and how it relates to the whole picture?

I'm so confused...

 

[Hip]

I'm so confused...

Don't worry, the nitric oxide metabolism in the body is very complex, and I don't think anyone fully understands the whole picture. I think the only thing we can sensibly do it try some NO-based therapies, as you are doing, and then seeing if it helps.

A brief overview of NO in the body is found in this post. In the post, I also speculate that high NO in some areas of the body (eg NO from fighting viral infections) might inadvertently cause low NO in other parts. This is just pure speculation though.


Regarding the basal level of NO:
Originally I never understood how there could be a basal level of NO in the blood, because NO has an incredibly short plasma half life of just 1 second, so literately moments after NO is created by one of the three enzymes which make it in the body (namely iNOS, eNOS and nNOS), this NO will have already disappeared.

However, it turns out that NO can bind to the albumin in the blood, to form a stable compound called S-nitroso-albumin. It is this S-nitroso-albumin that then carries the NO around in the blood, and it is this which creates the stable blood level of NO, called the basal level.


When you place these natural ammonia-oxidizing bacteria (AOB) on your skin, what they do is constantly create NO that enters your bloodstream through the skin, and this NO attaches to the albumin in your blood, forming S-nitroso-albumin, and thereby raising your blood basal NO level.

Dave Whitlock points out that the basal NO level in the blood is a fundamental factor that determines the rate of production of new mitochondria in your cells (making new mitochondria is called mitochondrial biogenesis, or mitochondriogenesis). The higher the basal NO level, the more new mitochondria you make. (The other major factor that influences the rate of production of new mitochondria is the thyroid hormone T3, and low T3 will also lead to less new mitochondria being produced).

Whitlock thinks that basal NO may be low in ME/CFS, and thinks this low NO level will lead to reduced production of mitochondria in your cells. The average mitochondrion in your cells only has a lifespan of less than a month, so mitochondria need constant replacement. You have around 1000 to 4000 mitochondria per cell, depending on cell type.

Whitlock thinks ME/CFS may be simply caused by low basal NO, causing reduced mitochondrial production and replacement, leading to insufficient mitochondrial numbers in the cells.


Whitlock thinks this presumed deficit of mitochondria will lower energy output, because there are not enough mitochondria to supply the energy needs of the cell.

Also, if the mitochondria in your cells are not replaced regularly, you get a population of older, worn out mitochondria, and older mitochondria are inherently more leaky, and so produce more ROS.

So Whitlock's low NO hypothesis purports to explain how low energy and increased ROS arise in ME/CFS.


I found Whitlock's hypothesis interesting, because although other researchers have suggested a possible mitochondrial dysfunction in ME/CFS, nobody apart from Whitlock has considered the possibility that the mitochondria might be fine in ME/CFS, but it is just the number of mitochondria that is too low.

That being said, all this is pure speculation, because no studies have been performed that have measured the actual number of mitochondria in the cells of ME/CFS patients. I would be interested in seeing such a study undertaken.

 

[Hip]

@SOC @Valentijn

I wonder if Whitlock's hypothesis, detailed in my post just above, speculating that ME/CFS patients may have low mitochondrial numbers in their cells, could help explain the 2-day CPET results?

Whitlock hypothesizes that due to insufficient production of new mitochondria, ME/CFS patients have older, worn out mitochondria in their cells, which generate much more ROS than brand new mitochondria. So could the ROS generated in the cells on the first day of the CPET test the somehow cause all the problems with energy production on the second day of the CPET test?

I am not sure what the mechanism might be though, ie, I am not sure how the ROS could cause the reduction in the lactate threshold seen on the second day of the CPET test in ME/CFS patients, where cells too quickly switch from aerobic to anaerobic energy production.

 

[Valentijn]

I am not sure what the mechanism might be though, ie, I am not sure how the ROS could cause the reduction in the lactate threshold seen on the second day of the CPET test in ME/CFS patients, where cells too quickly switch from aerobic to anaerobic energy production.

I don't know enough to offer an educated opinion. But my general feeling is that NO and ROS theories are too simplistic to explain ME/SEID. I suppose that's one of the attractions of immune or infectious theories - they seem complex enough to account for a complex disease.

Anyhow, I think there's plenty of experts in the area now trying to account for our unique (so far) 2-day CPET results. I'm happy enough to leave them to it

 

[Hip]

But my general feeling is that NO and ROS theories are too simplistic to explain ME/SEID.

Same here, but perhaps NO and ROS theories could be part of the overall picture. So for example you might have a chronic ongoing infection causing many ME/CFS symptoms, but that infection might also have some knock-on effects on NO levels.

 

[JPV]

@Hip, Thanks for taking the time to explain NO. I guess it's just going to come down to N=1 and a little bit of luck... hopefully.

Seriously, even with all the science that's used to explain the effects of any given intervention, there's dozens of possible explanations as to why something may, or may not, work. It really comes down to trial and error at the end of the day.

 

[Violeta]

This link about mitochondrial misfunction shows how viruses might be the root cause of more than one thing talked about in this thread.

http://www.hindawi.com/journals/av/2013/738794/

2. Viruses Regulate Ca2+ Homeostasis in Host Cells

The core protein of HCV causes oxidative stress in the cell and alters apoptotic pathways [64, 105–107]. The E1, E2, NS3, and core protein of HCV are potent ROS inducers and can cause host DNA damage independently [107, 108] or mediated by nitric oxide (NO) thus aiding in virus replication.

The protein X of HBV is known to stimulate NFκB [198, 199], SAPK [200, 201], and PI3K/PKB [202] to prevent apoptosis. It is possible that the diverse functions of HBV protein X occur at different times of virus replication cycle in the infected cells. The BALF1 protein encoded by EBV contains BH1 and BH4 domains

 

[Rand56]

@Hip, Ok, I purchased, and just received, Whitlock's AO+ Mist and will be experimenting with it over the next few weeks.

I've read some of his blog posts and interviews but I'm still having a hard time wrapping my head around some of the seemingly paradoxical aspects of high and low NO.

It's been mentioned on this thread, and elsewhere, that those with ME/CFS tend to have very high NO. Is there some counterintuitive reason that boosting NO, in his proposed manner, would somehow regulate high NO? Are we talking about different forms of NO or diametrically opposed distribution in different parts of the body?

I'm also not really clear on what is meant by "basal" NO and how it relates to the whole picture?

I'm so confused...

hi JPV

Anything positive or negative to report on Whitlock's AO+ Mist?

 

[JPV]

Anything positive or negative to report on Whitlock's AO+ Mist?

I've only taken it for a week (it comes in a 4 week supply) but I can't really say for sure yet. There were a couple of days that I felt pretty good but it's hard to say if it was due to the spray as I'm also trying other things such as Clostridium Butyricum.

I feel like one of the issues is that it's supposed to use bacteria from your sweat as a substrate. I'm pretty sedentary so I don't really sweat very much. I wonder if Beet Root Juice might be more reliable in this respect.

I'm going to hold off of experimenting with it for now. I have to move a lot of stuff into storage, over the next few weeks, as we get ready to paint my condo. That will probably be a good time to give it a better trial. I'll keep you posted on how it goes.

 

[Adlyfrost]

I have always felt hyper and a little poisoned after eating too much raw greens, carrot juice and beets. After eliminating high oxalates I couldn't figure out why. I thought possibly: overmethylation from lots of folinic acid OR too much nitric oxide turning into dangerous levels of peroxynitrite.

Recently I tried taking a tiny bit of hydroxocobalamin like 2-400mcgs after getting this feeling. My ears unclogged and felt instantly calm, maybe too calm. Hoping I can do that raw vegan diet that I always wanted to do now! But cautiously optimistic.

Any one else have problems with raw greens / too much nitric oxide?

 

[Adlyfrost]

http://www.tandfonline.com/doi/abs/10.1300/J092v08n02_04?journalCode=icfs20

This article talks about elevated nitric oxide and CFS and how hydroxocobalamin may help. However in my experience I think my levels may fluctuate and sometimes I need more NO and must eat more greens for energy and sometimes my body fails to break NO down making me hyper and sick.

 

[Freddd]

I have always felt hyper and a little poisoned after eating too much raw greens, carrot juice and beets. After eliminating high oxalates I couldn't figure out why. I thought possibly: overmethylation from lots of folinic acid OR too much nitric oxide turning into dangerous levels of peroxynitrite.

Recently I tried taking a tiny bit of hydroxocobalamin like 2-400mcgs after getting this feeling. My ears unclogged and felt instantly calm, maybe too calm. Hoping I can do that raw vegan diet that I always wanted to do now! But cautiously optimistic.

Any one else have problems with raw greens / too much nitric oxide?

@Adlyfrost

Below is a list of folate deficiency symptoms that many people get in a paradoxical way. It takes me 15mg of methylfolate to get rid of most or all of these symptoms intermittently, 30mg to get rid of all of them on a constant basis. Carmen Wheatley's GORILLA IN THE ROOM ... Has a lot to say about how AdoCbl and cofactors are a complete solution to to the peroxynite and nitric oxide inflammation problem instead of the incomplete "workaround" pathway of HyCbl.

If folinic acid, like folic acid, has a maximum of about 800-1000mcg maximum conversion to methylfolate, then amounts beyond 800-1000mcg can be a problem for just about everybody and 20% can't use it at all and 30% to a lesser extent, as that is the biological limit of conversion of folic acid. My experience is that while folic acid appears to block about 10x of folic acid dose and 20x the folinic dose in l-methylfolate. It is unknown what percentage have trouble with folinic acid. People who have trouble with vegetable folates also appear to have trouble with folinic acid. That percentage of people is also unknown\ but not uncommon.


Group 3 - Induced and/or Paradoxical Folate deficiency or insufficiency, partial methylation block to methyltrap on 1 or more internal triage levels. Frequently called “NAC DETOX” or “GLUTATHIONE DETOX”. Can be caused by folic acid, folinic acid and for some people, like me and quite a few others, excess vegetable folates. Further excess B1, B2, B3 and/or inositol can increase methylfolate deficiency symptoms.

IBS – Diarrhea alternating with constipation
IBS – Normal alternating with constipation
Headache, Increased malaise, Fatigue


These symptoms appear in 2 forms generally, the milder symptoms that start with partial methylation block and the more severe symptoms that come on as partial methylation block gets worse or very quickly with methyltrap onset.

Edema - An additional thing I would like to mention. I would never have found it without 5 years of watching the onset of paradoxical folate insufficiency and trying to catch it earlier and earlier and to figure out what was causing it and to reverse it. For me the onset order goes back to the day of onset now with edema and a sudden increase of weight. I noticed that within 2 hours of taking sufficient Metafolin I would have an increase in urine output.

Old symptoms returning
Edema

Angular Cheilitis, Canker sores,

Skin rashes, increased acne, Increased itchy acne on scalp and face, Skin peeling around fingernails, Skin cracking and peeling at fingertips,

IBS – Diarrhea alternating with constipation, IBS – Normal alternating with constipation
Headache, Increased malaise, Fatigue


Increased hypersensitive responses, Runny nose, Increased allergies, Increased Multiple Chemical Sensitivities, Increased asthma, rapidly increasing Generalized inflammation in body, Increased Inflammation pain in muscles, Increased Inflammation pain in joints, Achy muscles, Flu like symptoms

IBS – Steady diarrhea, IBS – Diarrhea alternating with normal, Stomach ache, Uneasy digestive tract,

Coated tongue, Depression, Less sociable, Impaired planning and logic, Brain fog, Low energy, Light headedness, Sluggishness, Increase irritability, Heart palpitations,


Longer term, very serious

Loss of reflexes, Fevers, Forgetfulness, Confusion, Difficulty walking, Behavioral disorders, Dementia, Reduced sense of taste, bleeding easily

 

[helen1]

@Adlyfrost Apart from what Fred says about the difficulty some have with converting folinic acid (greens) to folate there's the difficulty some of us have with oxalates.

Beets and carrot juice are high in oxalates and spinach is extremely high. If your body can't get rid of oxalates, levels will build up if you're eating high oxalates foods and can cause joint pain - even gout - and cognitive problems. Maybe that's part of your situation?

Edit: just saw your other thread where you mention oxalates. Have you thought of trying a lower oxalate diet to see if you feel better?