Nitric Oxide Metabolite Production During Exercise in CFS: A Case-Control Study

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Tate Mitchell to CO-CURE today

Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study

Surez A, Guillamo E, Roig T, Blzquez A, Alegre J, Bermdez J,
Ventura JL, Garca-Quintana AM, Comella A, Segura R, Javierre C.
J Womens Health (Larchmt). 2010 May 14. [Epub ahead of print]

1 Department of Physiological Sciences II, Medical School, University
of Barcelona , L'Hospitalet, Barcelona, Spain .

http://www.ncbi.nlm.nih.gov/pubmed/20469961


Abstract

Abstract Background: Chronic fatigue syndrome (CFS) is a disabling
illness of unknown etiology that is characterized by fatigue
associated with a reduced ability to work, lasting for more than 6
months, and accompanied by a specific set of symptoms. The diagnosis
remains difficult because of the absence of laboratory tests and is,
therefore, made largely on the basis of the symptoms reported by the
patient.

The aim of this study was to analyze differences in blood
nitrate levels in CFS patients and a matched control group after a
physical exercise test.

Methods: Forty-four consecutive female
patients with CFS and 25 healthy women performed an exercise test
using a cycle ergometer with monitoring of cardiopulmonary response.
Blood samples were obtained for biochemical analyses of glucose,
lactate, and nitrates at the beginning (under resting conditions) and
after the maximal and supramaximal tests.

Results: Plasma nitrates
differed between the groups, with higher values in the CFS group (F =
6.93, p = 0.003). Nitrate concentration increased in relation to
workload and reached higher values in the CFS group, the maximum
difference with respect to the control group being 295% (t = 4.88, p <
0.001).

Conclusions: The main result of the present study is that
nitric oxide (NO) metabolites (nitrates) showed a much higher increase
after a maximal physical test in CFS patients than in a group of
matched subjects. This combination (exercise plus NO response
evaluation) may be useful in the assessment of CFS.

PMID: 20469961 [PubMed - as supplied by publisher]
 
D

DysautonomiaXMRV

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Hi, I was forced to do exercise in a Gym when hospitalised after being diagnosed with POTS and being in hospital for 6 months. I've had ME for 19 years.(of ME).
I was told POTS was a form of somatization disorder, due to my mother believing I had ME.

So in the gym, I did what they commanded with obvious effects afterwards with someone who was bed ridden 22hrs a day.

I had the presence of mind to get urine samples done post exercise (back in the ward I always become very unwell) and it showed elevated nitrites, which would confirm the research above - because of oxidative stress and Nitric Oxide being elevated in ME/CFS at rest, never mind after exercise. (I know I have that as I got tested and it showed tissue damage).

Great research, thanks for posting it's good to see someone finding out at a research level in ME CFS , what I found out 5 years ago by guess work but was never listened to by doctors.
 
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Thanks for posting. This is interesting.

This appears to be testing out Martin Pall's theory re: elevated levels of peroxynitrite being the cause of Chronic Fatigue Syndrome. I don't have access to the full text, but I'd be curious to know if they cited Dr. Pall. My understanding is that there have been a number of theoretical papers about nitric oxide (NO) being implicated as a cause of CFS, but that it's difficult to test this.

Let's hope that some other researchers follow up with some further studies.

ps: Here's a link to the abstract of one of Dr. Pall's theoretical articles re: nitric oxide and CFS/ME -

Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Pall ML. Medical Hypotheses. 2000 Jan;54(1):115-25.
 

Dolphin

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Most of the introduction

Thanks for posting. This is interesting.

This appears to be testing out Martin Pall's theory re: elevated levels of peroxynitrite being the cause of Chronic Fatigue Syndrome. I don't have access to the full text, but I'd be curious to know if they cited Dr. Pall. My understanding is that there have been a number of theoretical papers about nitric oxide (NO) being implicated as a cause of CFS, but that it's difficult to test this.

Let's hope that some other researchers follow up with some further studies.

ps: Here's a link to the abstract of one of Dr. Pall's theoretical articles re: nitric oxide and CFS/ME -

Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Pall ML. Medical Hypotheses. 2000 Jan;54(1):115-25.
Yes, they did reference Dr. Pall.

One theory about the etiology of CFS is that it is related to
elevated peroxynitrite levels.7 Increased levels of inflammatory
cytokines, including tumor necrosis factor-a (TNF-a),
interleukin-1 (IL-1), interleukin-6 (IL-6), and interferon-g
(IFN-g), stimulate the production of elevated levels of inducible
nitric oxide synthase (iNOS), which in turn synthesizes
increased amounts of nitric oxide (NO). NO reacts rapidly
with superoxide to form peroxynitrite, a potent oxidant. The
elevated peroxynitrite and NO then impact the tissues involved,
producing some of the symptoms of CFS.8 Oxidative
stress and NO have been proposed to play an important role
in CFS pathophysiology.9 Maes et al.10 found that the production
of cyclooxygenase-2 (COX-2) and iNOS was significantly
higher in CFS patients than in normal controls,
showing significant and positive intercorrelations between
COX-2, iNOS, and nuclear factor-kb (NF-kb) and between
COX-2 and iNOS on the one hand and the severity of illness
on the other. NO, synthesized from l-arginine by NOS,
reacts rapidly with the heme group; indeed, the affinity
of heme for NO is higher than that for oxygen. In the absence
of oxygen, NO is bound to hemoglobin in a relatively stable
form, but in the presence of oxygen, it is converted to nitrate
and binds to the heme iron. The hemoglobin is thus oxidized
to methemoglobin, and, finally, the nitrate is excreted in the
urine.11

7. Pall ML. Elevated, sustained peroxynitrite levels as the cause
of chronic fatigue syndrome. Med Hypotheses 2000;54:115
125.
8. Pall ML. Elevated peroxynitrite as the cause of chronic fatigue
syndrome: Other inducers and mechanisms of symptom
generation. JCFS 2000;7:4558.
9. Nijs J, De Meirleir K. Oxidative stress might reduce essential
fatty acids in erythrocyte membranes of chronic fatigue
syndrome patients. Nutr Neurosci 2004;7:251253.
10. Maes M, Mihaylova I, Kubera M, et al. Not in the mind but
in the cell: Increased production of cyclo-oxygenase-2 and
inducible NO synthase in chronic fatigue syndrome. Neuroendocrinol
Lett 2007;28:463469.
11. Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology,
pathophysiology, and pharmacology. Pharmacol Rev 1991;
43:109142.
 

Dolphin

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Dolphin

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Figure 1

Figure 1:

One doesn't have to know much about NO to realise that a difference like this in CFS might be interesting!
 

alex3619

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Hi Dolphin, Marty is probably enjoying this paper. The nice thing about the graph is there is absolutely no overlap between patients and controls. This begs a follow-up study or three. Bye, Alex
 
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This looks very interesting both because of the size of the difference and because it's based on an exercise challenge. Does the paper say how 'sedentary' the controls were relative to patients (eg SF36 PF for both)?
 

Dolphin

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This looks very interesting both because of the size of the difference and because it's based on an exercise challenge. Does the paper say how 'sedentary' the controls were relative to patients (eg SF36 PF for both)?
No SF-36 scores (I'm not sure they would be that useful for controls - I imagine most healthy controls would be 80+, possibly 90+ - i.e. they can go for walks, etc. without difficulty, they just don't do them)
The CFS group comprised 44 female patients (mean age
46.59.4 years) with a mean weight of 64.911.3 kg, mean
height of 1.620.05 m, and mean body mass index (BMI) of
24.73.5. They were referred consecutively to the Department
of Physiological Sciences II of the University of Barcelona
for a battery of examinations, and all were free of other
diseases. They all met the Centers for Disease Control and
Prevention (CDC) criteria for CFS,2 and in each case, the diagnosis
was confirmed by consensus between two physicians.
Twenty-five healthy women (mean age 41.08.6 years) with
a mean weight of 63.87.7 kg, mean height 1.610.06 m, and
mean BMI of 24.83.4 served as the control group. The
controls were considered to be sedentary subjects on the following
grounds: their occupation did not require physical
effort, they did not perform any special physical activity, and
all their other activities (e.g., hobbies) were sedentary. Mean
energy expenditure in the CFS group was 1.20.1METS=h
during the day and in the control group 1.30.1METS=h
during the day, expressing the energy cost of daily physical
activity in both groups (by convention, 1 MET equals 3.5mL
O2=kg=min or, equivalently, 1 kcal or 4.184 kg=h).
A VO2 max of 25.6 for the control group is quite a lot score - some CFS groups would score higher than that:
In the maximal test, the CFS group achieved a lower
maximal workload (77.4+/-27.4 W) than the control group
(132.6 +/-29.0 W) ( p<0.001). In the supramaximal test, the
maximal workload in the CFS group was again lower
(147.6+/-60.9W vs. 236.2+/-53.9 W) ( p<0.001). The oxygen
uptake pattern at the three time points (rest, maximal, and
supramaximal) also differed between the groups, with lower
values in the CFS group (F19.8, p<0.001). The maximal
peak of _VVo2 with respect to body weight was 33% lower in the
CFS group (t5.7, p<0.001): 17.1+/- 5.5mL=kg=min in the
CFS group vs. 25.6+/-6.0mL=kg=min in the control group.
 
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This looks really solid and could prove to be very important. As ever, what's needed is independent replication.

I'd also like to see them testing under 'real world' exercise conditions: CFS patients don't normally push themselves to this kind of maximal exertion or close to it - and don't need to for PEM to emerge. Encouragingly, the authors write:
Further studies are needed to examine possible differences in
response to submaximal (rather than maximal and supramaximal)
exercise in CFS patients