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Inhibitors of the renin-angiotensin system for low flow POTS?

Discussion in 'Problems Standing: Orthostatic Intolerance; POTS' started by Emootje, Jan 13, 2012.

  1. Emootje

    Emootje Senior Member

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    Julian Stewart found high levels of angiotensin II in low flow POTS. High levels of Angiotensin II causes a decrease in cutaneous neuronal nitric oxide and an increase in oxidative stress and sympathetic tone. An angiotensin II type 1 receptor blockade corrects this cutaneous nitric oxide deficit.

    Has anyone experience with an ANG II blocker or a ACE inhibitor for POTS?

    http://ajpheart.physiology.org/content/294/1/H466.full.pdf html
    http://hyper.ahajournals.org/content/53/5/767.full.pdf html
    http://ajpheart.physiology.org/content/294/1/H466.full.pdf html
    http://ajpheart.physiology.org/content/293/4/H2161.full.pdf html
     
  2. CAcfs

    CAcfs Senior Member

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    Would adding NO help? I am taking Acai and it seems to be helping me....it says on the bottle that is does something with NO levels. I also noticed in Xymogen's Mitochondrial Renewal Kit there is a supp called NO Max....so I'm thinking there is some kind of ME/CFS link with NO levels. I haven't researched it at all though, so I'm not sure if you are supposed to increase them or decrease them or regulate them....etc etc.
     
  3. ramakentesh

    ramakentesh Senior Member

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    Apparently NO supplementation wont work because the deficet in this case is neuronal rather than endothelial bioavailability. I think Low Flow POTS represents a fairly small subset of POTS patients (20% was a figure raised in a webinar) and it consisted of almost excluslively female POTS patients.
    My understanding is that ultimately the low flow state is in part mediated by neuronal NO Potentiation of sympathetic drive, and vasoconstriction and impaired blood flow from ROS.
    Stewart's group have been using intravenous antioxidants like vitamin C to correct blood flow deficits in the cutaneous vasculature and also losarten to aid in the catabolism of angiotensin II.
    A larger subset of POTS patients - according to more recent work from Stewart and Medow - have excessive NO neuronal and endothelila activation. Obviously supplementation of NO through l-arginine or other mediators may actually worsen this mechanism.
     
  4. ramakentesh

    ramakentesh Senior Member

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    In low flow there is a paradox - low renin and aldosterone and high angiotensin II levels. In other POTS patients there is low renin and aldosterone responses and perhaps even elevated peripheral dopamine under orthostatic stress resulting in postural salt loss through extraction from the kidneys.
     
  5. Emootje

    Emootje Senior Member

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    I think that decreased baroreceptor sensitivity plays a major role in hyperadrenergic CFS/POTS (see figure below).

    BRS.jpg

    I'm now trying to lower my oxidative stress in the CNS, hoping that my sympathetic tone will calm down. In theory this will increase my baroreceptor sensitivity and that will calm the SNS down.

    My options to increase baroreceptor sensitivity so far:

    Antioxidants

    • Taurine
    • Vitamin C
    • Omega 3
    • Folic Acid (also increases BH4)

    Lower oxidants production
    • AT-1 inhibitors
    • ACE inhibitors
    • No sugar/fructose

    NADPH oxidase inhibitors
    • Naloxone
    • Dextromethophan
    • Minocycline
    • Trimetazidin
    • Apocynin (black indian hemp, picrorhiza kurroa)

    Others
    • Slow deep breathing (for example Ujjayi)
    • Avoid sleep deprivation (sleep deprivation decreases baroreceptor sensitivity)

    CAcfs
    In low flow POTS:
    "NO deficits are reversed by Ang-II type-1 receptor (AT1R) blockade, ascorbic acid (AA) and tetrahydrobiopterin in skin" If you have low flow POTS you could try folic acid or l-methylfolate to increase NO by increasing tetrahydrobiopterin.

    In normal flow POTS:
    According to the recent work from Stewart and Medow, mentioned by Ramakentesh, normal flow POTS have excessive NO. I agree with Ramakentesh, adding NO to this subgroup could make things worse.
     
  6. ramakentesh

    ramakentesh Senior Member

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    Will be interesting to see how it goes.

    I guess Normal Flow could fit your theory of acetylcholine toxicity as there is an excessive NO vasodilatory response to normal levels of ach.

    With my POTS even foods that contain minute traces of ace activity have made me feel worse.
     
  7. ramakentesh

    ramakentesh Senior Member

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    Other considerations would be that angiotensin II blockade like Losartan will work better chronically than in the short term in theory.

    However, other researchers have noted the elevated angiotensin II levels in POTS and do not at this stage believe an NO based mechanism is at play, rather there is resistance to angiotensin II from unresponsive ANg II receptors in the vascular bed but not interestingly in the kidney or other targets. As Ang II is a vasoconstrictor, this unresponsiveness results in increased NE and sympathetic activity to compensate for this unresponsive vasoconstriction. So here the mediator is no NO or reduced nNOS activity, but rather unresponsive ANG II mediated vasoconstriction perhaps from desensization because of chronic elevated ANG II levels.

    Vandebilt had a new paper published just days ago in regard to Angiotensin II and the lack of vascular response to angiotensin II infusion. This paper specifically talks about baroreflex abnormalities associated with elevated ANg II so may be of interest.

    Another potential mechanism could be autoantibodies clogging up ANG II receptors although this is speculative - however these have been found in a number of other pathologies such as preeclampsia, etc.

    Therefore, potentially NO supplementation may not have any benefit in any cases. I know from patients that have dosed with L-arginine and other substrates that have attempted to increase NO bioavailability the results seem to follow a similar course: a rapid improvement and then a severe crash after a short period.

    Some patients do report benefit from Taurine and a few other supplements that might work indirectly on eNOS and nNOS bioavailability so its hard to say.

    Laslty a few patients have reported that nitroglycerine during an autonomic storm (a severe exaccerbation of POTS with body shakes and mental confusion) improves them dramatically.

    It could even be that NO levels are abnormal in some areas - such as splanchnic circulation hyperactivation, thoratic or cerebral reduced.

    thank you for your posts - they were refreshingly well researched.
     
  8. ramakentesh

    ramakentesh Senior Member

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    lastly can I ask where you obtained that figure? Perhaps if there is signs of innate immunity activation then TNF alpha blockade would also be beneficial.
     
  9. Emootje

    Emootje Senior Member

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    Thanks for the interesting responses, it is very informative but it also makes it very complicated. Next month I'm going to try a natural ace inhibitor and a natural NADPH oxidase inhibitor, hopefully it gives me more insight.
    The above figure is self made. :Retro smile:
     
  10. ramakentesh

    ramakentesh Senior Member

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    let us know how it goes. My general feeling is that an ang II blocker wouldbe the way to go.

    have you ever tried b12 or licorice? what results did you get if you dont mind me asking. thanks again
     
  11. ramakentesh

    ramakentesh Senior Member

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    Another angle you might be interested in is Asymmetric Dimethylarginine - a competitor of arginine that reduces its bioavailability.

    Found to increase sympathetic drive in kidney disease:

    http://www.ncbi.nlm.nih.gov/pubmed/21940841

    found to be elevated in patients with fibromyalgia and perhaps provide a link between altered cytokine expression and abnormal vascular consequences and a low flow state:

    http://www.ncbi.nlm.nih.gov/pubmed/21291875

    Or perhaps NET deficiency:

    http://circep.ahajournals.org/content/1/2/103.short
     
  12. Emootje

    Emootje Senior Member

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    I find this very interesting because blockers of the renin-angiotensin-aldosterone system lowers asymmetric dimethylarginine levels.

    "Antagonist drugs of the renin-angiotensin-aldosterone system, such as angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers, and aldosterone antagonists, diminish plasma ADMA levels by mechanisms that are unclear. Possible pathways include improvements in oxidative stress as impacted by angiotensin II, a ROS precursor"
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694252/pdf/cln64_5p471.pdf

    And yes I tried b12 and licorice, both supplements gave no relief. l-arginine gave some benefit by improving my small fiber neuropathy (I believe this (ischemic) neuropathy is caused by excess vasoconstriction in nervus vascular beds). Inosine (NO inhibitor) gave no relief and slow deep breathing gave me the best results. (less nausea, neuropathy and more energy)
     
  13. ramakentesh

    ramakentesh Senior Member

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    Fascinating. I hadnt seen that article. AMDA is one of the culprits that until recently has avoided much attention so that is my interest. Also it is elevated in some systemic autoimmune diseases where autonomic features occur.

    Did either b12 or licorice make you feel worse?

    And yes Ive often said this about neuropathy. People seem to assume their condition is caused by neuropathy but what if its the opposite from chronic reductions in blood flow?

    Honestly it is refreshing to speak with someone who has conducted extensive research on these issues.

    There is also some interesting supplements that are reputed to increase NO bioavailability: Pycnogenol as an example.

    lastly the leaves of salvia elegens are reputed to contain both Ang II blockade and ace activity.
     
  14. Emootje

    Emootje Senior Member

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    Thanks you Ramakentesh. Your knowledge of herbs is very helpful.
    Salvia Elegens seems like a good candidate for low flow patients but it's hard to find. Can't find it on iHerb...

    And yes, pycnogenol and some other flavonoids are helpful in dealing with my small fiber neuropathy.

    B12 and licorice did not make me feel worse nor did I noticed any improvement.
     
  15. ramakentesh

    ramakentesh Senior Member

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    You can often find Salvia elegens at nurseys as pineapple sage. Its also a beautiful plant.
     
  16. Emootje

    Emootje Senior Member

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    Thank you again, Ramakentesh.
    Can I ask about your situation? Are you a low, normal or high flow POTSer? Hyperadrenergic? Low blood volume? Splanchnic pooling?
    And can you tell me what treatment works for you?
     
  17. ramakentesh

    ramakentesh Senior Member

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    Goji berries are full of ace but not ANG II blocking. I ate some of those in a chicken dish and promptly fainted after a bath an hour later LOL. My friend and I are currently writing a paper for his research on herbs that may have benefit in POTS at least.

    I wish I knew what type I am. I started with a hyper presentation but over the years my relapses have gone more the other way and presyncope/weakness is my main feature. Deonding on which delineation you are looking at, I think I would say that I am definately low flow or normal flow although Im not sure i have ever noticed much splanchnic pooling. My orthostatic BP is generally high when I feel well and normal when I feel like death. My veins have been described over the yeasr as like an old person's, like a person with very low blood pressure and like a person who has spent two days in a desert without water so Im quite sure that my condition at least in part relates to chronic hypovolumia.

    I never crave salt or salty foods, but i crave liquid all day long and it goes straight through me when im upright. Intravenous Saline works much better than injestion and I felt so much improvement after it that its amazing. Therefore I am keenly watching the work being done by Vanderbilt in relation to dopamine and kidney function - salt handling in POTS.

    The best treatments that have worked for me thus far are saline infusions which were very impressive, alpha agonists (first DHE and then butchers broom), licorice tea for a boost in BP. We have also found a couple of chinese herbs of interest although they seem to help more with the feelings of excessive sympathetic activity rather than orthostatic tolerance. Medications have been less helfpul for me. Some have done little or even nothing. I could be totally functional on 1 litre saline a day if I could get it perhaps with a mild beta blocker for heart rate.

    My own theories of my condition are quite different to the literature. And they are based largely on conjecture rather than research.

    I believe that for me at least there is an autoimmune process at play. I also suffer from Ankylosind Spondylitis and when one flares up the other goes away. Further, i suffer POTS as relapses and remissions. Perhaps there is an autoimmune process destroying peripheral NET resulting in increase NE and peripheral dopamine, which stimulates d1 dopamine receptors in the kidneys and results in excessive orthostatic salt loss and dynamic hypovolumia? Alternatively perhaps there is an inflammatory condition in the splanchnic vasculature that resuilts in excessive fluid loss into surround tissues (which might explain why butchers broom helped me but does very little for many). Im open to most of them - other than deconditioning LOL.
     
  18. ramakentesh

    ramakentesh Senior Member

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    At the moment our herbs are split into three catagories:

    cognitive function - we have a few but its hard to say yet.
    orthostatic tolerance - hit and miss unfortunately
    sympathetic excess/wired and tired - these ones are the most promising.
     
  19. Emootje

    Emootje Senior Member

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    Low-flow POTS is characterized by pallor, so if you are pale you are probably low flow.
    I'm low flow, very pale and hate everything that constricts my vessels (eg cold weather). So I try to stay as far away from alpha-1 agonists as possible. My instinct tells me that people who do better on midodrine/butchers broom are probably normal or high flow.

    Are you sure your fainting is caused by goji berries? Maybe it was the bathing. Head out water immersion (bathing) causes natriuresis which causes hypovolemia when you get out of the bathroom. This hypovolemia makes us more susceptible to fainting.

    I would love to hear about the herbs that deals with the excessive sympathetic activity, it is a big challenge to calm the sympathetic nevus system down, any addition information is welcome.

    Thanks again.
     
  20. ramakentesh

    ramakentesh Senior Member

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    Perhaps I am low flow - i have postural hypertension and feel worse in cold rather than hot environments. I also have suspected NET deficiency. I am definately hypovolumic but my tachycardia is never super high and my symptoms wax and wane a lot - even daily and intermingle with ankylosing spondylitis.

    The way I have approached it is that I only seem to have bluing when orthostatic and have never noticed it while lying down. I am generally not pale, but I go blue when im bad. Vanderbilt recently reviewed 15 patients with excessive ang II and found that they had abnormal responses to ang II infusion suggesting the ang II receptors were desensitized causing baroreflex issues and vagal withdrawal.

    From my understanding the concepts of flow breakups is evolving and there arppears to be many different groups with potentially many different mediators. Some alpha agonists have made me feel worse, others better.

    At the time I ate the goji I was having daily baths. I understand that baths can cause peripheral vasodilation and worsen symptoms but I am highly sensitive to the cold. the goji made it so bad I didnt feel like i could get out of the bath without assistance and i felt very light headed all day afterwards.

    Symoathetic excess herbs Id have to pm you with as my friend doesnt want them in the public domain yet :)
     

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