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Cortisol And Aldosterone Cause Vascular Calcification

Discussion in 'Scientific Studies' started by haidut, Oct 1, 2017.

  1. haidut

    haidut Member

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    In one of his newsletter circa 2015, Ray wrote about the role of aldosterone in heart failure, heart attacks, shock, and edema. He conjectured that aldosterone antagonists would one day be recognized as therapeutic for these conditions. Almost all types of heart disease start with vascular calcification, which elevates blood pressure (BP) and can also lead to a plaque rupture causing heart attack. Even is there is no plaque rupture, the chronically elevated BP leads to chronic strain for the heart and is a factor in both heart failure, strokes, dementia, and glaucoma. As such, resolving this calcification is the target of a number of new drugs Big Pharma is pushing as treatment for heart disease.
    This study below shows that vascular calcification may be caused by excessive cortisol, which in higher concentrations activates the mineralocorticoid receptor (MR) - the same receptor that aldosterone activates. Antagonism to the glucocorticoid receptor (GR) did not prevent or reverse the calcification but antagonism to MR did. According to the study, lowering excessive cortisol through 11b-HSD1 inhbition is also a viable option as treatment, and of course antagonism to MR would be the main target.

    A novel role for the mineralocorticoid receptor in glucocorticoid driven vascular calcification
    "...In vitro studies revealed increased phosphate-induced calcification in mouse VSMCs following treatment for 7 days with corticosterone (100 nM; 7.98 fold; P < 0.01), 11-DHC (100 nM; 7.14 fold; P < 0.05) and dexamethasone (10 nM; 7.16 fold; P < 0.05), a synthetic glucocorticoid used as a positive control. Inhibition of 11β-HSD isoenzymes by 10 μM carbenoxolone reduced the calcification induced by 11-DHC (0.37 fold compared to treatment with 11-DHC alone; P < 0.05). The glucocorticoid receptor (GR) antagonist mifepristone (10 μM) had no effect on VSMC calcification in response to corticosterone or 11-DHC. In contrast, the mineralocorticoid receptor (MR) antagonist eplerenone (10 μM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone; P < 0.01) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone; P < 0.01) VSMC calcification, suggesting this glucocorticoid effect is MR-driven and not GR-driven. Neither corticosterone nor 11-DHC altered the mRNA levels of the osteogenic markers PiT-1, Osx and Bmp2. However, DAPI staining of pyknotic nuclei and flow cytometry analysis of surface Annexin V expression showed that corticosterone induced apoptosis in VSMCs. This study suggests that in mouse VSMCs, corticosterone acts through the MR to induce pro-calcification effects, and identifies 11β-HSD-inhibition as a novel potential treatment for vascular calcification."

    Vitamin K is well-known to prevent and reverse vascular calcification but it has no effects on aldosterone and the renin-angiotensin system. A more direct dietary approach would be to simply increase salt intake as sodium lowers aldosterone by a feedback mechanism. Another intervention would be to supplement with pregnenolone, which is a potent aldosterone (MR) antagonist and quite a few people have reported on its rapid effects of reducing water retention in higher doses. Progesterone is also a MR antagonist, and DHEA/emodin are 11b-HSD1 inhibitors and as such both of them should also help with this issue.
    Pregnenolone Is A Potent Aldosterone Antagonist (antimineralocorticoid)
    DHEA, In Low Doses, Directly Inhibits Cortisol Synthesis
     
  2. Mito

    Mito Member

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    In a previous post (below), you mentioned K2 & methylene blue for high blood pressure. Do you still like (low dose) MB for high BP?

     
  3. OP
    haidut

    haidut Member

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    MB can control low BP, as it raises BP for many people. This is why it is used for shock victims in hospital as their BP is low. Taurine and K2 are probably best for high BP. Also, methyl palmitate apparently has a potent and immediate effects on lowering BP. But the overall goal should be to raise CO2 as that is what keeps vessels supple. In the absence of CO2, NO rises as the emergency vasodilator.
     
  4. aguilaroja

    aguilaroja Member

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    Thanks for the excellent topic and references. There are some gratifying horizons in recent research, about the dangers of mineralocorticoid excess, and the hazards of vascular smooth muscle cell calcification and shift toward osteoblasts.

    Vascular Consequences of Aldosterone Excess and Mineralocorticoid Receptor Antagonism. - PubMed - NCBI
    “The beneficial actions of [mineralocorticoid receptors (MRs)] antagonism in experimental hypertension include improved endothelial function, reduced hypertrophy and remodeling, and in atherosclerosis beneficial actions include reduced plaque area, inflammation, oxidative stress and endothelial dysfunction. Aldosterone excess is detrimental and MR antagonism is beneficial in humans also.”

    Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation. - PubMed - NCBI
    “Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL-18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC.”
    “IL-18 enhances VSMCs osteogenic differentiation and subsequent VC induced by β-glycerophosphate via TRPM7 channel activation. Accordingly, IL-18 may contribute to VC in proinflammatory conditions.”

    Ray Peat Email Exchanges - Ray Peat Forum Wiki
    “Although I think knowing your PTH and free fatty acids will be useful (in judging use of calcium, sugar, aspirin, niacinamide, etc.), another test that could help to clarify the nature of the inflammation would be the serum interleukin-18, since it's associated with liver damage and increased ferritin, and symptoms of inflammation. Since TSH increases IL-18, finding it elevated would be another argument for keeping your TSH very low.”

    Cortistatin inhibits calcification of vascular smooth muscle cells by depressing osteoblastic differentiation and endoplasmic reticulum stress. - PubMed - NCBI
    “…vascular smooth muscular cells (VSMCs) play an important role in the development of vascular calcification (VC). Cortistatin (CST), a novel bio-active peptide, has been shown to exert multiple protective effects on the cardiovascular system.”
    “CST directly inhibited β-GP-induced calcification of VSMCs in vitro, probably by suppressing ERS and phenotypic transformation of VSMCs into osteoblastic cells.”
     
  5. Malris

    Malris Member

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    Haidut,

    Thanks for the awesome post and the follow-up. I have a basic question for you only tangentially related, but hopefully easily answered: Do you have a "go-to" post on how to raise CO2?
     
  6. OP
    haidut

    haidut Member

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    I don't have one post, but several of them. Thiamine, biotin, niacinamide, and MB are probably the most effective ones in raising CO2 levels. See below.
    https://raypeatforum.com/community/...rly-to-dca-and-may-be-helpful-in-cancer.3895/
    Thiamine Is A Carbonic Anhydrase Inhibitor As Effective As Acetazolamide
    Niacinamide Causes Dramatic Increase In Nad And Fall In Lactate
    Using Vitamins (biotin) For Improving Glucose Control (first study in section 3)
    The effects of methylene blue (MB) on tumor respiration
     
  7. Malris

    Malris Member

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    Awesome, Haidut. Thank you.
     
  8. RedStaR

    RedStaR Member

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    What do you think about sodium bicarbonate as a blood alkalizing agent?
     
  9. DaveFoster

    DaveFoster Member

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    @haidut

    Do you think thyroid and a good diet would be enough in most (non-severe) cases? You'd have the regulation of progesterone, pregnenolone, DHEA along with cortisol antagonism, and then the salt from the diet of course.
     
  10. OP
    haidut

    haidut Member

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    Sure, that's what I would try first at least. But some supplementation may be needed in cases of established calcification in order to reverse it. Vitamin K and pregnenolone are probably the first things I would try supplement-wise.
     
  11. DaveFoster

    DaveFoster Member

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    Dr. Peat's spoken quite a bit about the importance of getting enough calcium as well. Thanks for the info.
     
  12. Regina

    Regina Member

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    If mineralocorticoid receptor is activated in trauma stress (stage 1 GAS), is this what causes loss of magnesium? That might take the myth out of "psychic vampirism". The alarm stage stress/shock can cause a kind of de-mineralization??? (in addition to the increased serotonin from learned helplessness).

    btw: it is amazing to re-read this, having recently come through the other side. I.e., returning more to the state of the rat that did not endure the alarm stage stress. Thereby, will not have to spend the rest of my life with an animalistic mind (pituitary). Yay. Thank you!!!
     
  13. OP
    haidut

    haidut Member

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    Well, anything that acts like mineralocorticoid will lead to sodium retention at the expense of magnesium and potassium. How would "psychic vampirism" be related to magnesium loss though?
     
  14. Regina

    Regina Member

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    I think just what you said above. If someone is so disturbed by intentional attack that MR is activated, this mineral derangement is another facet of the shitstorm.
     
  15. Regina

    Regina Member

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    I would add that by "animalistic mind", I mean like the grasshopper:locust study that haidut cited in this interview.
    And also, if I could understand the 4th phase of water better, I might be able to comprehend these energetic changes -- such as the desalination.
     
  16. OP
    haidut

    haidut Member

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    Here is that study on serotonin turning nice grasshoppers into savage locusts.
    Genes Do NOT Matter (much)
     
  17. Regina

    Regina Member

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    Thanks so much!!:bouquet: Can't wait to read this tonight (after strategically trying to avoid the locusts in class tonight).
     
  18. Regina

    Regina Member

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    Sensei -
    Great article! Although the writer does seem to correlate the spike in serotonin with brain growth. "The brain grows to manage the animal’s newly complicated social world, which includes the fact that, if a locust moves too slowly amid its million cousins, the cousins directly behind might eat it."
    It's so interesting to observe/participate in class with these ideas in my head. The teacher tonight is by far the most technically proficient. He holds forth but is not an authoritarian. By the end of class, even the locusts had softened up. We were able to do things (koshi and jujinages - hip and elbow throws) that are normally scary, painful and end up with people not speaking to, fighting or threatening each other. He left us all pleasant grasshoppers. Really neat.
     
  19. Travis

    Travis Member

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    There are tons of studies showing emodin can safely inhibit 11β-HSD₁ without interfering with 11β-HSD₂—most done on diabetes.

    Of course enoxolone binds 11β-HSD₁ much better, but it also strongly interferes with 11β-HSD₂ in the kidneys.

    I found, just yesterday, a good mineralcorticoid receptor antagonist called wedelolactone—a natural molecule of Eclipta species. There are exactly zero data on its binding to the mineralcorticoid receptor, or any mention of this at all . . . anywhere, but it has been shown to both lower blood pressure and cause hair growth so it must be so. It has also been shown to stimulate Na⁺ excretion.

    I think it has the structure for it too, and does not appear to have any crosstalk with the androgen receptor—as does spironolactone. Here is the study showing it's effect on blood pressure and kidneys:
    And one on . . . hypertension in rats. (Would love to see that little arm-cu tail-cuff sphygmomanometer.)
     
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