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Funky Sympatholysis

At the moment my present idea of exercise is more appropriate for playing with the family dog: "Sit up. Roll over. Play dead."

My Memorial Day weekend was the kind of memorable occasion I'd like to forget. I had a minor illness which others here will recognize as a serious problem when it comes on top of ME/CFS. It was nothing more than an apparent viral upper respiratory infection with little fever: no point in going to a doctor even if possible. The catch naturally was that there was no posture in which I could be comfortable. Lying supine and drowning was out, while sitting up presents difficulties after some minutes even without a respiratory problem. Lying prone was another non-starter. I ended up mostly on one side or another with a roll of toilet paper rather than the box of tissues (which ran out.) Did I mention coughing? Living on oatmeal limited my gastric problems from material that drained in that direction.

Since I can't forget this episode, I'll try to use some thoughts it provoked concerning exercise to illustrate a fact of human physiology most people never hear about, because it happens without their awareness. That assumes an ingenious evolutionary solution to the problem of upright posture is working, which may be true for 99% of the population without ME/CFS.

What I'm discussing may not be that important to those of you with some other form of this illness, but for those who have serious issues with orthostatic intolerance it could be an eye opener. If you can only spend 4 hours a day upright without deteriorating, over a period of days or weeks, you will find this more enlightening than others.

Some four-legged animals can sleep standing up. Horses are a good example, though even there you can find a few who like to lie down in a safe location. It would seem safe to assume their sympathetic nervous system is not unusual active while asleep. Even if their brains are quite active there will be a block on movement while dreaming which prevents them from acting out horse nightmares which might carry them to doom. (Anyone with actual observations on horse nightmares feel free to chime in.)

The point is that it takes very little activity by voluntary muscles to keep a horse standing, even asleep. This is not true of humans, even if I've known some in military service who made the attempt.

Upright posture on two legs is a balancing act, and for animals approaching two meters tall there must be a corresponding hidden balancing act dealing with the flow of blood to various parts of the body. To prevent most of your blood ending up below the waist, there must be vasoconstriction to prevent blood vessels expanding under increased pressure due to the gravity gradient. This is a classic example of something the sympathetic nervous system is used for.

There is, however, a catch. Those muscles which were not active while you were horizontal must now have increased blood supply when you are standing to cope with the increased workload. Since muscle activity without an oxygen supply results in local hypoxia, this becomes the trigger for a process called functional sympatholysis. Even a brief episode of hypoxic activity in a muscle should trigger a biochemical change which causes the associated blood vessels to relax the vasoconstriction due to the heightened sympathetic activity in upright posture, allowing increased flow of oxygenated blood to muscles in use maintaining posture.

Added: I'm disappointed in all the overview articles I've seen explaining the subject to non-specialists, and the reference above is heavy. Here's a conference indicating that the reason for this lack of a simple overview is that the subject is still a work in progress.

Added later: Here's a review of purinergic signalling in autonomic function which may help. Burnstock is the discoverer of purinergic signalling.

The chemical changes of local anaerobic metabolism result in definite changes in metabolites of energy production, including those classified as purines like ATP or ADP. Functional sympatholysis is controlled by a purinergic signalling cascade.

This is far from the only thing these metabolites do. In various aspects of the cell danger response these same molecules are attached as markers to misshapen biomolecules, even multiple times. The resulting complex powers organelles within the cell responsible for degrading foreign or misfolded molecules. In infectious disease this diversion of energy resources has a secondary effect of causing the infected host to reduce activity and avoid conflict until the infection passes. In a life-threatening short-term emergency the host can overcome these metabolic advisories temporarily to avoid being eaten via a burst of endocrine hormones kicking in the fight-or-flight response. When the problem is not short-term things get nastier.

Chronic diversion of ATP to pathways that degrade complexes like the combination of autoantibodies and target molecules will result in a form of chronic illness resembling the abnormal fatigue of infectious disease. Except for the case of vasovagal syncope, where you get a kind of rest by passing out when blood pressure drops as sympathetic vasoconstriction suddenly relaxes, all muscular activity will require an active sympathetic nervous system. If you already had purinergic signalling taking place before muscular activity there won't be much functional sympatholysis increasing blood flow to active muscles. Cramping is almost certain.

Note that we are talking about hypoxia in tissues around particular muscles, not a drop in O2sat, and not necessarily what somebody else considers your overall anaerobic threshold. We are also talking about a defect in a very specific physiological function.

Now, supposing you tried to explain this to a generic M.D., what would happen? Well, a prescription for exercise is certain because exercise is known to increase functional sympatholysis. "If you spent more time windsurfing and wrestling alligators you wouldn't have these cramps in unused muscles." One thing I can assure you the "expert" will not think is that exercising muscles which are already above local anaerobic threshold (no matter what state other parts of your body are in at the same time) is simply going to make the problem worse.

So, my situation last weekend, constantly finding new muscles which had not given any problem earlier suddenly cramping when needed to cough or avoid postural collapse has an explanation.

This isn't entirely due to a recent change. I've noticed a problem with an ache in my shoulders and neck when I've been upright too long, which I now know is called "coathanger ache" (as if you left the coathanger in when you put on a shirt,) since I got my six-foot height at age 16.

Back in those halcyon days when I could perform exercise that actually looked like exercise to other people, I had noticed that I was exceptionally prone to problems like cramps and pulled muscles if I was not very careful about warm-up and stretching. Any card-carrying psychobabbler will immediately deduce that this put me off exercise, with all concomitant problems. This would be thoroughly wrong.

What I did instead was make a careful study of the problem of stretching, this was also when I acquired my first books on the physiology of exercise. The majority of books on stretching were positively harmful. If you went through the routines and performed range-of-motion tests you could see range-of-motion decrease as natural means of protecting joints from overextension were triggered. Even books aimed at rehabilitation medicine regularly carried bad advice for people with what was then a relatively minor problem of mine.

The book I settled on was never the most popular, but it was written by a medical doctor who had carefully studied how to avoid training injuries in team sports. Believe me, these degrade performance a lot more than training enhances it. It had explicit diagrams for how to deal with each muscle group needed in particular activities. This added about 30 minutes to a workout, but the injuries stopped.

There you have it. A description of a familiar problem with exercise or simply remaining upright which takes in everything from immune activity to mitochondria to purinergic signalling to hypoxia that is localized rather than general.

I've tried to explain this before, without much success, so I won't be too disheartened if it is still hard to grasp. Let me know about problems in the presentation, but keep in mind I will edit this to correct problems, so you may have to edit comments so that they still make sense.

Added: I just realized I've indulged in a private joke by calling the kind of M.D. who treats generic patients instead of the individual in front of him/her a "generic M.D."

The generic doctor has a stimulus/response pattern of activity which is poorly suited to patients who persist in having specialized problems. This first round, when the problem manifests itself de novo is to prescribe drugs to lower either heart rate or blood pressure seen in cases where the heart is laboring to force blood to tissues that are not getting it. The patient next experiences the problems of low blood pressure, and low pulse pressure (systolic-diastolic) in particular, which make it hard to stand up. Fixing the numbers then means prescribing a vasoconstrictive drug which acts on all blood vessels irrespective of activity. Too often raising systolic pressure causes no change in pulse pressure, which remains in the range seen by patients with heart failure, something this patient does not have. At this point the generic doctor reaches the end of the road. He has no tools to correct problems in regulation of hemodynamics behind to whole scenario, and this especially applies to local hemodynamics where functional sympatholysis takes place.


It depends Marco, does the light bulb want to change? There's one in my stairwell which requires some tricky maneuvering on a tall ladder which I can tell has no intention of changing.
Regardless of the wishes of the light bulb I still have major problems with them. If they don't come out or go in easily the first time it will take me several attempts, needing to rest my arm muscles in between as they start to cramp.

Post onset my first experience with 'exercise intolerance' was during Ju Jitsu 'warm up' exercises at shoulder level or above. I didn't just 'wilt' - I went down like a sack of spuds and took a while to regain consiousness. I know from previous discussions that others here have similar problems. Thing is I had similar issues many years prior to onset. As a young (short lived) army cadet I just couldn't keep my arms up during brief boxing sparring despite being otherwise fit.

If I remember correcltly, functional sympatholysis has been discussed here in the context of the potential benefits of NO donors (I may be wrong but it has definitely been discussed).

Strikes me that 'cell danger signals' arising from a faulty response here might stir up microglia and increase sympathetic signalling which could cause things to spiral downwards pretty quickly.

It might be interesting to look at other conditions (inc T2 diabetes) where functional sympatholysis has been noted and at which pathways are involved.
Just a comment that microglia are in the brain, which could account for cognitive effects, but a great deal of this takes place far downstream of the brain. That paper on autonomic function even talks about yet another division called the enteric nervous system, which is even less dependent on the brain.

I am interested in moving discussion away from inaccessible parts of the brain where possible. There were gruesome experiments on animals during the 20th century where the entire cerebral cortex was ablated. You implicitly reference these when you use terms like 'decorticate posturing'. One thing not commonly mentioned is that heartbeat, breathing and digestion continued in animals lacking major neural structures thought necessary for consciousness. A human with such damage would be in a permanent vegetative state. If we can work on part of the problem without bringing in the full panoply of mysteries of consciousness and hidden motives, we should do so rather than wait for any progress by people attacking fundamental mysteries with misconceptions and the wrong tools.
One more thing Marco mentioned concerning T2 diabetes. If you do searches for hypoxia and purinergic signalling you will see quite a range of pathologies which appear to originate that way. Beyond nerves and muscles, or organs like islands of Langerhans, you can even find evidence that localized hypoxia may be present at the time rheumatoid arthritis becomes a pathological process. Research on precisely the mechanisms behind functional sympatholysis is likely to provide insight into a range of currently misunderstood pathologies.
Microglia are in the brain of course but I wasn't suggesting anything approaching consciousness. Rather metabolic feedback to sub-cortical areas might enhance sympathetic tone which in turn (in the absence of an appropriate functional sympatholysis response) would lead to further focal hypothia. A positive feedback loop between peripheral tissues and the brain.
One psychiatrist among my correspondents thinks I have made a very reasonable point: people who routinely prescribe sympathomimetic or sympatholytic drugs ought to have some understanding of the natural process coping with such problems during upright posture. So far, he has had little success in finding relevant literature. There remain basic unanswered questions concerning exercise physiology, baroreceptors and local hemodynamics. The literature on purinergic signalling shows this is directly involved in mechanoreception, nociception, and sensing hypoxia and hypercapnia. We are talking about very fundamental processes with a much longer evolutionary history than any form of consciousness.
A few comments:
1. Horses (as I was told by someone who had a couple) are able to lock their shoulder and/or hip joints for sleep, so their nervous systems and muscles aren't required to maintain posture or balance during sleep. Apparently if a horse is asleep you can push it over. Seperate from sleep they also need to spend some time each day lying down.
2. Four legged animals are mostly lying down even where they're standing, because their bodies are horizontal. They aren't trying to spend, say, four hours a day upright. Even in healthy humans there is a measurable difference in the effort required to maintain circulation when the body is oriented from the horizontal to the vertical, noticeable for example when road cyclists "sit up", even on an exercise bike. One of the arguments in favour of the recumbent bicycle is the increased physical output possible when the body is horizontal.
3. It's difficult for most doctors to get their heads around these issues because the sympathetic and parasympathetic nervous systems have always been regarded as irrelevant to medical practice and thus education. It's part of the curriculum for biologists and pharmacists, but medicos can complete their training never having heard of it, let alone being aware of its significance. Under these conditions it's impossible to explain one's symptoms to a doctor using this framework, and doctors will prescribe drugs or other treatments in complete ignorance of the impact on the SNS. I'm pretty sure this is the mechanism that results in asthma medications ultimately making asthma worse in at least some patients, because bronchodilators wind up the SNS big time.
An attempt to explain the process of functional sympatholysis to another person who did not have medical training brought up an important point. My interlocutor wondered how high levels of purinergic signalling during an actual infection could interfere with a process which uses purines to signal that blood vessels need to relax to permit increased blood flow. It turned out they were making the common assumption that biological signalling is based on level sensing. As I've said repeatedly, nobody calibrates level sensors on huge numbers of different cells. From experience, I can tell you that a complex system, like that needed to fuel Space Shuttles, involves a constant struggle with calibration of sensors. It was rare to have an operation in which everything worked as designed, which meant we had a constant problem of figuring out which sensors to believe. Biological signalling typically avoids the entire problem by using techniques which do not depend on precise sensing of levels of biochemicals. In the case of functional sympatholysis the trigger is not absolute levels of purines, but the rapid change in levels resulting from muscle activity with inadequate perfusion due to vasoconstriction caused by sympathetic nerves. It is not easy to increase pressure on the arterial side, except by increasing overall systolic pressure. What happens instead is that the burst of purines resulting from anaerobic metabolism triggers veins downstream from the muscle to relax, increasing the pressure differential between arterial and venous blood pressure, and thus increasing the flow.
(continued from below) In addition to the common misconception about biological signalling based on levels, this episode also illustrates the problem introduced by assuming that convenient clinical measurements tell the whole story. The invasive cardiopulmonary exercise tests run by David Systrom's group at Brigham and Women's hospital could not be described as convenient, and they tell quite a different story concerning hemodynamics measured right at the heart. Measuring what goes on at individual muscles remains a topic for future research.

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