Missing Link? Endothelin1 high in pwMS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.
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MegansMom
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Missing Link? Endothelin1 high in pwMS

Post by MegansMom »

As many of you know I have been a RN for many years. And so when my daughter was diagnosed with MS last year I dove nose first into everything I could about MS and subsequently CCSVI.
Of course I am just tickled that she had a clear cut case of CCSVI and symptomatic relief of her MS symptoms. But being a mom I was plagued with worry about re-stenosis and all the unknown things about CCSVI/MS.
It concerned me that the physicians seemed to be focusing mostly on the "plumbing" and proving the very existence of the condition. There are some that seem to be trying to figure it all out. That is the physiology and etiology behind these 2 very connected conditions.
I was intrigued by some of the findings. It is believed that the blockages, that is these valvular and other vessel blocking anomalies are congenital.( studies by Dr Lee) yet the condition seems to get worse over time eventually causing changes that lead to myelin and axon damage and activation of the immune system.
I was trying to understand endothelial function and how NO (nitric oxide) and Endothelin1 control vascular tone and function. Much has been studied on these things mostly studying arteries and hypertensive drugs.
Of particular interest was this

Increased Endothelin 1 Plasma Levels in Patients <shortened url>

Why would pwMS have levels of Endothelin1 hundreds times higher than normal people?
I truly think it fits.
My theory is that a baby is born. This baby is a person that will eventually be diagnosed with MS years later. But as a baby, a youngster and young person the persons vein anomaly(s)would cause some altered shear stress, some cerebral hypoxemia and some cerebral hypoglycemia. These things are all the triggers that increase Serum Endothelin1.
Endothelin1 is a very potent vasoconstrictor and it also can cause hypertrophy (thickening) and fibrosity (stiffening) of the blood vessels if in high levels. Over time this could cause the CCSVI to get worse. When the CCSVI gets worse the blood turbulence would get worse, causing more iron to be deposited, the altered shear stress would get worse, the cerebral hypoxemia would get worse, the hypoglycemia in the brain would get worse and the brain Cells- all types would be damaged by a slow incidious chronic starvation.
This supports the CCSVI causes MS.
Could Endothelin1 levels that are high be the reason that re-stenosis occurs?
Shouldn't we be looking for a way to lower the E1 levels to normal? now that sounds like a drug we could use.

Anyway this is food for thought. Maybe I should call our "friends" at Big Pharma and ask them to investigate this?
Last edited by MegansMom on Sun Feb 27, 2011 4:02 am, edited 2 times in total.
Cat (Catherine Somerville on FB)
MegansMom
My 35 yo daughter is newly dx 8/19/10 (had 12 symptoms)
Dx with Type A CCSVI- 1 IJV & double "candy wrapper" appearance of her Azygos
Venoplasty done Sept 21, 2010
Doing extremely well-
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Post by Cece »

Are endothelin-1 levels measured with a simple blood test? It's possible that they normalize on their own after successful CCSVI treatment. Yes, I agree, this is an important avenue for investigation.

For the physicians, particularly the vascular specialists, to be focused on the plumbing is a good thing, imo, because fixing the blockages is the number one thing that is going to make a difference. But once the number one thing is done, it makes sense to go after all the rest.
Could Endothelin1 levels that are high be the reason that re-stenosis occurs?
If restenosis were recurring in a slow chronic way over years, then I could get behind this. But restenosis is recurring within days (elastic recoil) or within months (elastic recoil or intimal hyperplasia) or is a complication of the procedure (clotting). If high levels of endothelin-1 caused super fast restenosis (within a year), I'd expect MS to be a faster illness than it is.
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Post by pairOdime »

Someone should design a study to measure ET-1 levels pre & post CCSVI treatment...that might be useful information.

http://www.ncbi.nlm.nih.gov/pubmed/11315981
J Neuroophthalmol. 2001 Mar;21(1):37-8.

Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Haufschild T, Shaw SG, Kesselring J, Flammer J.
University Eye Clinic, Basel, Switzerland.
We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients.
A specific radioimmunoassay was used to determine ET-1 plasma levels.
The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005)....Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease.
The plasma ET-1 level is markedly and significantly increased in patients with MS.
It's a paradigm shift
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CCSVI causes CCSVI

Post by 1eye »

Look, I know we all have 'MS', most of us, and that's why we're here. But isn't the point we should be making to all these people supposedly interested in our health (and for that matter, that of a significant number who haven't got 'MS' so far) that CCSVI worsens CCSVI? Yes I and many others think it is bad for 'MS' (symptoms and the disease processes), but vein narrowing, reflux, and slowed perfusion, hypoxia, and hypoglycemia will cause trouble to the diseased vein itself, whose job, when healthy, is to drain dexoygenated and hypoglycemic blood down to where it can get replenished?

If this blood is not getting through the head fast enough (or the places the azygous drains) it will not feed the very veins it is being drained by, and they will get sicker! Of course it worsens over time! It is autodestruction by its very nature.

Why can people not get it through their heads that *anyone* with CCSVI, regardless of whether they have 'MS' now or later, is in serious trouble. This is a major, worldwide health crisis, and it is being kept quiet by people who make money off of it! So humanity's inhumanity to humanity becomes a threat to a lot of people's health. There are likely more than a few people who are making financial gains off of this, at the cost of their own health and that of their own loved ones, without even knowing it.
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Post by David1949 »

If the shortened link doesn't work try this one.

http://journals.lww.com/jneuro-ophthalm ... ts.11.aspx
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Post by Cece »

Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease.
If they looked to see if there was a correlation in the level of ET-1 and the severity of CCSVI stenoses, I believe they would find one.

1eye, yes, that CCSVI worsens CCSVI seems like a major point! But then it has to be accepted that CCSVI itself is bad for one's health. Seems obvious to me but there is controversy over it.
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Post by jimmylegs »

http://www.ncbi.nlm.nih.gov/pubmed/9457516
Modulation of endothelin-1-induced contractions by magnesium/calcium in porcine ciliary arteries.

http://www.springerlink.com/content/481162444r825777/
Magnesium-deficiency elevates circulating levels of inflammatory cytokines and endothelin

http://www.ncbi.nlm.nih.gov/pubmed/1471664
Effect of magnesium sulfate on plasma endothelin-1 levels in normal and preeclamptic pregnancies.

http://onlinelibrary.wiley.com/doi/10.1 ... x/abstract
Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans (that one's for you LC :) )
Last edited by jimmylegs on Sun Feb 27, 2011 10:43 am, edited 2 times in total.
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Post by jimmylegs »

http://www.ncbi.nlm.nih.gov/pubmed/8403787
Magnesium sulphate reverses the carotid vasoconstriction caused by endothelin-I, angiotensin II and neuropeptide-Y, but not that caused by NG-nitro-L-arginine methyl ester, in conscious rats.

http://onlinelibrary.wiley.com/doi/10.1 ... 02342/full
Assessment of the effects of endothelin-1 and magnesium sulphate on regional blood flows in conscious rats, by the coloured microsphere reference technique
"Of particular interest was the finding that MgSO4 caused increases in flow in the cerebral and coronary vascular beds.
This, and our previous studies, have shown that MgSO4 can reverse vasoconstriction in a number of vascular beds, and indicate that this compound may have therapeutic benefit in conditions associated with vasospasm."

good old mag :)
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Post by pairOdime »

http://www.ncbi.nlm.nih.gov/pubmed/21169360

J Biol Chem. 2010 Dec 17. [Epub ahead of print]
Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop.
Simonson MS, Ismail-Beigi F.
Case Western Reserve University, United States.

Endothelin-1 (ET-1), a potent vasoconstrictor, has been implicated in the pathogenesis of collagen accumulation, extracellular matrix remodeling, and renal and cardiac fibrosis in diabetes. ……Taken together, these results demonstrate that an autocrine signaling loop involving MCP-1 and IL-6 contributes to ET-1-induced collagen accumulation.
It's a paradigm shift
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Post by 1eye »

Here is a *very* interesting paper. Two interesting citations, both a tad outdated, but look at who's sharing the page! Tracy Putnam and Mark (MS) Freedman. Whew!!
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Post by jimmylegs »

zinc connection?

http://www.ncbi.nlm.nih.gov/pubmed/10916081
Zinc deficiency further increases the enhanced expression of endothelin-1 in glomeruli of the obstructed kidney.

http://www.ncbi.nlm.nih.gov/pubmed/10775140
Thrombin induces endothelin expression in arterial smooth muscle cells.

http://circres.ahajournals.org/cgi/cont ... a;85/5/394
Peroxisome Proliferator-Activated Receptor (PPAR) Activators Inhibit Thrombin-Induced Endothelin-1 Production in Human Vascular Endothelial Cells by Inhibiting the Activator Protein-1 Signaling Pathway

http://jn.nutrition.org/content/135/9/2114.abstract
Zinc Deficiency Increases Plasma Lipids and Atherosclerotic Markers in LDL-Receptor-Deficient Mice
"adequate zinc may be a critical component in protective PPAR signaling"
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Post by jimmylegs »

interesting:
http://www.ncbi.nlm.nih.gov/pubmed/17454788
Nitric oxide affects serum ferritin levels in children with iron deficiency.
In iron deficiency, serum levels of ferritin decrease. The lack of iron has been thought to be the main factor in this decrease, but another potential factor is nitric oxide, which has been shown to affect ferritin metabolism in vitro. The aim of this study was therefore to evaluate in children with iron deficiency the relation of serum ferritin, nitric oxide degradation products (nitrate and nitrite), and endothelin-1, a protein closely related to nitric oxide function. ... In children with iron deficiency, nitrate and nitrite levels were significantly higher (p < .009 and .01, respectively). Also, serum ferritin was negatively correlated with serum levels of nitrate and nitrite (p = .034, r = -.254 for nitrate and p = .01, r = -.593 for nitrite). No statistical relationship was found between serum ferritin and endothelin-1.
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Post by lyndacarol »

To MegansMom – I was very interested in your sentence, "Endothelin1 is a very potent vasoconstrictor and it also can cause hypertrophy (thickening) and fibrosity (stiffening) of the blood vessels if in high levels."

No one will be surprised (My focus on excess insulin is well known!) when I add the information again that excess insulin thickens and stiffens smooth muscles, which are found in the walls of blood vessels, and other locations such as sphincter muscles and muscles surrounding the urinary bladder and intestines (connection to bladder and bowel problems?).

And thank you, JL, for always thinking of me: "Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans (that one's for you LC)." The term "insulin resistance" includes excess insulin; the research cited ties endothelin-1 to the mix of excess insulin well, in my opinion.
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Post by jimmylegs »

you're welcome LC i like finding studies that connect different perspectives.
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Post by 1eye »

Conclusions: The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.
Sure would be nice to know the hows and whys of ET-1 overproduction, or even production period, but I wonder if sugar and oxygen depletion have something to do with it. If blood going through is locally low in those things, isn't one way to cope with that to slow it down to allow more absorption of what is left, to take place?

Maybe some people with venous shunts in their jugulars ought to have their blood analyzed.
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