Missing Link? Endothelin1 high in pwMS

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

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 6:42 pm

From Squeakycat http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236687/
Abstract
Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

Quote,
from Ed,
"the link between ET-1 and artherosclerosis is that ET-1 is elevated by arthereosclerosis, not the other way around.

What is interesting about ET-1 is the things that cause it to be elevated. The first is hypoxia. The second is sheer stress of the type caused by turbulent blood flow. But it also is elevated as a response to cytokines released as a part of the inflammatory cascade.

From this perspective, it is fairly easy to see why ET-1 is elevated in MS, almost regardless of what causes MS. If MS is in part caused by the hypoxia and sheer stress associated with CCSVI, then it would be elevated. If MS involves an inflammatory response to a breech in the blood brain barrier and infiltration of things that shouldn't cross the blood brain barrier which trigger an inflammatory response, then you would expect it to be elevated. Or, if MS is caused by a bacterial infection which triggers an inflammatory cascade, you would expect to find it elevated.

It plays no role in causing these various conditions such as athereosclerosis or inflammation. It is simply upregulated when you have such a condition.

I will separately send you a link to a very detailed article on ET-1 which goes into all of this in great detail. It is a long and dense article, but I think it will answer all your questions on why we should expect ET-1 to be elevated in MS and why it would play no role in restenosis.

Ed"

Thanks Ed for getting my mind on track, it needs a bit more help nowadays, I blame the Protocol ;)
Nigel
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Advertisement

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 7:14 pm

If the ET-1 is crossing the BBB;
If the concentration of ET-1 gets high enough in the CSF will that cause symptoms and atrophy and things like Thalamas link issues, CSF flow issues?
Could be a cascade of issues?

;)
Nigel
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Thu Apr 11, 2013 1:48 am

http://www.biomedcentral.com/1471-2377/13/9

Conclusions
JVR and higher plasma levels of ET-1 are associated with cough syncope/ pre-syncope. Although sample size of this study was small, we showed a synergistic effect between JVR and plasma ET-1 levels on the occurrence of cough syncope/pre-syncope. Future studies should confirm our pilot findings.

Keywords:
Cough syncope; Endothelin-1; Jugular venous reflux

Background
Syncope is defined as a transient loss of consciousness with subsequent spontaneous recovery, resulting from global cerebral hypoperfusion [1]. Besides syncope, a lesser degree of compromised cerebral blood flow (CBF) may lead to pre-syncope symptoms, such as wooziness, light-headedness, nearly fainting sensation and/or visual dimming. Cough syncope refers to syncope upon coughing, [2] the pathogenesis of which is unclear and probably multifactorial.

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide derived from vascular endothelial cells [3]. Besides its direct vasoconstriction effect, increased ET-1 levels may result in decreased nitric oxide (NO) availability, thereby predisposing to vasoconstriction [4,5]. ET-1 also contributes to the regulation of cerebral vascular tone. ET-1 levels have been shown as elevated in the plasma and cerebrospinal fluid (CSF) of subarachnoid hemorrhage (SAH) patients, with the presence of elevated ET-1 levels correlating with the persistence of cerebral vasospasm [4,6,7]. Additionally, ET-1 levels have been observed to decline in the absence of cerebral vasospasm, [7] and the administration of ET-1 antagonists prevents cerebral vasospasm [8]. Therefore, ET-1 is one of determinants of CBF. Endothelial dysfunction with imbalanced releases of NO and ET-1 has also been recognized in chronic obstructive pulmonary disease (COPD); those populations have been found with more frequent cough syncope [9,10].

Jugular venous reflux (JVR) is found frequently in transient global amnesia, [11] transient monocular blindness patients, [12] and elderly people with more severe age-related white matter changes [12]. JVR may occur during a Valsalva maneuver (VM) or Valsalva-like activities, such as cough, when increased intrathoracic pressure is beyond the competence of internal jugular venous (IJV) valves. VM-induced JVR, which may retrogradely transmit venous hypertension into cerebral venous system, decreases cerebral perfusion pressure (CPP) and consequently reduces CBF during Valsalva-like activities [13-16]. It has been suggested that JVR plays a role in the pathophysiology of cough syncope [17]. However, the low incidence of cough syncope, disproportionate to the higher frequency of JVR, [18] implies that additional factors should be involved. In the present study, we hypothesized that (1) the presence of JVR is associated with cough syncope, and (2) there is an interactive effect between JVR and the plasma ET-1 levels on the occurrence of cough syncope.



Interesting and Zivadinov's name is there too.
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Thu Apr 11, 2013 2:01 am

http://www.ncbi.nlm.nih.gov/pubmed/8160238
Does endothelin-1 play a role in the pathogenesis of cerebral vasospasm?
Cosentino F, Katusić ZS.
Source
Department of Anesthesiology, Mayo Clinic, Rochester, Minn. 55905.
Abstract
BACKGROUND:
Endothelin-1 is a very powerful endogenous vasoconstrictor substance produced by endothelial cells. Its long-lasting vasoconstrictor and hypertensive action has been well documented in several species, including humans.
SUMMARY OF REVIEW:
It is generally accepted that endothelin-1 may contribute to the pathogenesis of a number of cardiovascular diseases. In the cerebral vasculature, endothelin-1 has been proposed as a key mediator of cerebral vasospasm following subarachnoid hemorrhage. Availability of endothelin-1 antagonist provided a pharmacologic tool to test the role of endothelin in the development of vasospasm.
CONCLUSIONS:
This brief review is focused on the controversial results reported by different groups concerning the possible role of endothelin-1 in narrowing of cerebral arteries exposed to autologous blood.
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Thu Apr 11, 2013 2:05 am

http://www.sigmaaldrich.com/life-scienc ... thway.html
Hypoxia is a potent inducer of ET-1 gene expression in endothelial cells. This mechanism is important during myocardial ischemia.
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Thu Apr 11, 2013 2:25 am

From George Jelineck
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.
http://www.ncbi.nlm.nih.gov/pubmed/23509249
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby 1eye » Thu Apr 11, 2013 12:14 pm

Bosentan appears to lower ET1, but it has toxic side effects. There is also a Chinese herb, and there is the diet espoused by cheerleader. So can we reduce ET1 or not?
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
User avatar
1eye
Family Elder
 
Posts: 2852
Joined: Wed Mar 17, 2010 4:00 pm
Location: Kanata, Ontario, Canada

Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Thu Apr 11, 2013 12:35 pm

I have been having amazing discussions and findings with Squeakycat/Ed regarding this avenue of findings.

Until we understand if there is any harm being done by the ET-1 (A+B) then I believe we need to learn more about what is causing the higher levels in MS and see what can be done about the cause first! imo

;)
Nigel
User avatar
NZer1
Family Elder
 
Posts: 1506
Joined: Thu Feb 18, 2010 4:00 pm
Location: Rotorua New Zealand

Re: Missing Link? Endothelin1 high in pwMS

Postby Bethr » Thu Apr 11, 2013 6:23 pm

I'm finding this thread really interesting too. Since my recovery I've been researching hypoxia
as it's become obvious that was a major contributor to my symptoms, if not the cause.
Hypoxia controls many of the bodies functions, including iron absorption, which I had a problem with early in the piece, a mild overload. Hypoxia decreases another peptide called hepcidin. Hepcidin is the master iron controller, and and a decrease means more iron absorption (similar to the effects of genetic hemochromatosis for which i carry one C282Y gene anyway).
I can look back now and see the slow train wreck as the hypoxia got worse and the cyst in my neck
got larger and larger over the 20yr period since it was identified. The hypoxia was intermittent, on and off depending on my position I believe, upright or lying down, and how much exercise I was doing.
The cyst was mid line/very slightly left and attached upwardly to my tongue so it moved around, up and down.

five years ago - 1st symptom was fatigue, heavy like I'd been given an anesthetic, and coma like sleep in the daytime.

four years ago - 2nd Lost use of right hand, brain lesion on MRI, mild iron overload with skin hyperpigmentation, slow waves on EEG whilst awake, suspected MS or epilepsy. Episodes of chorea, painful stiff joints & shoulders, nerve pain in arms and legs, blister rashes and High and rising hemoglobin and hematocrit.

Three years ago - Discovered that bloodletting alleviated symptoms and kept hemoglobin down and gave me some energy, helped joint pain, but wore off after 6 weeks.

Three years later and after 10 pints of blood let, neck cyst is re-discovered and removed.
It has grown now to golf-ball size.
Outcome.....
All symptoms disappear slowly over following next six months, hemoglobin and hematocrit normalises.
No more fatigue, brain events, joint problems heal and disappear.

What gets me is all that happened just from not getting enough oxygen chronically over a long long
period of time. I was also a smoker, but gave up 18 mnths ago. I'm sure that was another contributor.
So my sister supposedly has had MS for a long time. Maybe I'm genetically more likely to get it.
But the causze for me was lack of oxygen, I'm sure of it, and no Dr picked it up, it was transient.

So was my ET-1 high? Probably, as I suffered the iron overload that is also tripped by hypoxia.
Did it mess me up? Definitely!!
I know that mine is a rare cause, but it certainly sheds some small light as to how these things are related.

Cheers..........
User avatar
Bethr
Family Elder
 
Posts: 475
Joined: Sun Dec 27, 2009 4:00 pm

Re: Missing Link? Endothelin1 high in pwMS

Postby Cece » Tue May 28, 2013 5:09 pm

http://hubbardfoundation.blogspot.com/
May Edition

What's News

Cerebral hypoperfusion..."Decreased blood flow may contribute to the pathology of MS..." click here

The orthodox theory of MS is that it is an "autoimmune disorder," meaning that the immune system is attacking intact (normal) myelin. This theory has never been proven. Zamboni's CCSVI theory proposes that abnormally low brain perfusion is at the heart of damage to oligodendrocytes and myelin, possibly due to oxidative stress (excessive free radicals). Although much of the focus by neurologists has been on the problematic use of ultrasound to detect abnormalities in the internal jugular veins our attention should in fact be on measuring brain perfusion.

This paper uses arterial spin-labelling to measure brain perfusion. These authors and several others found that perfusion is indeed abnormally low in MS. Traditionally this hypoperfusion has been attributed to damaged brain cells, the idea being that perfusion is reduced because the damaged brain does not need as much perfusion. But this paper demonstrates that perfusion can be returned to normal by injection of bosentan, a vasodilator.

At this point the missing pieces are to demonstrate that obstructions of brain draining veins are correlated with brain hypoperfusion and to find ways to improve perfusion and reduce oxidative stress. We are excited about the evidence that Nrf2 activator anti-oxidants such as Tecfidera, but also the supplement Protamdin have been proven effective for MS and are committed to continue the study of the role of venoplasty in improving perfusion.

From the new Hubbard newsletter.
Bethr, glad to hear you are doing well. Do you know if hypoxia decrease hepcidin locally or globally? Would the increase in iron absorption happen throughout the body or would it be concentrated in the brain/neck area? Slow train wreck is an apt way to describe it.
Cece
Family Elder
 
Posts: 8957
Joined: Mon Jan 04, 2010 4:00 pm

Re: Missing Link? Endothelin1 high in pwMS

Postby Bethr » Fri May 31, 2013 9:47 pm

Hi Cece, they say that Iron Metabolism is the new "Bacteria". So there is a huge amount of studies coming out currently.

This study is a couple of years old but good overall info.

http://www.hindawi.com/journals/ah/2011/510304/

Advances in Hematology
Volume 2011 (2011), Article ID 510304, 7 pages
doi:10.1155/2011/510304
Review Article

Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia
3. Hypoxia and Iron Metabolism

The profound effects of hypoxia on organismal iron metabolism have been well described. Early studies demonstrated that hypoxia affected dietary iron absorption [30–32] and increased erythropoiesis when humans were moved from sea level to high altitude [33]. As the partial pressure of O2 decreases through increased elevation, anemia, or localized tissue hypoxia, a battery of genes are induced by the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system. The HIF system senses O2 levels through degradation of HIF transcription factors (HIF-1α and HIF-2α) that are mediated by the partial pressure of O2 and iron-dependent hydroxylases. At normoxic O2 tensions, HIF-1α is hydroxylated by prolyl hydroxylase and then bound by the von Hippel-Lindau (VHL) protein leading ultimately to ubiquitination and proteasome degradation. During hypoxic conditions, the activity of hydroxylases is inhibited allowing HIF-1α to accumulate and bind along with HIF-1β to HRE found in the promoters of target genes. Similar to HIF-1α, HIF-2α stability is mediated by the partial pressure of O2 through prolyl hydroxylase and plays a dominant role in hypoxic signaling of EPO expression [34]. ]



Interestingly I think I've worked out why I started to overload iron early in the hypoxia episodes. It's because I don't have a spleen (from a car accident 35 years ago). The spleen contracts when you get hypoxic and pushes oxygen filled red blood cells out into the blood stream quickly so you can get the
extra oxygen that you need. Low hepcidin levels from hypoxia
increase your absorption of iron through the digestive system, as the body needs iron to make extra red blood cells.
I wouldn't need all that iron as I don't have a spleen and the iron would stay in my blood serum until stored (my serum iron doubled when I tried to ski the volcanoe last year) and I couldn't breath either as no extra red cells from the spleen to boost my oxygen levels and I was rushed back down to sea level.
Secondly, I'm a carrier of hemochromatosis gene C282Y (so are 10% of northern Europeans) and I already have a highish iron level. All my siblings do too.

The MS type symptoms for me were early in the piece when I had the mild iron overload coupled with a dental anaesthetic. Much more like porphyria than MS now that I can look back on it.

From reading I believe the hypoxia can be localised.

Cheers...
User avatar
Bethr
Family Elder
 
Posts: 475
Joined: Sun Dec 27, 2009 4:00 pm

Re: Missing Link? Endothelin1 high in pwMS

Postby 1eye » Sat Jun 01, 2013 11:08 am

To tie together a couple of things, is there any connection between sun exposure and ET-1, both effects which seem to be acquiring significance? I would hate to think that since the brain produces local ET-1, my lifetime of long hair has anything to do with it, and I must now become a skin-head! :-)
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
User avatar
1eye
Family Elder
 
Posts: 2852
Joined: Wed Mar 17, 2010 4:00 pm
Location: Kanata, Ontario, Canada

Re: Missing Link? Endothelin1 high in pwMS

Postby Billmeik » Sat Jun 08, 2013 9:08 am

Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.


k do.
User avatar
Billmeik
Family Elder
 
Posts: 694
Joined: Fri Nov 27, 2009 4:00 pm

Re: Missing Link? Endothelin1 high in pwMS

Postby 1eye » Sat Jun 08, 2013 9:24 am

If the level of ET-1 is high in the immediate area of the capillaries in the brain (someone say astrocytes can be a source?) won't they be oxygen-starved if, as I saw elsewhere, there is only enough room in one to pass a single O2 molecule normally? Invisible vasculature anyone?

If ET-1 is high, and nitric oxide is low, won't there be too much contraction and not enough dilation, at the same time? Heavens knows how vit-D fits into that, but I bet it does.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience
User avatar
1eye
Family Elder
 
Posts: 2852
Joined: Wed Mar 17, 2010 4:00 pm
Location: Kanata, Ontario, Canada

Previous

Return to Chronic Cerebrospinal Venous Insufficiency (CCSVI)

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users