Missing Link? Endothelin1 high in pwMS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Postby 1eye » Sun Feb 27, 2011 5:08 pm

In summary, exogenous endothelin-1 induced insulin resistance in healthy humans by reducing insulin-dependent glucose uptake in skeletal muscle without decreasing skeletal muscle blood flow.


But blood pressure went up by a factor of 8. Could that be because the endothelin-1 was impeding blood flow by vasoconstiction and the heart was trying to get more oxygen and more sugar through the vitals? Maybe the low sugar uptake was an attempt by the body to conserve in the presence of shrinking blood vessels and lowered blood availability. I don't think cause and effect can be determined in this very artificial situation.
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Postby cheerleader » Sun Feb 27, 2011 5:58 pm

Great find on the research of serum ET-1 levels in pwMS, Cat. It is the research of real pwMS, in vivo, not mice with EAE, that we should be focusing time and money on.

There is an ELISA blood test for ET-1
link
I'm pretty sure it's not standard.

Thought it might be good to give some background and explanations of endothelins, and what they do.
There are 3 members in the endothelin family. Not inherently good or bad, they all affect the endothlium, the lining of 60,000 miles of blood vessels in the human body. They are produced by endothelial cells.

Endothelins are proteins that constrict blood vessels (vasoconstrictors) and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure and heart disease. It is the over-expression of these proteins we want to avoid.

Endothelin 1: A 21-amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. (N Eng J Med 1995;333(6):356-63)
Synonym: et-1.


An over-expression of endothelin-1 can be linked to genetics, it can be caused by diabetes, or induced by hypoxic injury. It is linked to obesity, high fat diets, inflammation and modern life. When I started looking at Jeff's serum numbers at diagnosis (high coagulation, high liver enzymes) and his physical issues (jaundice, petechiae) I kept coming back to endothelial dysfunction. That's when I started trying to find out how to balance nitric oxide and calm down this response of hypercoagulation and vasoconstriction.

Weight loss reduces endothelin 1
http://www.ncbi.nlm.nih.gov/pubmed/16741046
Exercise
http://jap.physiology.org/content/95/1/336.abstract
and I wrote up the program for Jeff:
http://www.ccsvi.org/index.php/helping- ... ial-health
Zinc is in the program, so are antioxidants, sunshine, laughter, exercise, low fats, proteolytic enzymes, EGCG, quercetin, bromelain, and lots of other stuff. It's all in the program.

The good news is that even if you are predisposed to high endothelin 1 overexpression, there is much you can do with diet and lifestyle and supplements to counteract this. It can be reversed. Of course, I believe good flow and a reversal of disturbance and turbulant blood flow will help, which is why angioplasty for venous malformations is important. But much can be done with diet and lifestyle.

It baffles the mind how ET-1 levels could be 224% higher in pwMS, yet the connection to the vascular system is overlooked.
http://www.ncbi.nlm.nih.gov/pubmed/11315981
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Postby Shannon » Sun Feb 27, 2011 7:56 pm

Thanks for posting Jeff's regime for us, again. I need to look into making many changes! I cannot have the surgery, due to my insurance, and I feel that my condition is deteriorating. I need to do something fast, and these things (exercise, for example) are things that I know I need to implement sooner, rather than later.

I was just wondering what everyone thinks about so many of us with MS always having LOW blood pressure? They usually have to take mine more than once because I think they don't really believe they did it right the first time. I've been as low as 90/60 before!
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Postby jimmylegs » Sun Feb 27, 2011 8:34 pm

hey shannon i've been lower than that even it's ridiculous. for me hydration is the key to keeping it normal. found a study linking vasospasm and low blood pressure tho:
http://www.ncbi.nlm.nih.gov/pubmed/12747647
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Postby Shannon » Sun Feb 27, 2011 9:02 pm

Thanks! I'm reading it now. :) I know many others with MS have also reported have very low blood pressure readings, so I was trying to sort out what I was reading in this thread. I was getting the impression that we should be having high blood pressure, but I was probably just not reading it thoroughly enough.
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Postby ThisIsMA » Mon Feb 28, 2011 12:32 am

Reading up about endothilin-1 levels after reading this thread I came upon this study. The last sentance of which sounds promising for reducing restenosis after balloon angioplasty. Of course the study was from 1999 which makes me think if they were going to turn this information into a useful product they would already have done so...

http://cardiovascres.oxfordjournals.org ... 2/445.full


Altered endothelin-1 binding following balloon angioplasty of pig coronary arteries: effect of the ETA receptor antagonist, LU 135252

Abstract

Objective: Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis. Methods: Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated. Results: The pronounced neointima formation in the control group (neointima:media ratio=0.87±0.36) was significantly reduced by LU 135252 (0.43±0.30, P<0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P<0.026) and ETB (approximately 250%, P<0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA=11.5% increase; ETB=14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites. Conclusion: These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.
[b]


This also makes me wonder what the "endothelin (ETA) receptor antagonist LU 135252" is. It sounds like it might be a drug that was given to the pigs following angioplasty???

By the way, I found that when I googled "elevated ET-1 levels" there were a lot of studies implicating it in a lot of medical conditions, diabetis, various vascular diseases, etc. Interesting. I wish I had more of a background in this.

I often feel like there is SO MUCH knowledge out there, we may already have the answer to so many diseases in the clues within all this research, but who has the capacity to review it all (thousands upon thousands of studies) and put the clues together (connect the dots) to solve the puzzles.

And here's a more recent study:

http://cardiovascres.oxfordjournals.org ... 3.abstract


Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation

Abstract

Objective: Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis. Methods: Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated. Results: The pronounced neointima formation in the control group (neointima:media ratio=0.87±0.36) was significantly reduced by LU 135252 (0.43±0.30, P<0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P<0.026) and ETB (approximately 250%, P<0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA=11.5% increase; ETB=14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites. Conclusion: These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.


If its true that having elevated levels of ET-1 increases the risk of restenosis following balloon angioplasty, and if PWMS have elevated ET-1, then it seems like that could explain the high rate of restenosis that can occur following CCSVI treatment...

I wonder if testing for ET-1 levels prior to CCSVI treatment could be a predictor of who is more likely to restenose? Or if as they seem to say, ET-1 is released due to the damage caused by balloon angioplasty, maybe baseline levels don't matter?

Late night ramblings of a person with no medical background...

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Postby jimmylegs » Mon Feb 28, 2011 7:05 am

if PWMS have elevated ET-1, then it seems like that could explain the high rate of restenosis that can occur following CCSVI treatment...

it also seems to tie in nicely with the lower average levels of zinc and magnesium (among other things) typically seen in ms patients, in addition to elevated ET-1.
i'd be interested to compare ET-1 levels in patients pre and post angio, with some mag replete before, some zinc replete before, some mag AND zinc replete before, and some untreated, nutritionally 'ms average' before. and duplicate all that with healthy controls if feasible :)
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Postby cheerleader » Mon Feb 28, 2011 8:45 am

Mary Ann--
there are drugs formulated to be ET antogonists, but as I mentioned in my post above, lifestyle, nutrition and supplements are cheaper and readily available ET antagonists---

I learned all of this from Dr. John Cooke (Stanford cardiologist). His book is called The Cardiovascular Cure, and he addresses ways to mitigate endothelial dysfunction. We became correspondents, and his lab has created the first mouse model of CCSVI.

Dr. Cooke recommends L Arginine supplements, and a Mediterranean Diet, exercise, vitamin D---to re-balance endothelin 1 by boosting NO.
Check out his book...it's where I got my info, and how Jeff got to Stanford 2 years ago:
link

Jeff's doing well 2 years later, has lost weight, mountain bikes and skis again. His left jugular is FINALLY open to his brain, but it took a couple procedures. He had a congenitally malformed left venous sinus, which is open and flowing. His right side has remained opened since 1st procedure. He attributes this to his new lifestyle. He's had this problem his whole life, lost his peripheral vision as a child...but finally has normal blood flow. We hope to keep it flowing!
Here's the endothelial health program:
http://www.ccsvi.org/index.php/helping- ... ial-health

you're right, this is a problem in a host of other diseases, including many auto immune conditions, diabetes, cardiac and neurovascular disease. Endothelial dysfunction is epidemic.
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Postby Leonard » Mon Feb 28, 2011 9:14 am

ThisIsMA wrote:I often feel like there is SO MUCH knowledge out there, we may already have the answer to so many diseases in the clues within all this research, but who has the capacity to review it all (thousands upon thousands of studies) and put the clues together (connect the dots) to solve the puzzles.


I feel exactly the same. The question then becomes: how do we knock the heads together of these highly specialised neurologists, vascular specialists and endocrinologists? What would it need to get a true multi-disciplinary global cooperation going? Or is that something that is already happening anyhow? In our interest, it must be avoided that energies in the medical world are spent on abstruse debates of identity and status.

And of course, we should go on with this global college. Fascinating!
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Postby ThisIsMA » Mon Feb 28, 2011 9:24 am

Hi Joan,

Thank you for repeating all this stuff and for the link to the book. This morning I just had the humbling experience of thinking I was "discovering" new connections between CCSVI/ET-1 and collagen, which I wrote up in a post for this thread, then decided to do a little more searching before pressing send. And what popped up in google? ... but page 1 of the same thread I was posting to with the same information and even the same study I had "discovered" this morning!

This cog fog stuff is really scary. I am smart but now my memory sucks thanks to MS.

So I appreciate your patience and it REALLY helps to repeat this stuff.

By the way, I'm a big believer in using diet instead of drugs for health, I'm not on the injectables, never have been.

My obstacle to feeding myself well is fatigue. I do not have the strength to work and feed myself well. I struggle to keep weight on.

Someone should create a cookbook of endothelial protecting recipes that take next to no effort to prepare for people with MS fatigue who must cook for themselves. This might be a good CCSVI Alliance fundraiser?

What I have done that I'm hoping is helping my endothilial health, is replace all butter and margerine and other oils in my house with organic olive oil. For a butter alternative I have two wide mouthed glass jars with plasic lids that I keep in my fridge.

I pour olive oil into one of the jars, let it solidify in the fridge (which takes a couple of days), and take it out to spread on toast, gluten free frozen waffles, etc. When the first jar is about half gone, I fill the second jar, so that it will have a couple of days to solidify before I need it. This way I always have olive oil that is the consistency of butter on hand. And of course I use the room temperature olive oil as a replacement for other oils. it took a little getting used to because the flavor is somewhat different, but once I adapted, I now look forward to the taste of it. It is good stuff.

I'll try to pick up a copy of that book. Thanks again,

Mary Ann
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Postby ThisIsMA » Mon Feb 28, 2011 9:59 am

Joan wrote:

there are drugs formulated to be ET antogonists, but as I mentioned in my post above, lifestyle, nutrition and supplements are cheaper and readily available ET antagonists---


What I think would be a useful invention would be an angioplasty balloon that could be impregnated with ET antagonists that would release the ET antagonists into the vein wall at the site of the stenosis when the balloon is inflated.

Maybe that would counteract the site-specific increase in ET-1 that seems to occur due to injury of the vein wall during ballooning which can lead to restenosis.

If that would work then you wouldn't have to subject yourself to the systemic ET antogonists drug, although of course you'd want to keep on the endothelial health diet for overall health, and because PWMS have higher baseline ET-1.

Or perhaps it could be a biodegradable stent with impregnated ET antagonists that could be time released into the vein wall until the vein is healed from the angioplasty injury.

It does seem like some of these IR's should consider trying putting people on ET antogonists systemic drugs just prior to and after balloon angioplasty, for however long it takes the injury to the vein to heal. That one pig study implied that doing so would greatly reduce the rate of restenosis.

Of course I don't know what the side affects of that type of drug might be, which would also have to be taken into consideration.
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Postby Cece » Mon Feb 28, 2011 10:08 am

His left jugular is FINALLY open to his brain, but it took a couple procedures.

Thanks for sharing this, it is good news!

When I looked back to your husband's original thread, thinking he and I presented similarly, I saw that, no, mine was a simpler case, where both jugulars were large but blocked at the valve, but in him, that left jugular was much more of a challenge.

I am glad for the CCSVI docs out there who are up to the challenges!!
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Postby cheerleader » Mon Feb 28, 2011 10:09 am

No worries, Mary Ann. Jeff's worst symptom was fatigue and cog fog...know it well. It is very scary, which is why Jeff decided to have angio, even though his mobility was fine.

Dr. Cooke's book has some great recipes, and we have an endothelial healthy recipe thread on the Facebook page CCSVI in MS, under "discussions" Click on the blue letters under my signature to get there. I'm a big believer in sharing info for free, so a published book probably isn't in my future :)

A mediterranean diet, with low saturated fat, low salt, lots of fresh, organic fruits and veg, whole grains, fish, and nuts is best. If you have trouble keeping weight on, go for walnuts and dense protein, like chicken and fish. Make smoothies w/protein powder and frozen fruit and juice. Dr. Swank's diet site has good recipes, too. Jeff found that EGCG (green tea) and quercetin helped his fatigue before he got his angioplasty. Also, hydration is essential. Fresh water with organic lemon and stevia keeps us going. Hang in there-
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Postby frodo » Mon Feb 28, 2011 12:10 pm

Forget this post. I was just re-posting something that is alredy in other thread
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stenting tube

Postby 1eye » Mon Feb 28, 2011 1:25 pm

I was sitting on this because it really was not mine. I feel it is past time to share, and maybe has no merit anyway. My friend Dr. Bob said why don't they use something to adhere to the outside of the vessel (like a plastic tube with crazy glue on the inside) and use the balloon to press the outside of the vessel into the inside of the tube from inside the vessel? Advantages: no damage to inside of vessel like there would be with a stent (or maybe even a balloon), nothing permanent inside the vessel, no possibility of migration to inside of heart. Disadvantages: probably would have to be placed using an incision, unless some kind of magnetic gizmo could be used to make it follow a catheter on the outside of the vein.
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