This Is MS Multiple Sclerosis Community: Knowledge & Support

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.

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

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

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.

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

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.

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.

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.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!

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.



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.

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.