Nitric oxide and its possible implication in ME/CFS (Part 1 of 2)

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Nitric oxide and its possible implication in ME/CFS (Part 1 of 2)

Andrew Gladman explores the current and historic hypotheses relating to nitric oxide problems in ME/CFS. Part 1 of a 2-part series puts nitric oxide under the microscope and explores what it is, what it does and why it is so frequently discussed in the world of ME/CFS. Part 1 focuses on what nitric oxide is, how its produced and what exactly it does ...

Over the years there have quite a number of proposed disease mechanisms relating to nitric oxide (NO) problems of patients suffering with ME/CFS. Studies have however, over the years, proven somewhat inconclusive in the past.

Dr. Pall is historically one of the staunch believers in the hypothesis that ME/CFS is a result of abnormal functioning of the nitric oxide cycle and the downstream effects this can have.

Research studies exploring nitric oxide in ME/CFS patients has however been fractured at best with some showing too much nitric oxide, while others appear to show inefficient production of the chemical messenger.

There have also been numerous theories relating to how nitric oxide could potentially induce autoimmune disease, a hot topic in the current ME/CFS research community. Equally, there have been theories proposing that ME/CFS could indeed be a result of an autoimmune response targeting the nitric oxide cycle itself.

It is the hypothesis relating to autoimmunity that this article focuses primarily upon. It's easy to see why this area of research has become somewhat stagnant, given the competing hypotheses proposed!

Because of the conflicting evidence, nitric oxide and its many related hypotheses have been stuck somewhat in hypothesis limbo. However, recent studies appear to have revived this somewhat ailing line of research and could potentially point towards a novel subgroup in the heterogeneous ME/CFS cohort.

Over the course of Part 1 and Part 2, I will aim to explore the role and function of nitric oxide, the role the endothelium plays, how the hypotheses relating to nitric oxide could explain these symptoms of ME/CFS, and the current evidence to support these hypotheses.

What is nitric oxide and what are its functions?

Nitric oxide (NO) has been discussed quite extensively in many chronic diseases. Only within the last decade have the numerous functions that nitric oxide plays begun to be fully understood.

Firstly there is the role of nitric oxide as an endothelium-derived relaxing factor (EDRF) controlling the dilation of blood vessels and therefore having a major role in vascular tone. The endothelium in itself is an important part of this new hypothesis and is much more complex than it would first appear. It is therefore discussed at greater length in the following sections of this article.

Further to this, nitric oxide acts as an intracellular messenger and neurotransmitter, as such it plays quite an important role in the nervous system, with the brain being the organ containing the highest level of nitric oxide synthase enzymes.

Further roles of nitric oxide include functions within the immune response. Nitric oxide can be produced directly by phagocytes, acting as a toxin to pathogens through its ability as a free radical to damage DNA. Furthermore, it also acts as an activator and regulator for some cells of the immune system.

Further, ME-relevant functions of nitric oxide include a major role within the genesis of the mitochondria. NO in this instance is hypothesised to act as a universal "trigger switch" -- triggering the initiation of mitochondrial biogenesis -- the production of new mitochondria.

Mitochondria is an area of research that has demanded a lot of attention the field of ME in the past with numerous papers proposing dysfunctional mitochondrial, and therefore slow cellular genesis of ATP as a central mechanism with ME.

Finally, nitric oxide has a central role in the process of sensory sensitivity of neurones within the sensory nervous system. NO activates potassium/ATP channels on the surface of the neurone and hence has direct effect on controlling the transmission of nerve impulses (action potentials). It should also be noted that this list is non-exhaustive. There are further roles of nitric oxide which are still not fully understood!

Production of nitric oxide (NO)


Image showing where the ornithine cycle connects to the citrulline-NO cycle

Nitric oxide is produced through a specialised sub-loop of a cyclical series of biochemical reactions known as the ornithine cycle (also known as the urea cycle).

The ornithine cycle is active in hepatocytes (liver cells) and is the cycle through which the harmful ammonia produced through the breakdown of proteins is converted into urea which is then excreted through the urine.

This side loop is known as the citrulline-NO cycle and is active in cells where production of nitric oxide is required for the functions discussed previously. This sub-cycle and the importance of these enzymes other than nitric oxide synthase is only recently being researched and understood in all its subtle complexities.



Human inducible nitric oxide synthase enzyme (iNOS)
By A2-33 (Own work) [CC-BY-SA-3.0], via Wikimedia Commons

A logical hypothesis to individually make could be that an autoimmune response or perhaps damage from an infection could be targeted directly towards the enzyme nitric oxide synthase (NOS), which as the name suggests has the role of producing NO via the aforementioned cycle.
This idea is something we will continue to loosely explore in this article. We will discuss much deeper the implications of this in the second part of this article series.

There are 3 different types (isoforms) of nitric oxide synthase in humans: neuronal in the nervous system, inducible in phagocytes/cardiac tissue and endothelial in the endothelium, aptly abbreviated to nNOS, iNOS and eNOS respectively.

The structural similarities of these three enzymes likely means that an autoantibody targeted at one would likely be able to bind to and hence induce the same response in any of the enzymes. This may perhaps explain the wide range of seemingly unrelated symptoms that ME patients experience.

Because these enzymes are a specialised protein with a unique ability to catalyse reactions, their shape is incredibly important, specifically the 'active site' which is where the binding and reactions the enzyme oversees occur. The binding of an autoantibody changes this vital shape of the enzyme's active site through altering the bonding and folding within the larger structure.

Simply put, an enzyme is like a highly specialised machine with unique parts that it needs to function. The binding of an autoantibody would serve to change the shape of these specialised parts, rendering the machine incapable of producing the required volume of nitric oxide.

Interestingly, research has shown that iNOS appears to be functioning normally and perhaps even overproducing NO. This seems somewhat contradictory to the hypothesis that nitric oxide is being underproduced. However in general, nitric oxide synthase is grouped into two categories, inducible and constitutive. iNOS is in the inducible category while nNOS and eNOS are in the constitutive category.

Further to this, both nNOS and eNOS are known as calcium-dependent as they require the binding of calcium to produce nitric oxide. iNOS, however, is described as being calcium-insensitive further dividing nNOS and eNOS from iNOS.

Given this information it is easier to understand why dysfunction of NO production by nNOS and eNOS could occur while the exact opposite appears to be true for iNOS. This idea of dysregulation of nitric oxide production has been explored previously as a method of disease action in ME.

There is quite a volume of evidence supporting that, whether directly or indirectly, the production on nitric oxide is severely hindered. However, the mechanism through which this occurs is likely more convoluted than it first appears, meaning researchers have to be a tad more crafty in their hypotheses, mechanisms and conclusions.

Function of the endothelium


Diagram showing endothelial location in arteries, veins and capillaries.
By Kelvinsong (Own work) [CC-BY-SA-3.0], via Wikimedia Commons

Endothelial cells are incredibly important within the human body. They are primarily found lining the interiors of blood and lymphatic vessels, being present throughout the entire circulatory system, from the heart down to a single thin layer which line the capillaries.

There are many functions provided by these cells including control of blood pressure through vasoconstriction and vasodilation, formation of new blood vessels (angiogenesis), providing a semipermeable barrier between the blood vessels and the surrounding tissue, while also aiding in the process of blood clotting.

The large number of unique and important functions has led some researchers and scientists to regard the endothelium as an independent organ within the body.

There are also highly specialised and differentiated endothelial cells elsewhere in the body performing important filtering tasks, examples being the blood-brain barrier and the renal glomeruli.

The novel approach of considering the endothelium as a dynamic organ aids in the logical understanding of these cells providing a target for an autoimmune attack. The large number of functions performed by the endothelial cells mean that the cells present quite a variety of unique extracellular proteins, any of which could act as targets for an antibody mediated autoimmune response, with nitric oxide synthase being the obvious choice considering the hypothesised importance of NO in ME.

Many of the criticisms regarding the autoimmune hypothesis as a cause of ME/CFS relate to the lack of evidence of any measurable tissue damage caused. This new hypothesis could explain why this is so. As such, a mechanism explores the potential of a non-tissue damaging and non-inflammatory autoimmune response.

Furthermore, such a mechanism could potentially explain the wide ranging systemic symptoms. Current testing methods for endothelial dysfunction are highly specific, involving fairly complex techniques such as ultrasound flow-mediated dilation (FMD) among others, which themselves do not have complete efficiency.

Any endothelial abnormalities would be difficult to detect using standard diagnostic medical techniques, and endothelial function is currently unlikely to be tested in ME patients.

One of the major functions of the endothelium is the control of vascular tone, meaning the degree to which a blood vessel is dilated. This is achieved through processes known as vasoconstriction and vasodilation. The endothelium plays a dynamic role in both processes through the production and release of many different vasoactive chemicals.

To control vasodilation, the endothelium releases endothelium-derived relaxing factors (EDRFs) such as nitric oxide, while to control vasocontriction the endothelium releases endothelium-derived contracting factors such as thromboxane and endothelin.

These chemicals are produced and released directly by the endothelial cells, with the end result being stimulation of the surrounding smooth muscle to either relax or contract, hence dilating or contracting the blood vessel. Through this process of homeostasis, blood pressure can be tightly controlled while this mechanism is also used as an important mechanism in internal heat and temperature regulation.

If this hypothesis proves correct, NO production is disrupted meaning that vasocontriction likely dominates. It is then logical to assume that sufferers of ME have a lowered ability to regulate heat through vascular means. This is clearly supported by the heat intolerance and symptom flares many ME patients experience in both extreme warm and cool weather.

A potential hypothesis relating to underproduction of NO does therefore allow for the observation of quite marked dysregulation of vascular tone and endothelial function without any direct or measurable damage to the endothelium itself.

Thankfully this means that the increased risk of atherosclerosis many other autoimmune conditions such as lupus, diabetes and rheumatic diseases unfortunately suffer with, could appear to be very minimal or non-existent in ME.

For further discussion on the cardiovascular system in ME/CFS looking beyond nitric oxide, be sure to check out the recent article published here at Phoenix Rising.

Stay tuned for the second article in this series where we dig deeper into nitric oxide hypotheses in ME/CFS.



Phoenix Rising is a registered 501 c.(3) non profit. We support ME/CFS and NEID patients through rigorous reporting, reliable information, effective advocacy and the provision of online services which empower patients and help them to cope with their isolation.

There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. and we'd love to expand our Board of Directors. So, if you think you can help then please contact Mark through the Forum.

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Comments

Dealing with multiple measures etc. can be good, but also misleading. It depends on the accuracy of the model being used. Further if interventions or changes are being looked at over time then it can get sucked into problems such as the hill climbing problem (reference to an artificial intelligence issue) where you can find local optima and minima and think it defines the space.

I do agree though that we need to map all the interacting factors and then measure them all. I have long thought that we really need to see if the percentages of patients who have particular issues or fall into particular subgroups can actually do that for many subgroups simultaneously.

While the deficits of the current CDC investigation are obvious, it at least allows for many variables to be studied simultaneously. I do not know enough about specific measures though to tell if its adequate.

Another problem that can arise is due to the nature of that being measured. Most measures from blood are whole body averages. There are also temporal issues. This tells us far less than I like about what is happening in specific locations, or at specific times.

Yet investigation has to start somewhere.

Yet static timepoint measures tell us not that much about dynamic issues.

One thing that might would be to take a small number of patients, say 10, then track every kind of testing there is over time, say 100 days. That is probably too long for patients to cope, so maybe 10 days would suffice, or every tenth day over a long time frame, or something similar. In other words we need detailed longitudinal measures.

Sadly our scientific process is still not advanced enough to deal with real complexity in large complex dynamic processes. Yet we have to start somewhere.
 
http://townsendletter.com/FebMarch2010/cureNO0210.html

Table 1: Agents with Favorable Response in Clinical Trials Predicted to Lower Aspects of the NO/ONOO− Cycle.

Agent(s) Probable Mechanism Comments


flavonoids, ecklonia cava extract, algal supplements

chain breaking and other antioxidant activity

Some may act as peroxynitrite scavengers.

NMDA antagonists, other agents that indirectly lower NMDA activity; magnesium

All act to lower excessive NMDA activity


acetyl carnitine/carnitine, coenzyme Q10, low hyperbaric or normobaric oxygen

Improved mitochondrial function

Oxygen must be used with caution, particularly in severe cases of CFS/ME

hydroxocobalamin form of vitamin B12

Reduced in vivo to a form that is a potent nitric oxide scavenger.

Higher dosage (i.e., 5 to 10 mg) needed than is needed to treat a B12 deficiency; Typically used via IM injection, as an inhalant, or via nasal spray to obtain high blood levels; oral or sublingual should be useful but are clearly suboptimal because of limited absorption.

high-dose folates

Serves as precursor of 5-methyltetrahydrofolate (5-MTHF), a potent peroxynitrite scavenger.

Unclear whether folic acid, folinic acid, 5-MTHF and/or other forms of folate should be used; folic and folinic acid tested in published trials.

D-ribose, RNA, inosine

All act to increase uric acid levels (peroxynitrite scavenger); all may act to help restore ATP pools.

Published trial on D-ribose; trial currently in progress suggesting inosine can be helpful.

IV high dose, buffered ascorbate

Lowers both ends of central couplet (see below); may be particularly helpful agent.

Discussed in detail below.

sauna therapy

Acts to increase BH4 availabiity; mechanism via increased synthesis of GTP cyclohydrolase I.13

Trials published on MCS, FM and CFS/ME; discussed further below.

fish oil

Established as anti-inflammatory agent.

May also improve brain function.

Most studies involved CFS/ME and/or FM; however studies with sauna therapy and IV ascorbate have been published with MCS patients.
 
These last weeks my quest has been to understand NO and ammonia. I searched for a website for Martin Pall several times, but found nothing. Now @Gondwanaland linked me to an article about NO/ONOO- on the Inspire website. (This site puts a dark shield over the content unless you've joined. But I was able to copy the content and paste into a document, got the whole page fine....Having joined and then unjoined, I'm no longer able to access the page.:meh:) From that site I followed a link to a Yahoo NO/ONOO- forum, to which Pall, at least historically, responds. And from there I found his website.
I found the Yahoo group to be pretty inactive, with most of the posts of the past year concerning MCS and EMFs. However, it exists as a forum for asking questions. And in the File section there are a number of files and links. The forum and website are named The Tenth Paradigm.

I've also gotten much closer to understanding Pall's work from his 2 hour video from March 2014. The last 20" lists his suggested supplements, which are also covered on his site. I've gotten good symptom relief following his suggestions to add ALCAR, AdB12, reseveratrol, watermelon, switch my E succinate to Gamma E.

https://www.youtube.com/watch?feature=player_detailpage&v=6A7r1gemjto


https://groups.yahoo.com/neo/groups/TenthParadigmSociety/info
Group Description
"Every TRUTH passes through three stages before it is recognized. In the first, it is ridiculed. In the second, it is opposed. In the third, it is regarded as self-evident." ~~ Arthur Schopenhauer

The Tenth Paradigm Society mailing list is for the dissemination and discussion of information concerning the NO/ONOO- cycle mechanism, a new paradigm of human disease, proposed by Martin L. Pall, Ph.D.

Dr. Pall adopted the term "Multisystem Illness" to describe those diseases that fall under the tenth paradigm. They include: Chronic Fatigue Syndrome (CFS/CFIDS/M.E.), Multiple Chemical Sensitivity (MCS), Fibromyalgia (FM/FMS), Post-Traumatic Stress Disorder (PTSD), and Gulf War Syndrome (GWS).

There are fourteen other illnesses which are suspected of falling under this new disease paradigm. They are: Irritable Bowel Syndrome, Asthma, Tinnitus, Post-Radiation Syndrome (experienced by clean-up workers at Chernobyl), Multiple Sclerosis (MS), Autism, Overtraining Syndrome, Silicone Implant Associated Syndrome, Sudeck's Atrophy (a.k.a. Reflex Sympathetic Dystrophy), Post-Herpetic Pain, Chronic Whiplash-Associated Disorder, Amyotrophic Lateral Sclerosis (a.k.a. ALS or Lou Gehrig's Disease), Parkinson's Disease, and Alzheimer's Disease.

We will also discuss the research indications for treatment of these illnesses pointed to by the NO/ONOO- cycle and the implications for lifestyle, the environment and disability.

DISCLAIMER: Information provided here is intended for your general knowledge only and is not a substitute for professional medical advice or treatment for specific medical conditions. It is not intended to diagnose, treat, cure or prevent any disease.

More information about the Tenth Paradigm can be found at: http://www.thetenthparadigm.org/index.html

Dr. Pall's new book "Explaining Unexplained Illnesses" can be ordered from Amazon.com and other booksellers.
 
One of the first things I noticed when I got M.E., the very first day, was that my veins collapsed. I used to have garden hoses for veins now it looks like indentations where they used to be.
this.
i've never been veiny to any extent, but nowadays this got much worse - no any pump whatsoever in the gym.

Collapsed veins might be due to a crash in blood volume, but a failure of NO synthesis by the endothelium is another possibility.
Indeed the blood volume thing crossed my mind.. as did the idea that due to low blood volume the reduced NO production might be a correct physiological response in order to maintain local blood pressure. Obviously it's equally possible that overproduction of OO, ONOO in place of NO is causing the same effect.
some food for though from my personal experience - eatin table salt as crazy (like 1/2 teaspoon 30min before each meal, sublingual) does indeed makes me feel much better and stronger.

on the other hand any NO busters like arginine, citrulline, beet juice always makes me feel weaker, in the gym at least.

is there any way to determine the case - low blood volume or not? any definitive signs of NO overproduction only?
 
this.
i've never been veiny to any extent, but nowadays this got much worse - no any pump whatsoever in the gym.




some food for though from my personal experience - eatin table salt as crazy (like 1/2 teaspoon 30min before each meal, sublingual) does indeed makes me feel much better and stronger.

on the other hand any NO busters like arginine, citrulline, beet juice always makes me feel weaker, in the gym at least.

is there any way to determine the case - low blood volume or not? any definitive signs of NO overproduction only?
Definitive certainty in medicine is not quite as elusive as the holy grail, but almost. The best you can hope for is usually strong hunch worth investigating.

NO affects so much, I suspect it would be difficult to be sure though @alex3619 might have a better idea. But the issue might not only be NO overproduction, but production of ONOO instead of NO.

The two things that told me that blood volume as the issue were: I felt much better if I could drink a full two pints of water swiftly. I felt great when given 1.5litres of saline solution.

The two most common causes of low blood volume if you have not had serious injury are the two anti-urination hormones, one cauess sodium loss, the other potassium loss.
  1. If you are craving salty food and still have low normal or low Sodium that indicates Aldosterone deficiency might be the issue.
  2. If you are craving Potassium Sources such as Potatoes or Bananas and still have low Potassium that could indicate AVP deficiency.
The two hormones themselves can be tested for but GPs are not fond of doing the tests, they prefer the cheaper serum electrolytes which we often mess up the results of by compensating with diet.
 
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http://townsendletter.com/FebMarch2010/cureNO0210.html

Table 1: Agents with Favorable Response in Clinical Trials Predicted to Lower Aspects of the NO/ONOO− Cycle.

Agent(s) Probable Mechanism Comments


flavonoids, ecklonia cava extract, algal supplements

chain breaking and other antioxidant activity

Some may act as peroxynitrite scavengers.

NMDA antagonists, other agents that indirectly lower NMDA activity; magnesium

All act to lower excessive NMDA activity


acetyl carnitine/carnitine, coenzyme Q10, low hyperbaric or normobaric oxygen

Improved mitochondrial function

Oxygen must be used with caution, particularly in severe cases of CFS/ME

hydroxocobalamin form of vitamin B12

Reduced in vivo to a form that is a potent nitric oxide scavenger.

Higher dosage (i.e., 5 to 10 mg) needed than is needed to treat a B12 deficiency; Typically used via IM injection, as an inhalant, or via nasal spray to obtain high blood levels; oral or sublingual should be useful but are clearly suboptimal because of limited absorption.

high-dose folates

Serves as precursor of 5-methyltetrahydrofolate (5-MTHF), a potent peroxynitrite scavenger.

Unclear whether folic acid, folinic acid, 5-MTHF and/or other forms of folate should be used; folic and folinic acid tested in published trials.

D-ribose, RNA, inosine

All act to increase uric acid levels (peroxynitrite scavenger); all may act to help restore ATP pools.

Published trial on D-ribose; trial currently in progress suggesting inosine can be helpful.

IV high dose, buffered ascorbate

Lowers both ends of central couplet (see below); may be particularly helpful agent.

Discussed in detail below.

sauna therapy

Acts to increase BH4 availabiity; mechanism via increased synthesis of GTP cyclohydrolase I.13

Trials published on MCS, FM and CFS/ME; discussed further below.

fish oil

Established as anti-inflammatory agent.

May also improve brain function.

Most studies involved CFS/ME and/or FM; however studies with sauna therapy and IV ascorbate have been published with MCS patients.
Hi Heaps,

A very comprehensive list there!

It's also worth mentioning that good BH4 availability is required to produce NO rather than NOO or ONOO. It's effect in NO production is very similar to that of Cobamide if deficient when the producing enzyme is formed.
 
Let me point out some cross links in research. There was a paper last year I think that discussed possible acetylcholine receptor autoantibodies. Just a few days ago, there was a paper discussing ion channelopathy and acetylcholine receptor snps, single nucleotide polymorphisms. Different aspects of a bigger picture may be emerging, though the details are as yet elusive and any of this research may not stand up to long term scrutiny.

If all this is right there might be different types of ME and CFS, each targeting slightly different parts of the same interlocking pathways. So some might respond to NO very well, and others might not,

All of this is still very speculative, but its also encouraging.
 
The two most common causes of low blood volume if you have not had serious injury are the two anti-urination hormones, one cauess sodium loss, the other potassium loss.
  1. If you are craving salty food and still have low normal or low Sodium that indicates Aldosterone deficiency might be the issue.
  2. If you are craving Potassium Sources such as Potatoes or Bananas and still have low Potassium that could indicate AVP deficiency.
The two hormones themselves can be tested for but GPs are not fond of doing the tests, they prefer the cheaper serum electrolytes which we often mess up the results of by compensating with diet.
i think trough the last years my electrolytes are going down constantly, all of them, so i have low normal sodium and potassium at the same time. and this is how my gym shirt looks like after just 3-4 sessions (front and back):


P930010t4.JPG P93001s05.JPG


so there's definitely something is going on with a mineral loss.
my aldosterone was 335 pg/ml (ref 40-310 and 10-160), so def no deficiency here.
direct renin was 35.7 mcME/ml (ref 4-46 and 4-40)
ACTH 45 pg/ml (ref <46)

don't know about AVP, but since it stimulates ACTH secretion it's probably ok too?
 
i think trough the last years my electrolytes are going down constantly, all of them, so i have low normal sodium and potassium at the same time. and this is how my gym shirt looks like after just 3-4 sessions (front and back):


View attachment 15222 View attachment 15223


so there's definitely something is going on with a mineral loss.
my aldosterone was 335 pg/ml (ref 40-310 and 10-160), so def no deficiency here.
direct renin was 35.7 mcME/ml (ref 4-46 and 4-40)
ACTH 45 pg/ml (ref <46)

don't know about AVP, but since it stimulates ACTH secretion it's probably ok too?
When I had low blood volume, I did not sweat at all, my body preserved the fluid, so my gut hunch unless somebody else knows better would be you do not have that issue.

I wonder whether this might be more in the realm of expertise a Sports Nutritionist would have rather than an ME forum - I am just thinking electrolytes and sport are commonly discussed?
 
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Let me point out some cross links in research. There was a paper last year I think that discussed possible acetylcholine receptor autoantibodies. Just a few days ago, there was a paper discussing ion channelopathy and acetylcholine receptor snps, single nucleotide polymorphisms. Different aspects of a bigger picture may be emerging, though the details are as yet elusive and any of this research may not stand up to long term scrutiny.

If all this is right there might be different types of ME and CFS, each targeting slightly different parts of the same interlocking pathways. So some might respond to NO very well, and others might not,

All of this is still very speculative, but its also encouraging.
I think we have both been of the view for some time Alex that ME represents multiple subgroups each with different aetiologies. My personal suspicion is that there may well not be single aetiology per individual patient, rather a combination of two or three interlocking factors. Personally, pre-ME I have always sweated profuseley despite previously good fitness, hence my issue with blood volume may always have had an underyling water metabolism issue without the same impact as now.
 
When I had low blood volume, I did not sweat at all, my body preserved the fluid, so my gut hunch unless somebody else knows better would be you do not have that issue.
interesting.
maybe you're not hydrated that well - i drink like 3-4 L of clear water a day.
but anyway - the more pronounced effects of low blood volume/pressure i experience - the more i sweat in the gym, not less, that's for sure.

I wonder whether this might be more in the realm of expertise a Sports Nutritionist would have rather than an ME forum - I am just thinking electrolytes and sport are commonly discussed?
i was doing sports before i got CFS, but never experienced such a massive salts loss ever in my life.

Personally, pre-ME I have always sweated profuseley despite previously good fitness
me too, except that am still sweatin like a mofo to this day.
 
i think trough the last years my electrolytes are going down constantly, all of them, so i have low normal sodium and potassium at the same time. and this is how my gym shirt looks like after just 3-4 sessions (front and back):


View attachment 15222 View attachment 15223


so there's definitely something is going on with a mineral loss.
my aldosterone was 335 pg/ml (ref 40-310 and 10-160), so def no deficiency here.
direct renin was 35.7 mcME/ml (ref 4-46 and 4-40)
ACTH 45 pg/ml (ref <46)

don't know about AVP, but since it stimulates ACTH secretion it's probably ok too?
What are these pics of?

GG
 
What are these pics of?

GG
In my case I was drinking 14 litres of liquid a day to keep volume levels barely acceptable! My body just was not able to retain fluid due to Aldosterone deficiency. Medication side effects were also an issue.

ACTH can be stimulated by CRH with no AVP present, so not that does not necessarily follow!
A better indication would be how often you urinate and whether you feel dry with the levels of water you drink.
Having a good electrolyte balance makes hormone imblance seem unlikely, but it does depend on your electrolyte intake, I confounded tests by drinking salty water.

I don't really know enough about the regulatory mechanism for sweating to advise you on that. That was my reason for wondering whether a sports nutritionist might be a better source of advice re electrolyte consumation and sweating out what may be electrolytes.