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

Dolphin

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The findings were not that interesting:

Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study.

In Vivo. 2010 Nov-Dec;24(6):865-9.

Meeus M, VAN Eupen I, Hondequin J, DE Hauwere L, Kos D, Nijs J.

Source
Division of Musculoskeletal Physiotherapy, Artesis University College (AHA), Department of Health Sciences, Van Aertselaerstraat 31, 2170 Merksem, Belgium.

Abstract

AIM: since patients with chronic fatigue syndrome (CFS) often present elevated levels of nitric oxide (NO) and low levels of physical activity, this study aimed at revealing possible correlations between NO concentration and physical activity.

PATIENTS AND METHODS: thirty CFS patients and 29 age- and gender-matched sedentary controls wore an accelerometer for one week and underwent venous blood sampling at the beginning and the end of the week.

RESULTS: CFS patients were significantly less active (p=0.001), but no significant differences in the amounts of NO (p=0.464 and 0.569) or interaction between NO levels and activity levels in either the CFS patients or controls were revealed.

CONCLUSION: these results provide further evidence for reduced activity levels in CFS patients, but refute there being any interaction between the amount of blood NO and activity level in both groups. The blood NO was neither predictive of, nor dependent on the activity level in CFS.

PMID:21164046[PubMed - indexed for MEDLINE]
 

Dolphin

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Most of the introduction

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

Another characteristic mentioned in the CDCP definition is a substantial reduction of the premorbid activity level (1), evidenced by clinical research (2,3). In addition to the reduced activity level compared to the premorbid level or to healthy controls. people with CFS display an abnormal activity pattern their lifestyle appears to be characterised by activity peaks and longer bouts of rest after activity (3). The latter is in line with a physiological study showing a delayed recovery from exercise in CFS patients (4). Clinical studies revealed that overly vigorous exercise (5, 6) or even a 30% increase in activity (7), frequently triggers a relapse. However, the cause of this post_exertional malaise and the altered or reduced activity level remains unclear.

It is hypothesised that nitric oxide (NO) is involved in these phenomena of altered and reduced activity level and of exercise intolerance. It is known that patients with CFS present elevated levels of blood NO (8). Excessive NO concentrations are detrimental for physiological functions via the derivative peroxynitrite (9). Peroxynitrite is not a free radical, but leaves the hallmarks of oxidation typical of free radicals (9). Furthermore, NO as a mediator of vasodilatation, is critical for basal blood flow across many organs. In consequence, elevated amounts of NO in CFS can cause hypotension (10). As previously suggested (11), this may explain part of the abnormal exercise response in CFS. NO-induced vasodilatation may limit the capacity of the human body to increase blood flow during physical activity, limiting activity performance in CFS-patients. In addition, physical activity further increases NO amounts and vasodilatation and thus hypotension (12-14). In CFS patients this effect could be aggravated by the already elevated amounts of NO, explaining the malaise and the delayed recovery after physical activity (4). Secondly, pathological overproduction of NO will decrease oxygen consumption (15) and increase anaerobic glycolysis (lactate production) by modulating mitochondrial respiration (16) and iron metabolism (17). Finally, NO could alter muscular morphology and function by oxidative damage of cell membranes (18), structural proteins such as actin (9), and DNA (19), causing muscle weakness, soreness and fatigue. All these mechanisms compromise exercise capacity and worsen physical activity responses.

Therefore, it was hypothesised that NO plays an aetiological role in the reduced activity level and fluctuating symptom pattern in people with CFS. Either people with CFS are not capable of being physically active due to elevated NO amounts, or an activity peak could trigger NO release accompanied by post_exertional malaise.

In summary, the goal of this study was to investigate whether NO concentration in the serum was related to physical activity level in people with CFS and healthy sedentary controls.

References:
(spell-checker was going crazy here so I haven't gone through this but hopefully enough information for people to be able to recognise the study)

2 Vercoulen ill, Bazelmans B, Swaninck CM, Fennis IF,
Galama 3M, Jongen Fl, Jlommes 0, Van der Meer 3W and
Bleijenberg 0: Physical activity in chronic fatigue syndrome:
assessment and its role in fatigue.) Psychiatr Res 31: 661-
673. 1997.
3 Van der Werf 8, Prins 1, Vercouten 3, van der Meer I and Bieijenberg 0: Identifying physical activity patterns in chronic fatigue syndrome using actigraph assessment. .1 Psychosom Res
49: 373-379,2000.
4 Paul L, Wood L, Behan WMH and Maclaren WM:
Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. Eur I Neurol 6: 63-69, 7996.
5 Jammes Y, Steinberg 10, Mambrini 0, Brgeon F and Delliaux
5: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise.3 Intern Med 257: 299-310,2005.
6 Bazelmans B, B]ijenberg 0, Voeten MJM, van der Meer JWM
and Fotgering 14: Impact of a maximal exercise test on symptoms
and activity in chrnnic fatigue syndrome. I Psychnsnm Rca 59:
201-208, 2005.
7 Black CD, OConnor P3 and McCully KK: Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome: Dynamic Med 4: 3-lI, 2005.
8 Kurup RK and ICurup PA: Hypothalamic digoxin, cerebraL chemical dominance and myalgic encephalomyelitis. mt I Neurosc 113: 683-701,2003.
9 Beckman IS and Koppeno] WH: Nitric oxide, superoxide and peroxynitrite: the good, the bad and the ugLy. Am .1 Physiol Cell Physiol 271: CI424-1437, 1996.
10 Kindig CA, McDonough P. Finley MR. Behnkc 81. Richardson TE, Marlin Di, Erickson HH and Poole DC: NO inhalation reduces pulmonary arterial pressure but not hemorrhage in maximal exercising horses. I AppI Physiol 91: 2674-2678, 2001.
II Nut 3, Dc Meirleir K. Mccus M, McGregor N and Engelebienne P: Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Mcd Hypothes 62: 759-765,2004.
12 Clroux 1, Kouame N, Nadeau A, Coulombe U and Lacourciere
Y: Aftereffects of exercise on regional and systemic hemodynamics in hypertension. Hypertension 19: 183-191, 1992.
13 Brown MD, Srinivasan M, Hogikyan RV, Dengel DR. Glickman
50, Galecki A and Supiano MA: Nitric oxide biomarkers increase during exercise-induced vasodilatioa in the forearm. Tnt Sports Mcd 21: 83-89, 2000,
14 Piepoli M. Coats AJS, Adamopoulos S. Bemardi L. Feng YB, Conway I and Sleight P: Persistent peripheral vasodilatation and sympathetic activity in hypotension after maximal exercise. JAppI Physiol 75: 1807-1814, 1993.
IS Shen W, Hintze TH and Wolin MS: Nitric oxide: an important signaling mechanism between vascular endotlielium and parenchymal cells in the regulation of oxygen consumption. Circulation 92: 3505-3512, 1995,
16 Tatsumi T, Matobo 5, ICawahara A, Keira N, Shiraishi I, Akashi IC, Kobara M,Thnaka T, Katamura M, Nakagawa C, Ohta B, Shirayama T, Takeda K. Asayama 1, Flits H and Nakagawa M:
Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. I Am Coil Cardiology 35: 1338-1346, 2000.
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.
18 Fulle S. Belia S. Vecchiet J, Morabilo C, Veechiet Land Fano C; Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome. Neuromuscul Disord 13: 479-484. 2003.
19 Radak Z, Puesok S. Mcseki S. Csoni T and Ferdinandy P; Muscle soreness-induced reduclion in force generation is accompanied by increased nitric oxide content and DNA damage in human skeletal muscle. Free Radic Biol Med 26: 1059-1063. 1996.
20 Ber,,stein M, Morabia A and Sloutskis 0: Deflnition and prevalence of sedentarism in an urban population. Am .1 Public Health 89: 862-867, 1999.
 

alex3619

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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
 

Dolphin

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What was the selection criteria, demographics and other relevant characterisations (eg SF-36 PF scores)?
This is about all we got:
Patients and Methods:

Subjects. CFS patients were randomly selected from the medical
files available at the host university-based chronic fatigue clinic. All patients fulfilled the CDCP criteria for CFS (1). Therefore, all subjects underwent an extensive medical evaluation by the same physician prior to study participation. The patients were contacted by telephone to verify study requirements and to invite them for participation. An age- and gender-matched healthy sedentary control group was recruited from the staff of the University Hospital of the Vrije University Brussel and from acquaintances of the researchers. Sedentary was defined as having a sedentary job and <3 h moderate physical activity/week (activity demanding at least threefold the energy spent passively) (20). Both pstients and controls were Dutch speaking and aged between 18 and 65 years old. A total of 30 CFS patients and 29 healthy sedentary controls fulfilling all study requirements were recruited.
1. Fukuda et al. (1994)

CFS: 25 Female /5 Male, HC: 25F/5M.
 

ixchelkali

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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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This is about all we got...
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
 

Dolphin

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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.
 

Valentijn

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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?
 

alex3619

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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
 

alex3619

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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
 

jeffrez

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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.
 

taniaaust1

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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.
 

alex3619

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Link to other NO paper:
I think the Suarez et al (2010) paper which involved an exercise test is more interesting:
http://forums.phoenixrising.me/show...n-During-Exercise-in-CFS-A-Case-Control-Study
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
 

alex3619

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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