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Nitric oxide concentrations are normal and unrelated to activity level in CFS

Discussion in 'Latest ME/CFS Research' started by Dolphin, Jun 23, 2011.

  1. Dolphin

    Dolphin Senior Member

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    The findings were not that interesting:

  2. Dolphin

    Dolphin Senior Member

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    Most of the introduction

    I found the introduction very interesting. (I scanned this in so hopefully not too many errors):

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  3. alex3619

    alex3619 Senior Member

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    This study is very strange: I am not aware of any claim of an association with NO and ME/CFS. It is ONOO-, or peroxynitrite, an NO derivative, that is the postulated problem. However, this does raise a very weak argument against ONOO- because its formation does require NO. It might therefore be infered that higher NO could induce more damage, and exercise might do this. However, they seem to rule out that NO is the direct cause of PEM. This is a good thing, and expected. Bye, Alex
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  4. Dolphin

    Dolphin Senior Member

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  5. Snow Leopard

    Snow Leopard Senior Member

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    What was the selection criteria, demographics and other relevant characterisations (eg SF-36 PF scores)?
  6. Dolphin

    Dolphin Senior Member

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    This is about all we got:
    1. Fukuda et al. (1994)
    [​IMG]
    CFS: 25 Female /5 Male, HC: 25F/5M.
  7. ixchelkali

    ixchelkali Senior Member

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    Dolphin, did the paper specify anything about the patient cohort, such as what case definition was used? It's always hard to know how credible these paper are when you don't know if their "ME/CFS patients" have real ME/CFS or are simply fatigued.

    In any case, it's interesting to learn that someone's looking at nitric oxide and peroxynitrite in ME/CFS. I'd like to see more research on this.
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  8. Snow Leopard

    Snow Leopard Senior Member

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    I wish I knew more about statistics. Isn't it possible that if they increased the sample size (at least double), if they continued to measure the same effect, the p value could become close to 0.05?

    Given the effect size and the following calculator, the sample size seems to be insufficient:
    http://www.danielsoper.com/statcalc/calc01.aspx
  9. Dolphin

    Dolphin Senior Member

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    NO could still be relevant based on the other study: http://forums.phoenixrising.me/show...n-During-Exercise-in-CFS-A-Case-Control-Study - perhaps a high dose of NO (as happened with the CFS patients following exercise) could cause damage.

    (I haven't fully thought this bit through) Alternatively what they would need to look at is adjusting for activity counts - the NO produced at a certain unit level (it may be the reason people with CFS can't maintain higher levels); there might even not be a linear relationships e.g. if somebody has a certain NO count at an activity level of 200, call it NO(200), the level for the CFS patient of NO (250) could be a lot higher than a quarter more. They may not be analysing it well because there is heterogeneity in the CFS population with different people having an underlying severity level/activity ceiling but some people are closer to it than others. So that for two CFS patients, the "strain" of an activity level of 250 would be different (perhaps they could use data from VO2 max/similar to adjust). Anyway, I find Suarez et al (2010) more interesting.
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  10. Valentijn

    Valentijn Activity Level: 3

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    Don't nitric oxide and peroxynitrite have a very short half life? I thought that was the explanation for producing localized pain when using a muscle, versus pain throughout the body. So wouldn't it make sense that venous levels are pretty normal, since it wouldn't travel beyond the muscle being overused?
  11. alex3619

    alex3619 Senior Member

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    I think it more likely that NO would be an exacerbating factor in patients with low blood volume or OI (POTS, NMH). It does not seem to be particularly causal, except perhaps as it contributes to peroxynitrite.

    Earlier research by Pall and others looked at NO damaging molecules with an iron centre, including aconitase, which is essential for mitochondrial function. Its also known to stimulate pro-inflammatory eicosanoids. There is plenty of room for NO to be contributing. However I do not think any study to date has shown NO to be directly damaging to us. Indeed, by improving oxygenation it might be helpful. It does however interact with so many pathways that are affected in us that it may contribute to increased pathophysiology.

    One interesting possibility comes from the difference between NO and ONOO on damaging molecules like aconitase. NO will temporarily inactivate aconitase, reducing capacity but the molecule recovers. ONOO destroys it. Of course if NO is elevated under conditions of oxidative stress, and particularly near the mitochondria of an exercising individual, it will generate increase ONOO. This would produce a two phase response, a short recoverable phase and a longer phase with slower recovery due to the need to replace aconitase (which is imported from the cell).

    I do wonder what happens at sites of inflammation though. Immunological NO can be at high enough concentrations to be damaging - that is the point of it.

    Personally I think PEM or PENE will turn out to be a very complex phenomena. There is still not enough research in other avenues including cytokines and eicosanoids to rule very much out at this point. About the only thing I could say with close to certainty is its not due to deconditioning.

    ONOO has a very short half life indeed: the reason is its so destructive it immediately damages something and disappears. NO has a longer half life, but is still a localized hormone so far as I know. Maybe someone could give an accurate answer, but I suspect that ONOO is on the order of a few seconds, and NO is a handful more than that. This is just an educated guess however.

    Bye, Alex
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  12. alex3619

    alex3619 Senior Member

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    I would like to add a caveat to the earlier post. While average NO levels in the blood are not typically high enough to be damaging my view, that does not mean that concentrated levels due to iNOS activity (immune NOS) could not reach signitificant levels. This would occur in localized inflammatory zones.

    Similar if there are regions in the body (including the gut) where NO is very much higher it might not show up easily in testing. As a result there could be significant vasodilation in those areas, with a resulting drop in blood pressure. This is speculative though - I think there are people looking for this but it has yet to be demonstrated.

    Bye, Alex
  13. jeffrez

    jeffrez Senior Member

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    Agree w/ Alex. The issue is said to be peroxynitrite, not NO per se. With reduced antioxidant capacity in pwcs, the level of NO could be the same as in healthies, and yet the diminished ability of pwcs to quench the ONOO radicals leads to problems healthies don't experience. This study seems little more than useless, except fwiw in possibly ruling out excess NO.
  14. taniaaust1

    taniaaust1 Senior Member

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    "17 Qian ZM, Xao DS, KeY and Liao OK: Increased nitric oxide is
    one of the causes of changes of iron melabolism in strenuously
    exercised rats. Am J Physiol Regul Integr Comp Physiol 280,
    R739-743. 2001. "

    thanks for posting this study.. I found the above reference in this study to be interesting as I have some strange issue with my iron (no iron stores thou I eat 600-800g of meat per day at times even more) and have been looking for possible reasons for this iron thing of having no iron stores.
  15. alex3619

    alex3619 Senior Member

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    Hi Dolphin, yes this study seems to have more clear results.Its measure is nitrates though, not NO - they infer an elevated NO which seems reasonable. If we have a massive load of oxidative stress during or post exercise then a lot of NO will quickly be modified to peroxynitrite. I do not know the equations governing that however - so "a lot" is rather vague.

    The reason I keep coming back to peroxynitrite is synergy. Even small elevations in NO with small elevations in oxidative stress could result in significantly more peroxynitrite. In conditions of mitochondrial stress pumping out free radicals this could be very significant. OK, OK, I have long been a fan of Pall's work, though still not convinced. If exercise induces increased peroxynitrite damage one of the targets will be the mitochondria.

    The downside of focussing on this though is that most of the peroxynitrite would be in the active tissue - especially muscle. So the effect would be primarily muscular. Yet PEM or PENE have widespread effects. If NO or peroxynitrite are the trigger, it would be to a cascade of secondary reactions probably including eicosanoids and cytokines.

    One of the things that is not often mentioned, which I thought I should point out, Creation of long term memories is NO mediated, due to an effect on a process called long term potentiation or LTP. It is not clear how this fits with brain fog or memory issues though. I put forward an hypothesis on PR some years ago that this might be due to overstimulation of memory creation - blurring or diffusing the memory in the brain so that it is widespread instead of very sharply delineated.

    Bye, Alex
  16. alex3619

    alex3619 Senior Member

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    Hmmm, just found some old but interesting information that may change how we look at NO. LPS can induce NOS in many tissues, including macrophages. What I was saying earlier about localized NO might be a reality - gut NO might be very very high but average out to lower blood levels. Thats a worry. LPS translocation from the gut could be the driving force:

    http://www.acnp.org/g4/gn401000060/ch060.html
    "Under normal circumstances, macrophages possess no detectable NOS protein. Stimuli such as interferon-g and lipopolysaccharide (LPS) elicit new NOS protein synthesis over 2–4 hr, mediating the NO responses to inflammatory stimuli. It was first thought that macrophages contained the only form of inducible NOS. Following endotoxin treatment, inducible NOS activity has been demonstrated in a great diversity of animal tissues lacking macrophages (54). The hepatocyte inducible NOS which has been recently cloned (27) might represent the prototype for nonmacrophage inducible NOS. Conceivably the ubiquitous distribution of this form of inducible NOS reflects a primitive sort of immune response. The simplicity of the NO system might have sufficed to repel invading microorganisms early in evolution."
    [my bolding]

    Given the other research on LPS translocation, this could be a major issue, and worth thinking about.

    Bye, Alex

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