alex3619
Senior Member
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- Logan, Queensland, Australia
Hi aquariusgirl, I don't have any links, all the discussions were private. Some were on a research forum, some were to Vance Spence.hi alex
I am interested in the high intracellular calcium angle. If you have any links, pls share.
last I heard, Dr John McLaren Howard was looking into this.
High intracellular calcium would trigger prolonged acetylcholine activation in the peripheral vasculature, resulting in blood pressure drops. In my model this was postulated as a result of not elevated calcium itself, but elevated citric acid. Citric acid is a product of the mitochondria, and I will get back to that, but it is a powerful chelator. It can block both calcium and magnesium. The cell senses this, and so releases a massive burst of calcium to compensate when it needs to trigger a calcium signal. High levels of calcium will activate a molecule called calmodulin for up to six hours. Calmodulin will trigger nitric oxide and hence vasodilation. Blood pressure drops.
The high citrate hypothesis was popular through most of the nineties, then it died. The mitochondria make it, and can release it, it also pointed to nitric oxide and peroxynitrite as these destroy the enzyme that converts it to something else. I discussed this at length with Marty Pall. This enzyme is called aconitase, and it has one other important property. It is not made in the mitochondria, but must be folded and imported. That folding process requires glutathione, and high oxidative stress makes the glutathione unavailable. I had long discussions with Rich on this topic.
The evidence for citrate was high early morning urinary citrate in CFS patients (none defined as ME, it was not a diagnosis used then). They also found two other putative biomarkers. In around 2000 (I don't recall exactly) a UK group found that the other two biomarkers were breakdown products of two amino acids, serine and glycine. So they claimed the results were an artifact. However, they never explained why the breakdown occured. They only showed they could not find the two breakdown products in their samples. I do not recall what definition was used for the CFS patients - Oxford is likely, and so suspect, but it could have been Fukuda.
This same team then went on to show the could not find elevated urinary citrate. Almost everyone considered the matter closed. I did not. First, they didn't show where the high citrate came from, why it was a "failed" test. Second, their protocol could not work, a point that most missed because they were unfamiliar with the original research. The original research stipulated very early morning citrate, at no other time of day. The tests fails at other times, a point the original researchers did not emphasize enough. This means the citrate is released during sleep, presuming the finding is correct. The UK counterstudy used fasting CFS patients - fasting causes citrate levels to drop. The presumption they used was that fasting is the same as sleeping. At no point did they state the urine samples were early morning after sleep. It might have been, but it was never stated.
Now the body releases antioxidants during sleep, including melatonin. I was working on the "citrate flush hypothesis". Citrate is a great metal chelator. Theoretically it can flush the cells of divalent cationic metals, especially iron. I postulated that the mitochondria in CfS were releasing citrate overnight to flush the cells and remove metals, a known cause of oxidative stress. If this is correct, then many patients with oxidative stress, not just ME or CFS patients, could be found with high early morning (early waking is more accurate given our sleep issues) citrate.
Now the citrate bursts will disturb calcium, and calcium is one of two critical intracellular messengers. It will disturb every path that requires calcium to trigger, but it will also disturb the other messenger. This is a complex pattern, and one I wanted to look into more deeply. Recently I have become interested again, but I do not want to discuss that just yet.
I have not worked on my model in nearly a decade. It needs updating. Sorry for the long post, but you are only getting the highlights, not the details.
Bye
Alex
ps Just to clarify a minor point, nitric oxide does not destroy aconitase, only temporarily inactivates it. Peroxynitrite does destroy it however.