Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients, Bertinat et al (2022)

"ACE2, Much More Than Just a Receptor for SARS-COV-2."
URL=https://www.frontiersin.org/article/10.3389/fcimb.2020.00317
Ang II activates neutrophils and macrophages flux to the affected tissues and inhibits the production of nitric oxide
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Just came across this and thought of this thread.

I am still trying to make sense of it all but as I am understanding it... through a thick headache...

Given the nature of NO, its reduction in the experiment linked in the OP would imply some kind of ongoing inflammatory process in ME, if it proves replicable.

We dont know if it is AngII doing this but AngII also has this effect and is famous because of COVID as it is antagonistic to the product of ACE2 (which is Ang1-7) and may be implicated in COVID pathology (as the virus binds to ACE2 to enter cells).

So I would guess this finding might attract a little extra attention for that reason.

I still think replication is the first priority but would hope people would be more likely to try that because of the interest in COVID research.
 
I’m not up to reading much, but yesterday I was trying to understand this general area via YouTube explainer videos. It seems like NO issues might relate more generally to immune, neurological and cardiovascular/autonomic function. That sounds like a promising intersection for us, is there anyone here able to explain that succinctly? And could this specific result be a sign of those larger issues?

I’m puzzled too by the direction of the vasoconstriction issues - with my POTS I’m definitely having too much vasodilation, it’s visible.

A larger replication should be funded as a priority.
 
Eg is this relevant https://www.frontiersin.org/articles/10.3389/fphys.2015.00020/full
fphys-06-00020-g001.jpg

Haven’t been able to read article but
“Figure 1. Interrelation between nitric oxide and mitochondria in the pathophysiology of metabolic syndrome (a, in the vascular wall; b, in an adipocyte; c, in a hepatocyte). a: Insulin resistance contributes to decreased activities of signaling molecules, which leads to decreased eNOS activity. Superoxide generated in mitochondria can modestly, and peroxynitrite can strongly, oxidize BH4–BH2, leading to uncoupling of eNOS, increased production of ROS and endothelial dysfunction. Moreover, mtNOS becomes “uncoupled”; it switches from a NO-generating enzyme to a superoxide-producing enzyme. Increased production of peroxynitrite and superoxide anions generated from uncoupled mtNOS and eNOS damage mitochondrial ETC complexes, leading to mitochondrial dysfunction. eNOS then generates superoxide rather than NO, which contributes to vascular oxidative stress and further reduces NO bioavailability. Excessive mtNOS-derived NO can produce reactive nitrogen species, such as peroxynitrite, which may cause tyrosine nitration of mitochondrial components and may play a key role in apoptosis. Under the conditions of oxidative stress, the enhanced activity of iNOS, with less contribution of nNOS, in vascular smooth muscle cells induces the development of chronic metabolic inflammation.”
(Rene Sugar shared on Twitter)
 
Answering my own question

Salivary NO2− strips have a high level of reproducibility and repeatability in detecting changes in salivary NO2−.

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Salivary strips are not sufficiently accurate for the measurement of absolute concentrations of NO2−in saliva.

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The use of mouthwash produced an immediate and almost total suppression of the NO3−-reducing capacity of the oral bacteria.
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https://www.sciencedirect.com/science/article/abs/pii/S1089860319301363

so it seems like they’re worthwhile if you want to see if something can change your nitric oxide levels but not necessarily if you want to know if your levels are generally low.
 
When I was taking L arginine I was taking it at a much higher dose with other things.

Around 7 to 10g a day I think.

As a power mixed with a whey drink with the other stuff i was taking the whole lot with the aim of helping the endothelial lining of the circulation system.

It did do something, I gained an extra few percent capability, but 3 300ml whey drinks a day was calorific.

And a fair amount of work and cost.

Trying to do it whilst not at home sunk it, broke it from my routines and I haven't restarted it for more than the odd one, which stopped when the whey mix started tasting funny and it was over 50 quid for a new pouch.

For 50 quid plus they didn't even supply a tub.
 
By the way, I've read that regular exercise increases NO levels. If their theory is correct, does that mean that mild / moderate exercise could be beneficial if it doesn't trigger PEM? What about the results from the GET studies, maybe this has something to do with the positive results?
 
borko2100 said:
If their theory is correct, does that mean that mild / moderate exercise could be beneficial if it doesn't trigger PEM?
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It might but we need to see a lot more research. Of particular interest to me is the role of NO in memory and cognitive function, its not just about exercise. Of course avoiding PEM might be a major problem even if one is trying to do so while exercising.

borko2100 said:
What about the results from the GET studies, maybe this has something to do with the positive results?
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What positive results are in consideration? Their results are nearly all subjective outcomes in unblinded and potentially highly biased studies. The objective outcome measures that have been used consistently show no positive results, and one meta-analysis showed a decline in patient performance. Five independent reviews of outcomes in real world populations, three in Belgium, showed no positive results. The PACE trial showed a deliberate use of inappropriate data analysis that is known to create bias, namely the use of SD on SF36PF data that the main investigator knew produced a biased result ... he wrote a paper on it. Now we have the new NICE guidelines which do not consider there is sufficient evidence of efficacy to recommend GET in particular.

First we would have to identify clearly reliable positive results in order to even begin trying to figure out why. Current evidence of any positive results seem highly unreliable at best.
 
Isn't there a link between high RDW and NO? I wonder if this relates to decreased red blood cell deformability someone (Ron Davis and others?) found in pwME?
 
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borko2100 said:
By the way, I've read that regular exercise increases NO levels. If their theory is correct, does that mean that mild / moderate exercise could be beneficial if it doesn't trigger PEM? What about the results from the GET studies, maybe this has something to do with the positive results?
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Long way to go from that to this tiny study. There was overlap between NO levels in vitro anyway, although they results were pretty interesting, so, I'm not sure NO alone is the explanation. If it was replicated, whatever is causing low NO would likely be involved in other things as well. It did bring nnos to my attention, which is involved in creating fatigue and post-exercise fatigue, but I believe it is describing a more local fatiguing problem versus me/cfs fatigue.

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise.
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Removing inaccuracies in reality, where it is at variance with doctrine (clinical experience) to elucidate and enhance the truth?
 
boolybooly said:
I wonder what in ME patient plasma increases phosphorylation of eNOS in HUVECs?
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From Nitric oxide signalling in cardiovascular health and disease (Nature, 2018)

The constitutively expressed nNOS and eNOS are highly regulated by transcriptional, post-transcriptional (including microRNA), and post-translational mechanisms, including phosphorylation, acetylation, protein–protein interaction, S-nitrosylation, and S-glutathionylation. Conversely, the inducible isoform, iNOS, is mainly regulated through gene transcription under pro-inflammatory and oxidative stress conditions.
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