Missing Link? Endothelin1 high in pwMS

[ThisIsMA]

ThisIsMA said:

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.

Ah... I just figured out why they don't do that. Those IR's are pretty smart!

According to wikipedia at least some of those Endothelin Antagonist drugs have a very nasty side affect: liver damage. One Endothilin A receptor antagonist was recently voluntarily pulled from the market due to it causing fatal liver damage:

http://en.wikipedia.org/wiki/Sitaxentan

Here's the link to the page on endothelin receptor antagonists in general:

http://en.wikipedia.org/wiki/Endothelin ... antagonist

Mary Ann

[jimmylegs]

how fortunate that zinc also works to lower elevated endothelin-1, which is one of many ways to 'love your liver'

reposted: http://www.thisisms.com/ftopicp-155354.html#155354
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"

as for the 'love your liver' reference:
http://www.thisisms.com/ftopicp-54060.html#54060

[ThisIsMA]

how fortunate that zinc also works to lower elevated endothelin-1,

Hi Jimmylegs,

Can you recommend how much zinc an adult woman with MS should take? I am supplementing with 30 mg of zinc picolinate per day. I'm not sure if that's a good form of zinc. I just picked it up at the local grocery store.

I am home sick with a cold today which is why I have the luxury of writing all these posts.

Thanks,

Mary Ann

[prairiegirl]

There are some great links throughout this thread ( a lot of reading!)
I must say I got a big chuckle out of the "15 ways to love your liver" reference. "Put the six-pack back, Jack"...

as for the 'love your liver' reference:
http://www.thisisms.com/ftopicp-54060.html#54060

[jimmylegs]

@thisisma - actually zinc picolinate is a pretty good one but you may want to consider testing to find out if your current regimen is getting your serum level into the upper teens (units umol/L). i take 50mg/d of zinc but mine is zinc citrate and absorption might not be quite as high from that form.

@pg - glad you like

[Leonard]

The zinc relation is perhaps a bit more complex. It may well involve such things as ATP release by the RBC. That would elevate the nitrition condition, and is diabetes 2 related.

http://www.rsc.org/Publishing/Journals/ ... active.asp

They found that, when they administered zinc-activated C-peptide with metformin, the type 2 diabetic red blood cells released ATP at levels comparable to healthy ones. Diabetic red blood cells are more rigid and so normally release less ATP than normal cells. As metformin is positively charged at physiological pH, Spence suggests the metformin neutralises the phosphatidyl serine groups on the outer cell membrane, making it less negative and more able to interact with the C-peptide.

See also the parallel thread on this general chapter of this forum http://www.thisisms.com/ftopic-15188-45.html

[silverbirch]

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?

Havening had CCSVI and to help my MS I take my Vit and lead a good healthy life.
Can we get Vascular check up's in the way of blood test?
How is Nitro Oxide measured, Vascular tone, inflammation, all that can contribute to vascular wall problems ?
What is the liver test needed ?

My aim is to check the quality of my veins,

I will be seeing a vascular consultant/surgeon who is aware of CCSVI he is going to carry out a Doppler of my neck.... I was also going to try and get blood work done from him but what should I ask for ?

[Cece]

http://www.dmsjournal.com/content/4/1/2

A possible explanation of the current observation is furnished in the following argument: Sildenafil may decrease endothelin-1, a potent vasoconstrictor peptide, (ET-1) activity which is greater in diabetics than in healthy subjects; it was reported that blockade of endothelin receptor (ETA), which transudes the biological effects of ET-1, results in vasodilatation in patients with diabetes but not in control group

Endothelin-1 is abnormally high in pwMS (by 224%). Sildenafil is believed to improve cerebral vasoreactivity by lowering endothelin-1 levels.

[Cece]

http://www.ncbi.nlm.nih.gov/pubmed/23509249

Proc Natl Acad Sci U S A. 2013 Mar 18. [Epub ahead of print]

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.

D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J.

Source
Department of Neurology, Universitair Ziekenhuis Brussel, 1090 Brussels, Belgium.

Abstract
Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

Wow!!
This dovetails with the previous research posted by MegansMom that endothelin-1 is 224% higher in pwMS.
A drug called bosentan can lower the endothelin-1 to normal levels. This results in normalized cerebral blood flow. We could definitely use that!!

There are side effects to this drug: liver toxicity, anemia, interference with contraception, and fetal harm. It's not yet studied to see if it has any benefit. It does however warrant further research! I can't imagine this replacing the role of ccsvi angioplasty but it might be an ideal additional therapy.

[cheerleader]

A drug called bosentan can lower the endothelin-1 to normal levels. This results in normalized cerebral blood flow. We could definitely use that!!

There are side effects to this drug: liver toxicity, anemia, interference with contraception, and fetal harm. It's not yet studied to see if it has any benefit. It does however warrant further research! I can't imagine this replacing the role of ccsvi angioplasty but it might be an ideal additional therapy.

It never ceases to amaze, does it, Cece? Dr. John Cooke's been writing many years about increasing EDRF (our body's own ET-1 antagonist -called "endothelial-derived relaxing factor") with a Meditteranean diet, vitamin D and supportive minerals like zinc(!) and magnesium, exercise, and lifestyle changes--and has the research behind it to show how this reduces plasmic levels of endothelin-1 naturally.

Pharma proposes a solution that has side effects on the liver and unborn children???
Bosentan treats pulmonary aerterial hypertension by blocking ET-1, but that's not all it does....
http://www.fda.gov/ohrms/dockets/ac/01/ ... k(red).pdf

Here's Dr. Cooke's book again, for those new to the idea of increasing EDRF to regulate cerebral blood flow. http://www.amazon.com/The-Cardiovascula ... 0767908813
it's not about a pill....
and yeah, it's nice to see further validation of the idea that MS is a disease of endothelial dysfunction, but it's exhausting to see the new poisons that get thrown at pwMS.
cheer

[jimmylegs]

heyyy my ears are burning. what's all this then? ;)

i've already posted on correlations between elevated endothelin and the poor mineral status commonly seen in ms on this topic (eg magnesium, zinc, surprise surprise) but thought i would contribute a couple older bits from other related topics:

http://www.thisisms.com/forum/natural-a ... ml#p181683 (2011)

2011 update: magnesium also combats endothelin-1 in these scenarios...

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

Action of magnesium sulfate in the treatment of preeclampsia-eclampsia
Stroke. 1989;20:1273-1275
http://stroke.ahajournals.org/content/20/9/1273

also:
Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials
http://eurheartj.oxfordjournals.org/con ... /1/6.short
"Chronic homocysteinaemia in humans is accompanied by increased endothelin-1 (ET-1) levels, which is the strongest vasoconstrictor in human vasculature."

Serum cobalamin, homocysteine, and methylmalonic acid concentrations ...
http://www.ajcn.org/content/70/5/904.long
"Hyperhomocysteinemia, which is most strongly associated with low cobalamin concentrations, is also most common in elderly whites, whereas that associated with renal insufficiency is more common in blacks and Asian Americans.

don't know if this effect is 'portable'

Zinc deficiency further increases the enhanced expression of endothelin-1 in glomeruli of the obstructed kidney
http://www.nature.com/ki/journal/v58/n2 ... 1724a.html

will continue to scour for more helpful aids to endothelin supression

http://www.thisisms.com/forum/chronic-c ... ml#p139655 (2010)

http://www.ncbi.nlm.nih.gov/pubmed/10916081
Kidney Int. 2000 Aug;58(2):575-86.
Zinc deficiency further increases the enhanced expression of endothelin-1 in glomeruli of the obstructed kidney.
...We therefore designed the present study to examine the effect of Zn deficiency on the expression of ET-1...
...the expression of prepro-ET-1 mRNA and ET-1 was substantially increased in the OK of the Zn-deficient diet group relative to the OK of the standard diet group...

http://ajplung.physiology.org/cgi/conte ... 80/5/L1040
Am J Physiol Lung Cell Mol Physiol 280: L1040-L1048, 2001;
Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction

Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ETA and ETB receptors.
Although activation of the ETA receptor causes vasoconstriction, stimulation of the ETB receptors can elicit either vasodilation or vasoconstriction.
The actions of ET-1 are dependent on activation of at least two receptor subtypes, ETA and ETB.
ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation (17, 36).
In contrast, ETB receptors are present on both endothelial and smooth muscle cells in the rat pulmonary circulation...

i am still investigating potential causes of ETB receptor deficiency.

i have been trying to find out if the ETB receptor involves a zinc finger, which would make sense if correcting zinc deficiency lowers ET-1.

but, can't verify yet. have to switch tracks for the moment. will revisit later.

ciao!

question. are ms patients having endothelin-1 level tests done? that would be a neat experiment.. measure it, along with mag and zinc, then supplement mag and/or zinc, retest all three.

[cheerleader]

Hey JL--
yes, I should hope your ears are burning!! Zinc and mg are great from reducing ET-1 levels in plasma. Your research links are right on!
As far as testing for ET-1 levels in pwMS, it's not a routine test. Here's more on all this from earlier in the thread, just good to go over again (I'd forgotten since it was first posted over a year ago...)
High levels of ET-1 happen when the endothelium is stressed, and the cells release this protein as a response.

There is an ELISA blood test for ET-1
http://www.enzolifesciences.com/ADI-900-020A
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.

cheer

[jimmylegs]

ha! neat. maybe i'll do that experiment one day

[Cece]

http://www.ncbi.nlm.nih.gov/pubmed/16301255

Anesth Analg. 2005 Dec;101(6):1757-62.
A role for endothelin in neuropathic pain after chronic constriction injury of the sciatic nerve.
Klass M, Hord A, Wilcox M, Denson D, Csete M.
Source
Department of Anesthesiology, Emory Anesthesiology University School of Medicine, Atlanta, Georgia 30322, USA.
Abstract
The purpose of this study was to explore the role of endothelin in neuropathic pain. Endothelins (ET) are a family (ET-1, ET-2, ET-3) of ubiquitously expressed peptides involved in control of vascular tone. Injected ET-1 causes intense pain via activation of ETA receptors, modulated by analgesic signals initiated by ETB receptor activation. Using a rat model of chronic constriction injury of the sciatic nerve, we found that pharmacologic ETA receptor antagonism acutely and significantly reduced thermal and mechanical hyperalgesic responses 5 days after injury. Furthermore, ET-1 and the ETA receptor are locally upregulated at the site of chronic constriction injury at both the message and the protein levels, suggesting that ET-1 may be involved in establishing pain after the injury. These data point to ET-1 as an important mediator of pain in general and suggest that ETA antagonism deserves study as a potential novel therapy for neuropathic pain.

Endothelin-1 contributes to neuropathic pain. Could reducing levels of ET-1 reduce the neuropathic pain? Or is it not reaching the nerves if it is in the plasma?

[Cece]

Treatment of stenoses leads to reduction in ET-1.
http://www.ncbi.nlm.nih.gov/pubmed/21677436 (renal artery stenosis)
http://www.ncbi.nlm.nih.gov/pubmed/11137092 (carotid artery endoarterectomy surgery)

If CCSVI venoplasty is successful, ET-1 might become normalized.
Very interesting about the zinc and magnesium, I did not know they had an effect on ET-1!!