RENIN-ANGIOTENSIN-ALDOSTERONE SYSYTEM And HAIR LOSS PROCESS

Discussion in 'Scientific Studies' started by md_a, Apr 4, 2020.

  1. md_a

    md_a Member

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    I think excess cortisol-aldosterone- mineralocorticoid activation trough angiotensin system are main players in balding by cytokine activation and progressing to fibrosis. Focusing on TGF-β₁, which shuts off the anagen phase of the hair cycle, and 11β-HSD₁ expression should fix to the problem. Angiotensin 2 receptor (AT-1) is involved in the inflammation pathway.

    Angiotensin - Aldosterone has been shown to upregulate TGF-β₁. DHT upregulates 11β-HSD₁ expression.

    Cortisol synthesis depends on the enzyme 11β-HSD1 and it converts the inactive cortisone into the active cortisol.


    RENIN-ANGIOTENSIN-ALDOSTERONE SYSYTEM AND HAIR LOSS PROCESS

    Although hair follicles express almost a full set of RAAS-associated receptors, the role of this system in the regulation of hair growth has not yet been described.


    The data describing serum ACE activity in patients with alopecia areata are not consistent; however, both of the studies performed to date have exploited relatively small groups (102, 103). Moreover, one study has shown that in patients with mild or moderate alopecia areata, ACE tissue activity is decreased in the epidermis, as well as in follicular epithelium and endothelium.


    The role of RAAS in the hair loss process should be considered as highly possible due to reports linking to the intake of ACE-I to hair loss. Interestingly, discontinuation of ACE-I treatment or switching patients from ACE-I to ARB has resulted in hair regrowth. However, the mechanism of ACE-I-induced alopecia is unknown.


    There are some studies indicating the potential role of aldosterone and MR in hair loss. Postnatal MR overexpression in keratinocytes in mice has resulted in delayed alopecia, hair follicle dystrophy, and abnormalities of the hair cycle, without alternation of the interfollicular epidermis. Moreover, clinical studies have shown that both male and female patients with androgenic alopecia have higher aldosterone serum levels. The mechanism underlying this process may be associated with the skin microinflammation found in those patients. Despite the potential role of aldosterone, there is only one study evaluating the influence of MR blockade on hair. This showed that spironolactone treatment reduced hair shaft size and weight resulting in softer, finer hair and a slower growth rate in patients with hirsutism. In this study, the action of spironolactone was mainly associated with its antiandrogenic activity. Nevertheless, the potential role of MR blockade cannot be excluded.

    JPP No 3/2019 article 01
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    Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, 11β-HSD converts the biologically active cortisol to the inactive cortisone, which can no longer bind the mineralocorticoid receptor. 11β-HSD co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhizinic acid and enoxolone, can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome. Cortisol levels consequently rise, and cortisol binding to the mineralocorticoid receptor produces clinical signs and symptoms of hypokalemia, alkalosis and hypertension (i.e. mineralocorticoid excess).

    11β-hydroxysteroid dehydrogenase is expressed in the central nervous system of aged individuals. It is essential in Hypothalamo-Pituitary-Adrenal Axis function. 11β-hydroxysteroid dehydrogenase also partakes involvement in the decline of conscious intellectual activity due to ageing.

    11β-HSD1 is responsible for activating glucocorticoids while 11β-HSD2 is responsible for deactivating them.

    https://en.wikipedia.org/wiki/11β-Hydroxysteroid_dehydrogenase


    Mineralocorticoid overexpression is expressed in hyper-keratinization. Mineralocorticoid excess is due to cortisol. Elevated mineralocorticoid is the consequence of defective cortisol metabolism, thus implicating impaired 11β-HSD2 activity.

    A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. - PubMed - NCBI


    The local renin-angiotensin-aldosterone system (RAAS) is fully expressed in the human skin at the mRNA and protein level. Local RAAS is known to play a regulatory function in epidermal proliferation, wound healing, scarring, cutaneous heating adaptation, and aging. There are also some indications of its role in the regulation of hair growth and sebum secretion. Impaired wound healing, skin diseases associated with diabetes, cancer development, psoriasis, and scleroderma may be related to changes in skin RAAS activity. Extensive research has shown that RAAS-modulating drugs can affect the skin when applied orally or topically, creating new therapeutic approaches against dermatological diseases.

    https://www.researchgate.net/public...ayer_in_skin_biology_beyond_the_renal_horizon


    Linoleic acid - Arachidonic acid – Iron (heavy metals) are involved in inflammation – lipid peroxidation – hair loss.

    Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.

    Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis. - PubMed - NCBI

    Arachidonic acid is synthesized from α-linolenic acid derived from linoleic acid, an essential fatty acid, by the enzyme Δ6-desaturase. ... Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes.

    Arachidonic Acid - an overview | ScienceDirect Topics



    Oxidative Stress in Ageing of Hair

    Ageing of hair manifests as decrease of melanocyte function or graying, and decrease in hair production or alopecia. There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss.

    Oxidative Stress in Ageing of Hair \


    A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors

    AGA is the result of chronic GA-transmitted scalp tension mediated by pubertal and post-pubertal skull bone growth and/or the overdevelopment and chronic contraction of muscles connected to the GA. This tension induces a pro-inflammatory cascade (increased ROS, COX-2 signaling, IL-1, TNF-α, etc.) which induces TGF-β1 alongside increased androgen activity (5-αR2, DHT, and AR), which furthers TGF-β1 expression in already-inflamed AGA-prone tissues. The concomitant presence of DHT and TGF-β1 mediates perifollicular fibrosis, dermal sheath thickening, and calcification of the capillary networks supporting AGA-prone hair follicles. These chronic, progressive conditions are the rate-limiting factors in AGA recovery. They restrict follicle growth space and decrease oxygen and nutrient supply to AGA-prone tissues – leading to tissue degradation, hair follicle miniaturization, and eventually pattern baldness.

    A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors - ScienceDirect


    Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells

    The progression of androgenetic alopecia is closely related to androgen-inducible transforming growth factor (TGF)-β1 secretion by hair follicle dermal papilla cells (DPCs) in bald scalp. Physiological levels of androgen exposure were reported to increase reactive oxygen species (ROS) generation. In this study, rat vibrissae dermal papilla cells (DP-6) transfected with androgen receptor showed increased ROS production following androgen treatment. We confirmed that TGF-β1 secretion is increased by androgen treatment in DP-6, whereas androgen inducible TGF-β1 was significantly suppressed by the ROS scavenger, N-acetyl cysteine. Therefore, we suggest that induction of TGF-β1 by androgen is mediated by ROS in hair follicle DPCs.

    Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells


    Clove oil (eugenol) inhibited 97.3% lipid peroxidation and decreases TGF‐β1 expression

    Expression of TGF‐β1 was increased significantly in the diabetic control group. However, eugenol treatment decreases this increased expression.

    Results suggest that treatment with eugenol involved amelioration of diabetic nephropathy by decreasing TGF‐β1 expression.

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    Clove oil inhibited 97.3% lipid peroxidation of linoleic acid emulsion at 15 μg/mL concentration. However, under the same conditions, the standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and trolox demonstrated inhibition of 95.4, 99.7, 84.6 and 95.6% on peroxidation of linoleic acid emulsion at 45 μg/mL concentration, respectively. In addition, clove oil had an effective DPPH scavenging, ABTS+ scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe3+) reducing power and ferrous ions (Fe2+) chelating activities.

    https://www.sciencedirect.com/science/article/pii/S1878535210001899



    Multiple nutritional, environmental and lifestyle factors can directly affect hair follicles, to weaken and make them sensitive to the action of androgens. Hair loss can be corrected and hair growth can be improved by addressing these non-androgenic factors. Patients having hair fall, thinning, loss of volume and poor growth can be precursors to androgenetic alopecia. Recent research has shown that androgens inhibit hair growth through release of Transforming Growth Factor (TGF) ß1. Further study of this mechanism reveals that generation of Reactive Oxygen Species (ROS) induced by androgens leads to release of TGF ß1 and use of ROS scavengers can block the release of TGF ß1, explaining beneficial role of antioxidants in hair growth. The binding of ROS to intracellular proteins also causes hair loss by altering the protein structure, changing their immune recognition and converting them to new antigens targeted by inflammatory and immune systems. Calorie restriction and individual micronutrient deficiencies lead to a new process of intracellular destruction or autophagy before cell apoptosis, which could explain cessation of hair growth. Telogen is not a resting phase but now defined as active conservation of follicles under unfavorable conditions. Thus any stress, trauma, metabolic change or insult causes telogen. Micronutrients zinc, copper, selenium maintains immunity, control inflammation and preserve antioxidant activity of the cells. Vitamins A, C, D have a role in phagocytosis and antibodies maintaining resistance. Vitamin D3 modulates the hair-inductive capacity of dermal papilla cells. Vitamin and micronutrient deficiencies are prevalent among all the population of the world. Nutritive value of the foods has reduced over the years by 30%. Endocrine Disrupting chemicals are creating further damage to the hormonal balance of the body. All these can be countered by use of antioxidants and a well-planned nutritional program which will ensure strengthening and regrowth of hair follicles, without the use of Finasteride. https://www.researchgate.net/public...n_Hair_loss_and_Hair_Regrowth_Review_Articlen


    Lisinopril-Induced Alopecia: A Case Report

    The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines consider angiotensin-converting enzyme (ACE) inhibitors as one of the mainstay therapies in the management of heart failure. The widespread use of ACE inhibitors has been associated with several notable adverse effects such as hyperkalemia and an increased serum creatinine. There are no previous reports of alopecia associated with lisinopril use; however, a few previous cases of alopecia associated with other ACE inhibitors exist. This report discusses a case of lisinopril-induced alopecia of a 53-year-old male presenting to our outpatient heart failure clinic with a chief complaint of a new onset of alopecia. Upon evaluation, it was suspected that the patient’s alopecia was likely medication induced by lisinopril; therefore, lisinopril was discontinued and switched to an angiotensin receptor blocker (ARB), losartan potassium. Alopecia resolved in 4 weeks after the therapeutic intervention.

    https://journals.sagepub.com/doi/abs/10.1177/0897190016652554


    The beneficial effect of Ang-(1-7) in alopecia can be attributed to their vasodilation action on blood vessels (Santos et al., 2000). The vasodilation of arterioles present in the dermis improves irrigation of the hair follicles, increasing the supply of nutrients and oxygen. Thus, the cells of the hair follicle increase their proliferation, accelerating hair growth

    https://patents.google.com/patent/US20150313829A1/en


    TGF-β plays important roles in the induction of catagen during the hair cycle. We examined whether TGF-β2 could activate a caspase in human hair follicles. Using active caspase-9 and -3 specific antibodies, we found that TGF-β2 activated these caspases in two regions, the lower part of the hair bulb and the outer layer of the outer root sheath. In addition, we searched for a plant extract that can effectively suppress TGF-β action. We found that an extract of Hydrangea macrophylla reduced synthesis of a TGDβ-inducible protein. We confirmed that the extract has a potential to promote hair elongation in the organ culture system. Furthermore, it delayed in vivo progression of catagen in a mouse model. Our results suggest that the induction of catagen by TGF-β is mediated via activation of caspases and that a suppressor of TGF-β could be effective in preventing male pattern baldness.

    https://www.sciencedirect.com/science/article/pii/S0022202X15529412



    Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication.

    It was found that pre-treat with candesartan significantly suppressed transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) expression after incubation with TNF-α.

    http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652019000300701


    Related to stress


    Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats.


    Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

    https://www.ncbi.nlm.nih.gov/pubmed/16574788
     
  2. mrchibbs

    mrchibbs Member

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    Very interesting! Thanks.

    Ray regularly talks about the Renin-Angiotensin-Aldosterone pathway, even in this latest ORN talk (May 20).
    I need to understand it more. He even said explicitly that Aldosterone is the opposite of Progesterone.
     
  3. OP
    md_a

    md_a Member

    Joined:
    Aug 31, 2015
    Messages:
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    Thanks!
    I started implementing the information from Ray Peat in 2009, I went from a state of extreme hypothyroidism to a state of hyper with the help of the thyroid Cynomel / Cynoplus in just a few days because I took a large amount of thyroid, I reached 37.1 Celsius from 35.8 C with a lot of positive effects, this made me realize how important it is to keep my temperature at 37 and pulse 80-90 beats per minute, which is not easy to obtain in my case only with food without thyroid when it is cold and with the toxic environment in the city. When my temperature drops below 36.8, my extremities get cold and I don't feel ok. I think, those who do not respond to the thyroid is probably the thyroid product is not good or do not get enough. From the age of 14 I started to have hair problems and a few times my hair fell out in proportion of 80%, and so I tested various methods to recover it but with some side effects. Now I am 41 years old. Since 2009 I managed to keep my hair only with info from Ray Peat but without regenerating my areas where I had visible gaps, and in moments of stress, lack of good food and thyroid, my hair was starting to fall out massive and I quickly stopped it with the help of breathing in the bag about 2 hours a day, so in my case, CO2 helps me to stop hair loss, but for regrowth, I think that in addition to the internal part related to nutrition, light, we must emphasize on external stimulation. Recently I started reading about Covid-19 and how inflammation generally acts through the angiotensin 2 and so I noticed that it has also an important role in hair loss related to inflammation, cytokines, fibrosis...

    With the new information I started to test scalp massage with different combinations to see if I can regenerate from fallen hair. In the front part of my head, there are small hairless places and it seems that it is the first time I notice that hairs have started to develop in that area, which I find quite interesting. I don't know exactly what effect it had because I tested massage with salt in a little aloe for emodin plus a few drops of thyme oil, oregano, and cloves. I think that in the last 2 months I have massaged only 8 times without following a rigorous program for it. In time I will observe if I will have some success with this, I am still accumulating information.

    So, I think could help hair regeneration a massage 2 or 3 times a week that includes Kosher salt, a little coconut oil, essential oil for hair stimulation and TGF-β₁ inhibitor, carbonic anhydrase inhibitor, maybe urea.

    11b-HSD1 inhibitors: coffee, emodin, niacinamide, retinol (vitamin A), zinc, glycine, theanine, taurine, magnesium, thyroid, vitamin E, vitamin B6, vitamin B1, aspirin..

    “Eucalyptus oil, containing cineole or eucalyptol, is a traditional remedy for asthma, that inhibits the products of unsaturated fatty acid metabolism and the cytokines most associated with asthma symptoms.” RP

    I looked at some essential oils recognized as antiviral and I observed that they have a role of cellular protection, antioxidant, blocking lipid peroxidation and iron chelation. Ray Peat mentioned eucalyptus oil as being good for asthma because it chelates iron and prevents lipid peroxidation, and so I became curious to find out more.

    Assessment of Antioxidative, Chelating, and DNA-Protective Effects of Selected Essential Oil Components (Eugenol, Carvacrol, Thymol, Borneol, Eucalyptol) of Plants and Intact Rosmarinus officinalis Oil

    ABSTRACT: Selected components of plant essential oils and intact Rosmarinus officinalis oil (RO) were investigated for their antioxidant, iron-chelating, and DNA-protective effects. Antioxidant activities were assessed using four different techniques.

    DNA-protective effects on human hepatoma HepG2 cells and plasmid DNA were evaluated with the help of the comet assay and the DNA topology test, respectively. It was observed that whereas eugenol, carvacrol, and thymol showed high antioxidative effectiveness in all assays used, RO manifested only antiradical effect and borneol and eucalyptol did not express antioxidant activity at all. DNA-protective ability against hydrogen peroxide (H2O2)-induced DNA lesions was manifested by two antioxidants (carvacrol and thymol) and two compounds that do not show antioxidant effects (RO and borneol). Borneol was able to preserve not only DNA of HepG2 cells but also plasmid DNA against Fe2+-induced damage. This paper evaluates the results in the light of experiences of other scientists.

    https://sci-hub.tw/https://pubs.acs.org/doi/10.1021/jf501006y

    https://pubs.acs.org/doi/10.1021/jf...IC73s6Zv5qr4Ey0_HxtE-sHNiqJ1-IgKsudY9QV3xzGgI


    „Carboxytherapy is an injection of C02 gas below the skin with the use of a 30.5 gauge mesotherapy needle. Carboxytherapy is used for the treatment of hair regrowth or hair loss. It improves circulation at the injection site by forcing red bloods cells to release oxygen and pick up C02 which is then eliminated by the body. This process of oxygenating the area of concern allows for improved healing and nourishing of the hair follicles. For hair rejuvenation, the injection of C02 has a vasodilation effect which allows for the increased nourishment of vitamins and nutrients to the scalp for increased hair growth and stabilization of hair loss. It is considered a natural hair loss treatment and works well in combination with laser therapy.”



    „Measuring the amount of thyroid in the blood isn't a good way to evaluate adequacy of thyroid function, since the response of tissues to the hormone can be suppressed (for example, by unsaturated fats). In the 1930's accurate diagnosis was made by evaluating a variety of indications, including basal oxygen consumption, serum cholesterol level, pulse rate, temperature, carotenemia, bowel function, and quality of hair and skin. A good estimate can be made using only the temperature and pulse rate.”RP

    “If your thyroid is working efficiently, your pituitary doesn’t have much to do and you’re not likely to get a pituitary tumor, your adrenals don’t have much to do, and your ovaries don’t get over stimulated. The other glands have an easy job when your thyroid is working right. If your thyroid gets interfered with, you have to rev up your adrenals and your pituitary becomes commander in chief and tells everyone what to do.”RP

    “The process of inflammation and fibrosis is initiated in response to anything that blocks the adequate production of energy” Ray Peat

    “Between its formation and its exhalation, C02 participates in many essential processes, including the stabilization of the energy producing system. When there isn't enough C02, the conversion of glucose to lactate increases, as an inefficient alternative source of energy, and then to supplement the rapidly consumed glucose, the use of the amino acid glutamine for energy increases, with ammonia as a byproduct. Both lactate and ammonia stimulate breathing, which can be lifesaving if a simple lack of oxygen was the reason for the lack of C02; however, if the lungs have a normal supply of oxygen, increased ventilation resulting from ammonia and lactate will cause a further decrease of C02.

    Since C02 relaxes smooth muscle, cells that are working and consuming oxygen and glucose (producing C02 in proportion to their activity) cause nearby blood vessels to relax and expand, delivering more oxygen and glucose in proportion to the increased need. When C02 is decreased, blood vessels constrict, limiting the supply of glucose and oxygen. With restricted blood supply, cells have to resort to locally stored glycogen for glucose, and to the breakdown of internal proteins for glutamine.

    In hypothyroidism, with lowered oxidative metabolism, the organism is never far from stress and hyperventilation, with the chronic production of lactate and ammonia. The inefficient metabolism of diabetes has similar effects. Diabetes and hypothyroidism are very closely related, since the use of glucose is required for the activation of the thyroid hormone, which is required for the efficient use of glucose. Besides ammonia and lactate, other stress related substances can also increase the drive to breathe more, depleting the essential C02-endotoxin, acetylcholine, serotonin, hydrogen sulfide, nitric oxide, carbon monoxide, angiotensin, and estrogen, for example.

    The hypoxia inducible factor increases many enzymes that promote the reductive state-aromatase (Samarajeewa, et al., 2013), prostaglandin synthase/cyclooxygenase (Xing, et al., 2015), the enzymes of glycolysis (MarinHemandez, et al., 2009), glutaminolysis (Kappler, et al., 2017), and glutamatergic excitation (Hsieh, et al., 2017), for example. Two of the enzymes that it activates, angiotensin converting enzyme (ACE) and carbonic anhydrase, have fundamental roles in shaping metabolism. Angiotensin II, the peptide produced by ACE, increases blood pressure and water retention and activates the pituitary and adrenal stress hormones, especially aldosterone. Both angiotensin and aldosterone activate carbonic anhydrase. It seems that any chemical that causes contraction of blood vessels also activates carbonic anhydrase (Puscas, et al., 2001 ). When the carbonic anhydrase in the wall of the blood vessel is activated, it converts the acid C02 to bicarbonate, raising the pH of the cell, increasing its excitability. The alkaline shift in pH (the shift that becomes chronic in cancer cells) increases the excitation and energy expenditure of any type of cell. These shifts toward pseudo hypoxia, alkalinity, excitation, water retention, and inefficient energy production can be seen, either locally or systemically, in all of the chronic and degenerative conditions that are now known to involve inflammation. Stress modifies our breathing, causing a vicious cycle, in which the lactate and ammonia produced when stimulation exceeds our oxidative capacity stimulate more intense breathing, causing more carbon dioxide to be lost, reducing oxidative efficiency and increasing the formation of ammonia and lactate.

    Considering the crucial role of C02 in preserving the integrity of cells, there should be more attention to using it therapeutically-bag breathing (rebreathing expired air until the oxygen in the bag is uncomfortably depleted), bathing in it (using a bag or tub of pure C02), using carbogen (5% C02 in oxygen) in hospitals and for emergency resuscitation, and using carbonic anhydrase inhibitors such as acetazolamide in more situations, including psychiatric. Direct use of carbon dioxide is likely to be helpful in all the situations that are known to be benefitted by acetazolamide, without the risk of allergy to that drug-traumatic brain edema, mountain sickness, osteoporosis, epilepsy, glaucoma, hyperactivity (ADHD), inflammation, polyps of the intestine, and arthritis. Diabetes, cardiomyopathy (Torella, et al., 2014), obesity (Arechederra, et al., 2013), cancer, dementia and psychosis are also likely to benefit…

    Other things that should be taken into account in any therapy are the light environment and the intestinal flora ( endotoxin activates HIF), the cycles of sleep and activity, and the quality of environmental stimulation. Among the common inhibitors of carbonic anhydrase are the mildly oxidizing flavonoids such as apigenin and fisetin, some polyphenols, vitamin Bl, vitamin D (Mras, et al., 2012), progesterone (partly by blocking the activation by estrogen and aldosterone ), and emodin.” Ray Peat

    ...

    There are some studies indicating the potential role of aldosterone and mineralocorticoid receptors in hair loss. Clinical studies have shown that both male and female patients with androgenic alopecia have higher aldosterone serum levels. The mechanism underlying this process may be associated with the skin microinflammation found in those patients.

    ...

    „It has been known for many years that decreasing sodium intake causes the body to respond adaptively, increasing the renin-angiotensin-aldosterone system (RAAS). The activation of this system is recognized as a factor in hypertension, kidney disease, heart failure, fibrosis of the heart, and other problems. Sodium restriction also increases serotonin, activity of the sympathetic nervous system, and plasminogen activator inhibitor type-1 (PAI-1), which contributes to the accumulation of clots and is associated with breast and prostate cancer. The sympathetic nervous system becomes hyperactive in preeclampsia (Metsaars, et al., 2006).” Ray Peat

    ...

    „The ratio of estrogen to progesterone--regardless of age or gender-is an important factor in regulating minerals and water, cell energy metabolism, and blood pressure. The ratios of many other regulatory substances (including serotonin/dopamine, glucagon/insulin, and aldosteronelcortiso1+progesterone) vary according to the quality of the individual's level of adaptation. to the environment. Improving the environment can shift the ratio in the direction of restoration rather than mere survival.

    While stress typically causes the adrenal glands to produce cortisol, extreme stress, as described by Hans Selye, damages the adrenal cortex, and can cause the cells to die, leading to the death of the animal. There is evidence that it is the breakdown of unsaturated fatty acids that causes damage to the adrenal cortex in extreme stress. Although many factors influence the production of the adrenal steroids, arachidonic acid, even without being converted to prostaglandins, is an important activator of aldosterone synthesis. Adrenalin, produced in response to a lack of glucose, liberates :free fatty acids from the tissues, so when the tissues contain large amounts of the polyunsaturated fatty acids, the production of aldosterone will be greater than it would be otherwise. The continuing accumulation of polyunsaturated fats in the tissues is undoubtedly important in the changing relationship between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stress induced aldosterone, and belps to lower blood pressure, if it's taken in the evening, to prevent the increase of free fatty acids during the night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, leading to insulin resistance, and contributing to atherosclerosis (Prada, et al., 2000; Mroka, et aI., 2000; Catanozi, et al., 2003; Garg, et al., 2011).

    The same factors that support or interfere with cellular renewal in the pancreas and adrenal glands have similar effects in the bones, skin, skeletal and heart muscle, nervous system, liver, and other organs. In every case, the local circulation of blood is influenced by both local and systemic factors. The loss of control over the water in the body is the result of energy failure, and hypertension is one of the adaptations that helps to preserve or restore energy production. Lowering inflammation and the associated excess of free fatty acids in the blood, and improving the ability to oxidize glucose, will lower blood pressure while improving tissue renewal, but lowering blood pressure without improving energy production and use will create new problems or intensify existing problems...”

    Ray Peat - When energy fails: Edema, hypertension, heart failure sarcopenia, cramps, etc.

    ...

    „Most of the known biochemistry of lithium happens to overlap the actions of progesterone, e.g. , aldosterone antagonism. However, while lithium has an anti-thyroid action, progesterone supports secretion of thyroxine. And apparently inhibits the formation of reverse T3 that chemical blocks the action of thyroid hormone. I have seen several women substitute progesterone for lithium, and several of these have then gone on to rely on nutrition and light.” RP

    ...


    Angiotensin is a protein hormone that causes blood vessels to become narrower. It helps to maintain blood pressure and fluid balance in the body.

    What is angiotensin?

    The liver creates and releases a protein called angiotensinogen. This is then broken up by renin, an enzyme produced in the kidney, to form angiotensin I. This form of the hormone is not known to have any particular biological function in itself but, is an important precursor for angiotensin II. As it passes in the bloodstream through the lungs and kidneys, it is further metabolised to produce angiotensin II by the action of angiotensin-converting enzyme.


    The overall effect of angiotensin II is to increase blood pressure, body water and sodium content. Angiotensin II has effects on:

    Blood vessels – it increases blood pressure by causing constriction (narrowing) of the blood vessels

    Nerves: it increases the sensation of thirst, the desire for salt, encourages the release of other hormones that are involved in fluid retention.

    Adrenal glands: it stimulates production of the hormone aldosterone, resulting in the body retaining sodium and losing potassium from the kidneys

    The kidneys: it increases sodium retention and alters the way the kidneys filter blood. This increases water reabsorption in the kidney to increase blood volume and blood pressure.

    How is angiotensin controlled?

    An increase in renin production occurs if there is a decrease in sodium levels and a decrease in blood pressure, which is sensed by the kidneys. In addition, low blood pressure can stimulate the sympathetic nervous system to increase renin production, which results in increased conversion of angiotensinogen to angiotensin I, and so the cycle continues.

    The renin–angiotensin system is also activated by other hormones, including corticosteroids, oestrogen and thyroid hormones. On the other hand, natriuretic peptides (produced in the heart and central nervous system) can impede the renin–angiotensin system in order to increase sodium loss in the urine.

    What happens if I have too much angiotensin?

    Too much angiotensin II is a common problem resulting in excess fluid being retained by the body and, ultimately, raised blood pressure. This often occurs in heart failure where angiotensin is also thought to contribute to growth in the size of the heart. To combat these adverse effects, drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are used in the clinic, although these do have side effects and can lead to excessive retention of potassium (hyperkalaemia).

    What happens if I have too little angiotensin?

    Control of plasma sodium and potassium concentrations, and the regulation of blood volume and pressure, are all hormonal mechanisms that are impaired by low angiotensin levels. Absence of angiotensin can be associated with retention of potassium, loss of sodium, decreased fluid retention (increased urine output) and low blood pressure.

    Angiotensin | You and Your Hormones from the Society for Endocrinology

    ...

    Follicular hyperkeratosis also known as keratosis pilaris (KP), is a skin condition characterized by excessive development of keratin in hair follicles, resulting in rough, cone-shaped, elevated papules. The openings are often closed with a white plug of encrusted sebum. When called phrynoderma the condition is associated with nutritional deficiency or malnourishment….

    It can be treated with urea-containing creams, which dissolve the intercellular matrix of the cells of the stratum corneum, promoting desquamation of scaly skin, eventually resulting in softening of hyperkeratotic areas.

    Urea is an emollient (a skin softening agent). Urea enhances penetration kinetics of vitamin A into the various layers of human skin. Urea may also help to soften thick scalp plaques. Urea is also a source of nitrogen for hair growth.

    ...

    Inhibit the enzyme carbonic anhydrase

    Carbonic anhydrase is an enzyme which converts CO2 to bicarbonate. Inhibiting this enzyme will increase the amount of CO2 in the blood. Carbonic anhydrase inhibitors are anti-glaucoma, diuretic, anti-epileptic, and are also used to treat mountain sickness, intracranial hypertension, duodenal ulcers, neurological disorders, and even osteoporosis. (R)


    Safe natural carbonic anhydrase inhibitors include thiamine (24), biotin, coffee, nicotine, pomegranate (1 oz of juice) (25), courmarin (found in cinnamon and citrus), capsaicin (chillies), ferulic acid (bamboo shoots and coffee), gallic acid (garlic), syringic acid (red wine and vinegar), salicylic acid (aspirin) (26), apigenin (dried parsley, guava), eriocitrin (lemons) (27) and testosterone (28).


    Histamine (29), serotonin (30), and estrogen (31) are carbonic anhydrase activators, therefore their antagonism will increase CO2 production.

    8 best ways to increase CO2 and gain its benefits » MenElite

    ...


    HD: It’s interesting you say that; I read the article just a couple of days ago actually it was from the Drudge Report. It was that the increasing hairiness of females is actually becoming recognized. And I think there was a poll done in 2004 and I think 95% of females shaved. They did a recent poll here and I think it was down to 78% and they were saying that essentially that ‘au natural’ was becoming more ‘normal’ whether or not they are talking about hair on a male’s head or hair from a baldness perspective or not, I don’t know caller, but Dr Peat what do you think?

    RP: I think the hair on the head actually has the function of preserving heat, helping to keep the brain warm. Wearing a wool hat will substitute somewhat for not having enough hair on the head. And the other hair (armpits and pubic), I think that has the function of helping to somewhat distribute pheromones. The facial hair and arm hair has probably that pheromone distributing function. But I think that the body hair that is tending to appear more often in women is a sign of stress. That it’s probably related to that pheromone system shifting to an exaggerated steroid production in the skin.


    HD: So Dr Peat just to carry on with testosterone a little bit, it’s a bit of a divergent question but - in terms of men being able to maximize their testosterone production without thinking that they have to go to a gym and get aerobic and pump huge amounts of weights to build muscle - what would you say would be a good program for a male who wanted to increase lean muscle mass in order to be exposed to more testosterone? Because it’s the muscle itself that actually promotes a testosterone surge in the body; and by its own mechanism will directly relate back to testosterone itself.

    RP: Yeah muscle contraction activates the synthesis, locally in the muscle, of testosterone, and decreases the cortisol activity; so good physical work is probably the central thing to keeping your testosterone up. It shouldn’t be episodic, intense, stressful work; that is known to lower your testosterone and increase cortisol. And at the same time keeping your metabolic rate up so that you can do more intense activity without it being stressful. Having your liver very healthy is essential for keeping your testosterone up, because otherwise the episodes of falling blood sugar activate cortisol, oestrogen and all of the other stress hormones.

    Ray Peat, Endocrinology Part 3, KMUD, 2017

    ...

    From forum:

    I wrote Dr. Peat and he was kind to reply to a few questions. Well, actually, he didn't really answer each of my questions directly, but he did offer a lot of great information. I asked him if it was ok to share his answer on the forum, and he said he didn't mind. My words are in black; Ray's is in dark blue and the references he gave are in light blue.

    Hello Dr. Peat,

    My name is Brandon. I recieved this email address in the forum when requesting a way to contact you. If you don't mind, I'd like to get your perspective on the following questions concerning the pattern of common baldness in adult males:

    1. What is the basis for the onset of common pattern baldness in adult males, starting at the temples and vertex and developing into the virtually symmetrical horseshoe shape?

    2. Is the development of this precise pattern a sign of a systemic problem?

    3. How do you make sense of the association between pattern baldness and elevated prolactin and cortisol if women also experience elevations in these hormones, but don't show this pattern of baldness?

    I listened to the KMUD episode on hair loss and inflammation you were on, where you mentioned that prolactin and cortisol are elevated in people with baldness (I'm assuming you were referring to the common pattern baldness), but I didn't hear an explanation about how this elevation is related to the actual pattern of baldness seen in males.


    RP: Women are more strongly protected than men by progesterone against the stress hormones. Prostaglandins, which are one of the products of estrogen-related mast cells, are increased by the accumulation of polyunsaturated fats with aging, and correspond roughly to the health problems, such as the “metabolic syndrome,” that are associated in men with baldness. Testosterone has some of the protective effects of progesterone, except that with the gradual accumulation of the PUFA, it tends to be turned into estrogen, activating cortisol, prostaglandins, mast cells, and prolactin.


    J Am Anim Hosp Assoc. 2015 Mar-Apr;51(2):136-42.

    Canine alopecia secondary to human topical hormone replacement therapy in six

    dogs.

    Berger DJ(1), Lewis TP, Schick AE, Miller RI, Loeffler DG.

    (1)From the Iowa State University College of Veterinary Medicine, Ames, IA

    (D.B.); Dermatology for Animals (T.L., A.S., R.M.); and DVM Pathology Associates

    (D.L.).


    Dermatologica Sinica Volume 34, Issue 1, March 2016, Pages 10–13

    Assessment of semen quality in patients with androgenetic alopecia in an infertility clinic

    Emre Sinan Güngör, Şule Güngör, , , Ali Galip Zebitay. . . .

    Redirecting


    Urolithiasis. 2016 Oct;44(5):409-13.

    Relation of urinary stone disease with androgenetic alopecia and serum

    testosterone levels.

    Polat EC(1), Ozcan L(2), Otunctemur A(3), Ozbek E(3).

    (1)Department of Urology, Okmeydani Training and Research Hospital, Sisli, 34384,

    Istanbul, Turkey. dremrecan@hotmail.com. (2)Department of Urology, Derince

    Training and Research Hospital, Kocaeli, İzmit, Turkey. (3)Department of Urology,

    Okmeydani Training and Research Hospital, Sisli, 34384, Istanbul, Turkey.


    Am J Phys Anthropol. 1992 May;88(1):59-67.

    Relations between sex hormone level and characters of hair and skin in healthy

    young men.

    Knussmann R(1), Christiansen K, Kannmacher J.

    (1)Institut für Humanbiologie, University of Hamburg, Germany.


    Singapore Med J. 2010 Dec;51(12):931-6.

    The association of insulin resistance and metabolic syndrome in early

    androgenetic alopecia.

    Acibucu F(1), Kayatas M, Candan F.

    (1)Department of Endocrinology and Metabolism, Faculty of Medicine, Cumhuriyet

    University, Sivas 58140, Turkey. dr.feto@hotmail.com


    J Drugs Dermatol. 2016 Aug 1;15(8):1001-4.

    Stress and the Hair Growth Cycle: Cortisol-Induced Hair Growth Disruption.

    Thom E.


    J Cutan Pathol. 1975;2(2):58-70.

    Male pattern alopecia a histopathologic and histochemical study.

    Lattanand A, Johnson WC.


    J Cutan Pathol. 2014 Apr;41(4):364-9.

    A prostaglandin D-synthase-positive mast cell gradient characterizes scalp

    patterning.

    Larson AR(1), Zhan Q, Johnson E, Fragoso AC, Wan M, Murphy GF.


    Thank you so much for your reply. Do you have a sense of why the pattern of baldness is the way it is (horseshoe)?


    RP: I think the pattern is just an expression of the interacting gradients that shape all development. In the skin, pheromones and electrical fields are among the factors that affect sweat, oil, hair, fibroblasts, inflammatory, and pigment cells. Each type of cell responds to changing gradients in its own way.


    RP: I think a lot of experimenting is needed, for example with topical use of carbonic anhydrase inhibitors.


    I asked him if there are any over the counter products that are carbonic anhydride inhibitors.

    RP: Vitamin B1, curcumin and silymarin.


    I asked Dr Peat about references for the concept of "gradients."

    RP: The background is Charles M. Child’s work in embryological gradients, Joseph Needham’s Chemical Embryology, Tracy Sonneborn’s work, and Gershom Zajicek’s streaming organism


    Then I asked him how pattern baldness may be reversed and if there is a point where's it's too late.

    RP: As long as there are stem cells in the organism, and energy, I think the patterns of aging can be reversed. Cell respiration, and the resulting CO, are basic factors


    ...


    Drugs similar to acetazolamide, sulfonamides that inhibit carbonic anhydrase have recently been discovered to stop the growth of a wide variety of tumors. -Ray Peat, PhD


    Lactic acid and carbon dioxide oppose each other. Cancer patients have a deficiency of carbon dioxide because of the respiratory defect where lactic acid is formed from glucose despite the presence of oxygen (Warburg effect/aerobic glycolysis). Carbonic anhydrase inhibitors cause the body to retain carbon dioxide. Those living at high altitude retain more carbon dioxide (Haldane-Bohr Effect) and have less susceptibility to degenerative disease, including cancer. High altitude itself acts naturally like carbonic anhydrase inhibitor therapy.

    Carbonic Anhydrase Inhibitors as Cancer Therapy – Functional Performance Systems (FPS)
     
  4. LeeLemonoil

    LeeLemonoil Member

    Joined:
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    1,900
    Gender:
    Male
    @md_a
    Essential oils are powerful substances indeed, and both peppermint and Rosmarin oil have some publications out suggesting a role in preventing hairloss, maybe even assisting regrowth.
    Limonene, major component of citrus oils is a broadly protective, anti-stress substance that inhibits mmp2 and mmp9 as well as inhibiting elastase. Hairloss prevention very likely.
    Best data in hairloss and EO component is out about Cedrol, seems nearly as effective as minoxidil without the sides. All EOs show very good penetration ability

    Im not sure about b-Ecdysterone, there are manly highly intriguing publications about it, but it remains unsure if it can be considered more on the protective side or exerts its effects via estrogen mimicry - which isn’t all bad but definitely not recommendable wholesale.

    The newest publication about b-Ecdysterone is about its role in the angiotensin-renin signaling system





    https://www.biorxiv.org/content/10.1101/2020.04.08.032607v1

    20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor

    20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysone receptors (EcRs) and at least one membrane GPCR receptor (DopEcR) and displays numerous pharmacological effects in mammals. However, its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERβ receptor. The goal of our study was to better understand 20E mechanism of action.

    A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) was used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with Angiotensin-(1-7), the endogenous ligand of Mas. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using small interfering RNA (siRNA) or pharmacological inhibitors.

    17β-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin-(1-7) antagonists. A mechanism involving cooperation between Mas receptor and a membrane-bound palmitoylated estrogen receptor is proposed.

    The possibility to activate the Mas receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and indeed this mechanism may explain the close similarity between angiotensin-(1-7) and 20E effects. Our findings open a lot of possible therapeutic developments by stimulating the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.
     
  5. OP
    md_a

    md_a Member

    Joined:
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    243
    Interesting, thank you very much, I will read and experiment if it`s safe. :)
     
  6. mrchibbs

    mrchibbs Member

    Joined:
    Nov 22, 2017
    Messages:
    1,808
    This is fascinating. Just a few days ago Ray referred to Progesterone as the ''opposite'' of Aldosterone (May 20 interview on One Radio Network). I think the RAAS pathway is probably more aligned with the process of hair loss, and that would explain why there have been stories of complete reversal of baldness on cyproterone acetate and spironolactone (in particular the paper which showed full reversal of baldness in a 73 y.old. man taking spironolactone for several months for heart problems.) Both cyproterone acetate, spironolactone are known aldosterone antagonists, and finasteride probably is as well, seeing as they are all made from progesterone as the starting molecule. I think this reinforces the importance of exogenous progesterone and possibly topical use of progesterone on the scalp as well (as part of a larger set of physiological interventions, including thyroid)

    Thanks so much for sharing your story! I discovered Danny Roddy and then Ray around 5 years ago but didn't understand what they were talking about haha, it took me a while to learn and understand. I really do think thyroid is the #1 basic thing to fix, and until you've raised your metabolism to normal levels, it's impossible to expect any reversal of pathologies. Proper thyroid function lowers serotonin, allows muscles and tissues to fully relax (and chronic tension is a feature of MPB), and it increases production of progesterone, and improves resilience to stress via greater energy, and the different enzymes and endocrine function work better at higher temperatures.

    Moreover, as this quote by Ray implies, the mere fact of becoming hypothyroid with decreasing energy production, is enough in itself to start the fibrosis of the hair follicles. Much like cold feet and hands send inflammatory signals to the rest of the body, a ''colder'' head and less energy for hair growth probably triggers the cytokines to stimulate prostaglandins production, which actively creates a state of chronic inflammation on the scalp, which goes unresolved because of low energy, leading to fibrosis. I think this explains why some guys are able to stop hair loss by applying aspirin to the scalp, since it inhibits prostaglandins production and thus prevents inflammation (and thus fibrosis) from forming in the first place.

    Of course there are other factors at play in the cascade like parathyroid, prolactin and estrogen, but they follow from low thyroid. I think estrogen, parathyroid, prolactin and histamine all play a role in trying to ''restart'' hair growth, but with the low thyroid, it doesn't work and they stay elevated chronically instead of just for a while. This is probably why there has been random hair growth success stories with anti-histaminic substances, or with anti-prolactin meds like bromocriptine, or even with topical anti-estrogen like fulvestrant. They all target a part of the ''balding physiology'' and get probably work to break out of it, as long as the underlying stressors (i.e. low thyroid, emotions, EMF etc.) are under control. It's about a balance of stress/energy.

    Ray has talked about this, progesterone has a synergistic effect with T3. Any men balding (or women with PCOS) needs more progesterone I think, and it should help improve response to thyroid hormone.

    Again, this explains the comparative ''frailty'' of men from an evolutionary perspective. I think this comes from the fact that one ''dominant'' male can reproduce with many women, so stressed out men in the toxic culture probably have a a tendency to break down faster from a physiological standpoint because they are less valuable from a biological perspective. Women of reproductive age are also impacted by the stressors of modern life (darkness, EMF, PUFAs, estrogenic substances etc.), but the higher progesterone protects their physiology from collapsing under stress, at least for a while.
     
  7. OP
    md_a

    md_a Member

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    243

    Thank you for the comments, they are very useful, you are very skilled, I read you with great pleasure.

    I am attaching some studies found at random only to strengthen the inflammatory role of Angiotensin 2 by the Angiotensin 2 receptor AT1.


    The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease

    Abstract

    Non-alcoholic fatty liver disease (NAFLD) is currently considered an important component of metabolic syndrome (MetS). The spectrum of NAFLD includes conditions that range from simple hepatic steatosis to non-alcoholic steatohepatitis. NAFLD is correlated with liver-related death and is predicted to be the most frequent indication for liver transplantation by 2030. Insulin resistance is directly correlated to the central mechanisms of hepatic steatosis in NAFLD patients, which is strongly correlated to the imbalance of the renin–angiotensin system, that is involved in lipid and glucose metabolism. Among the emerging treatment approaches for NAFLD is the anti-hypertensive agent telmisartan, which has positive effects on liver, lipid, and glucose metabolism, especially through its action on the renin–angiotensin system, by blocking the ACE/AngII/AT1 axis and increasing ACE2/Ang(1–7)/Mas axis activation. However, treatment with this drug is only recommended for patients with an established indication for anti-hypertensive therapy. Thus, there is an increased need for large randomized controlled trials with the aim of elucidating the effects of telmisartan on liver disease, especially NAFLD. From this perspective, the present review aims to provide a brief examination of the pathogenesis of NAFLD/NASH and the role of telmisartan on preventing liver disorders and thus to improve the discussion on potential therapies.


    Conclusion

    In conclusion, blocking RAS to inhibit the ACE/Ang II/AT1R axis and increase ACE2/Ang-(1–7)/Mas axis activation is an important strategy in treating NAFLD. Of all the RAS blockers, telmisartan is the most promising drug, not only because of its favorable pharmacokinetic proprieties and safety, but also because it seems to exert additional AT1-independent benefits on metabolism via partial PPAR-γ agonism and/or a positive central action on the HPA axis. However, large multicenter randomized-controlled trials are needed to consolidate these findings. Currently, treatment with telmisartan and with other RAS blockers can only be formally recommended in NALFD patients with an established indication of anti-hypertensive therapy.

    The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review | Hypertension Research





    Cancer, inflammation and the AT1 and AT2 receptors

    The evidence relating to over-expression of AT1 with cancer progression is compelling. To this effect, AT1 blockade has been hypothesised as the mechanism to overcome cancer associated complications in organ graft recipients [45]. Additionally, a study undertaken in 1998 suggested that hypertensive patients taking ACE inhibitors were significantly less at risk of developing cancer than those taking other hypertensive treatments [46].


    Tumour progression has been significantly slowed with AT1 receptor antagonists [47, 48]. The results appeared to far exceed the expectations of simple inhibition of angiogenesis. Reduction of MCP-1 was noted [48], as was the expression of many pro-inflammatory cytokines. The activity of tumour-associated macrophages was also noticed to be severely impaired [48]. The importance in reducing the action of tumour-associated macrophages in extracellular matrix decomposition is not to be underestimated, since, in this action, they further progress remodelling by releasing stored TGF-β [49]. The similarity of action of tumour associated macrophages with those in the tissue healing and repair environment has been noted [49]. The tumour suppressant action of tranilast, an AT1 antagonist, [50] has been more widely explored [51–54]. In one study on the inhibition of uterine leiomyoma cells, Tranilast also induced p21 and p53 [55]. Similarly, the AT1 blocker losartan has been shown to antagonise platelets, which are thought to modulate cell plasticity and angiogenesis via the vascular endothelial growth factor (VEGF) [56]. It has been postulated that losartan and other AT1 blockers can act as novel anti-angiogenic, anti-invasive and anti-growth agents against neoplastic tissue [56]. Furthermore, it has been shown that angiotensin II induces the phosphorylations of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in prostate cancer cells. In contrast, AT1 inhibitors have been shown to inhibit the proliferation of prostate cancer cells stimulated with EGF or angiotensin II, through the suppression of MAPK or STAT3 phosphorylation [57]. Angiotensin II also induces (VEGF), which plays a pivotal role in tumour angiogenesis and has been the target of various therapeutics, including antibodies and aptamers [58]. Although the role of angiotensin II in VEGF-mediated tumour development has not yet been elucidated, an ACE inhibitor significantly attenuated VEGF-mediated tumour development, accompanying the suppression of neovascularisation in the tumour and VEGF-induced endothelial cell migration [59]. Perindopril, another ACE inhibitor has also been shown to be a potent inhibitor of tumour development and angiogenesis through suppression of the VEGF and the endothelial cell tubule formation [60].


    Conclusions

    The invasiveness and immunosuppression of many cancers appears dependent on inflammation and the upregulation of AT1. Two mechanisms for upregulation of AT1 are discussed: 1) evolutionary changes to take advantage of this pro-inflammatory control mechanism, 2) AT1 expression induced by an alternating environment of hypoxia and oxidative stress. Immunosuppression as a common protection mechanism of solid tumours against immune responses has been verified from current literature and experimental procedures, as has the implication of cytokines and chemokines in tumour growth and metastasis. Given the involvement of AT1 in the immunosuppression and inflammatory processes, as well as in the expression of the pro-inflammatory cytokines and chemokines, it becomes evident that the AT1 receptor is essential for tumour protection and progression. A combination therapy consisting of AT1 receptor antagonists, NSAID for further control of the inflammation and immune therapy in the form of tumour vaccines should provide a novel and successful treatment for solid tumours.


    In the renin-angiotensin system, the angiotensin II receptors AT1 and AT2 seem to have opposing functions. The actions of AT1 being principally pro-inflammatory whilst AT2 provides protection against hypoxia, draws inflammatory action to a close and promotes healing. The various direct and indirect mechanisms for feedback between the receptors, their induced products and the external hormonal system in the control of inflammation and healing are summarised in a highly simplified model which none the less can be used to explain how many key promoters and inhibitors of disease exert their effects.


    From a review of the current disease literature, it has been demonstrated that the role of AT1 and AT2 in inflammation is not limited to cancer-associated inflammation, but is generally consistent and system wide. Potential therapy by manipulation of these receptors, although at an early stage, has been demonstrated for some of these diseases and it is proposed that this approach will provide an effective basis for the treatment of autoimmune, inflammatory and neurodegenerative disorders using existing drugs. AT1 receptor blockade should, in addition, provide a treatment to alleviate the damage caused by bacterial and viral infections, where their destructive action is through chronic inflammation. Given the importance of the immune suppressant effect of inflammation in cancer, it is anticipated that AT1 blockade should also serve to elicit a more effective immune response to other invaders that seek to corrupt the wound recovery process.


    Manipulation of the AT1 and AT2 receptors has profound and exciting implications in the control of disease.

    Cancer, inflammation and the AT1 and AT2 receptors | Journal of Inflammation | Full Text



    Related to stress

    For anxiety, angiotensin II may have a role through the HPA axis and sympatho-adrenal axis. Another contemporary review argues that excessive brain AT1R activity is associated not only with hypertension and heart failure but also with brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation {1}. AT1R blockers decrease brain inflammation and have numerous other effects, pointing to the potential for such treatments in reducing brain inflammatory processes. One such example is mood disorders associated with pro-inflammatory cytokines. This is a novel approach to addressing stress-induced and inflammatory brain diseases that eventually may produce new treatments.

    Faculty Opinions Recommended Article: The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress.



    Angiotensin II (AngII) plays important roles in the regulation of cardiovascular function. Both peripheral and central actions of AngII are involved in this regulation, but mechanisms of the latter actions as a neurotransmitter/neuromodulator within the brain are still unclear. Here we show that (1) intracerebroventricularly (i.c.v.) administered AngII in urethane-anesthetized male rats elevates plasma adrenaline derived from the adrenal medulla but not noradrenaline with valsartan- (AT1 receptor blocker) sensitive brain mechanisms, (2) peripheral AT1 receptors are not involved in the AngII-induced elevation of plasma adrenaline, although AngII induces both noradrenaline and adrenaline secretion from bovine adrenal medulla cells and (3) i.c.v. administered AngII elevates blood pressure but not heart rate with the valsartan-sensitive mechanisms. From these results, i.c.v. administered AngII acts on brain AT1 receptors, thereby inducing the secretion of adrenaline and pressor responses. We propose that the central angiotensinergic system can activate central adrenomedullary outflow and modulate blood pressure.

    Angiotensin II acting on brain AT1 receptors induces adrenaline secretion and pressor responses in the rat



    May have beneficial effects in polycystic ovary syndrome


    According to our knowledge, these are the first case reports demonstrating that the angiotensin II receptor antagonist telmisartan, besides being an effective antihypertensive drug, may have beneficial effects in polycystic ovary syndrome patients. The case reports provide interesting new information about unexpected effect and possible new indication of telmisartan in patients with polycystic ovary syndrome.


    Since insulin resistance plays a major role in the pathogenesis of polycystic ovary syndrome, several trials have confirmed that insulin-sensitizing drugs, metformin (7-9), and thiazolidinediones (11-13,23,24) have favorable endocrine, reproductive, and metabolic effects in polycystic ovary syndrome. Considering that telmisartan may have insulin-sensitizing effects related to its ability to activate PPAR gamma (14-18), we hypothesized that the administration of telmisartan would also improve menstrual dysfunction, hyperandrogenemia, and hyperinsulinemia of patients with polycystic ovary syndrome.


    As we assumed, after 6 months of treatment with telmisartan, we observed significant reduction in free testosterone (around 35% on average), DHEAS (around 40% on average), and androstenedione concentration (around 20% on average) in all 4 patients. Three out of four women improved their menstrual cyclicity. One additional menstruation in one woman and two additional menstruations in the other two women were attained in 6 months of telmisartan treatment. The intensity of telmisartan effects appeared to be in the usual range for insulin-sensitizing drugs, metformin, or thiazolidinediones in patients with polycystic ovary syndrome.

    Decreased Androgen Levels and Improved Menstrual Pattern after Angiotensin II Receptor Antagonist Telmisartan Treatment in Four Hypertensive Patients with Polycystic Ovary Syndrome: Case Series



    Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells.

    Abstract

    Smooth muscle cells were cultured from rat thoracic aorta and labeled to a stable specific activity with 45Ca2+, myo-[2-3H]inositol, or 32Pi. The efflux of 45Ca2+ was monitored over 10-sec intervals. Angiotensin II (AII) increased the amount of 45Ca2+ lost by 5-fold in the first 10-sec interval after the addition of AII and by 10-fold in the second 10-sec interval. AII-stimulated 45Ca2+ release was blocked by the angiotensin antagonist [1-sarcosine, 8-leucine]AII and by La3+. The removal of external Ca2+ had no effect on AII-stimulated 45Ca2+ release. Depolarization with high external K+ only slightly increased 45Ca2+ efflux and had no effect on AII-induced 45Ca2+ release. AII had no effect on the initial rate of 45Ca2+ influx. These results indicate that the rapid 45Ca2+ efflux evoked by AII is probably due to the release of 45Ca2+ sequestered intracellularly rather than to an increase in the Ca2+ permeability of the plasma membrane. AII provoked rapid increases in the levels of phosphatidic acid and phosphoinositides in the cells. These increases in phospholipids were associated with increases in phospholipase C-generated inositol phosphates (tri-, di-, and mono-). It appears that AII simultaneously increases phosphoinositide hydrolysis and synthesis in vascular smooth muscle, and both phospholipid effects may contribute to inositol triphosphate generation, which was sufficiently rapid to have a role in intracellular Ca2+ mobilization.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC392242/



    The Renin-Angiotensin-Aldosterone System and Calcium-Regulatory Hormones

    ..These results suggest that in the acute setting, angiotensin II may exert a stimulatory effect on PTH that can be mitigated by lowering angiotensin II with an angiotensin converting enzyme inhibitor; however, acute increases in aldosterone do not appreciably alter PTH. In contrast, in the chronic setting aldosterone may increase PTH, and this effect may be mitigated by a mineralocorticoid antagonist--observations that were similar to those reported in the aforementioned cohorts of subjects with primary aldosteronism. Thus, this study by Brown and colleagues provides evidence implicating multiple RAAS components interacting with PTH, and a differential temporal effect dictating their relationships(67). In assessments of parathyroid pathology, both normal and adenomatous parathyroid tissue have been shown to express the angiotensin type1 receptor and the mineralocorticoid receptor, and the expression of these receptors was 3-4 fold greater among adenomatous tissue, giving further support to direct actions of angiotensin II and/or aldosterone on the parathyroid(67)….

    CONCLUSIONS

    In summary, growing evidence suggests interactions between calcium-regulatory hormones and the renin-angiotensin-aldosterone system with potentially important clinical implications. Calcium and vitamin D have been shown to inhibit renin secretion and expression, whereas a bi-directional and stimulatory relationship between parathyroid hormone and aldosterone (and possibly angiotensin II) has been observed. With this mounting evidence, new questions are raised that may have notable implications for future clinical outcomes research.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769794/



    High Calcium Diet Down-Regulates Kidney Angiotensin-Converting Enzyme in Experimental Renal Failure

    Abstract

    Background: Calcium salts are used as phosphate binders in renal failure, while high calcium diet also improves vasorelaxation and enhances natriuresis. The influences of calcium intake on renal renin-angiotensin system (RAS) are largely unknown.


    Methods: Four weeks after NTX, rats were put on 3.0% or 0.3% calcium diet for 8 weeks (12-week study). In additional experiments, 15 weeks after NTX, rats were put on similar diets for 12 weeks (27-week study). Appropriate blood, urine, and kidney samples were taken. Renal angiotensin-converting enzyme (ACE) and angiotensin II receptors (AT1, AT2) were examined using autoradiography, ACE also using Western blotting, and connective tissue growth factor (CTGF) using immunohistochemistry.


    Results: In the 12-week study, albuminuria increased 5-fold in NTX rats, but only 2-fold in calcium NTX rats on 3.0% calcium. In the 27-week study, high calcium intake decreased blood pressure, retarded progression of renal failure, reduced glomerulosclerosis, interstitial damage, and aortic calcifications, and improved survival from 50% to 92% in NTX rats. In both experiments plasma parathyroid hormone and phosphate were elevated after NTX, and suppressed by high calcium diet, while kidney ACE was down-regulated by 40% or more after increased calcium intake. In the 27-week study renal CTGF was decreased and cortical AT1 receptor density reduced after high calcium diet.


    Conclusion: High calcium diet down-regulated kidney ACE, reduced albuminuria and blood pressure, and favorably influenced kidney morphology in experimental renal failure. These findings suggest a link between calcium metabolism and kidney ACE expression, which may play a role in the progression of renal damage.

    https://pubmed.ncbi.nlm.nih.gov/15569305/

     
  8. mrchibbs

    mrchibbs Member

    Joined:
    Nov 22, 2017
    Messages:
    1,808
    @md_a

    Thank you for your kind words, and for the studies, I will dive into them tonight to see if I can learn a bit more about the angiotensin receptor.
     
  9. OP
    md_a

    md_a Member

    Joined:
    Aug 31, 2015
    Messages:
    243
    Thanks!
    Angiotensin II Blockade Upregulates the Expression of Klotho, the Anti-Ageing Gene, in an Experimental Model of Chronic Cyclosporine Nephropathy

    Abstract

    Background: The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin-angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury.

    Methods: Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription-polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG).

    Results: CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion.

    Conclusions: Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.
    Angiotensin II Blockade Upregulates the Expression of Klotho, the Anti-Ageing Gene, in an Experimental Model of Chronic Cyclosporine Nephropathy - PubMed

    ...

    Ray Peat klotho protein (anti-aging) similar to Vitamin D.
     
  10. LeeLemonoil

    LeeLemonoil Member

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    @md_a

    Karel Slama, a known insect-researcher thinks that ecdysteroids are actually a semi-hydrophilic form of vitamin D or a D-Vitaminoid.
     
  11. OP
    md_a

    md_a Member

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    Thanks, I didn't know that, very interesting.

    Are Ecdysteroids insect hormones?
    The polyhydroxylated derivatives of 7-dehydro, 6-ketocholesterol (Ecdysone, Ecdysteroids, Ecd) were accidentally discovered in the search for an insect moulting hormone in 1965. The first Ecd compound, named ecdysone (“ecdysis” = shedding off the cuticle), was isolated from silkworm pupae. It was defined as the insect moulting hormone secreted by the prothoracic glands (PG), in accordance with the currently recognised “brain-PG” hormonal theory.
    ...
    In vertebrate animals, Ecd generally exhibit effects that are similar to the vitamin D3 (calciferol), eventually combined with anabolic growth effects similar to the androgenic steroid hormones. These conclusions can be documented by the pronounced anabolic effects of Ecd in domestic animals (rabbit, swine, cattle, sheep, Japanese quails). In addition, there exists a plethora of beneficial pharmacological effects in the human body (increased growth of bone and muscles, improved physical and mental state, improved muscle strength in athletes, metabolic stimulation, tonic effects, neurogenic, psychogenic, immunogenic, antiallergenic, anti- stressoric, anti-cancerogenic and many other more or less sufficiently supported data). A retrospective look at the history of vitamin D shows that the pioneers working on the elucidation of the rickets bone disease observed long ago (during 1930-ies) that the active compound was somehow related to 7-dehydrocholesterol, which could be converted from other sterols by UV-irradiation. They looked for the antirachitic vitamin D among the purely lipophilic fish oils and animal fat.

    I am convinced that Ecd represent a previously overlooked, special group of the amphoteric, both partly lipid and partly water soluble class of the esential vitamin D. Ecd possess the 7-dehydrocholesterol unsaturation, which is stabilised by the conjugated 6-keto group. In contrast to the so far known precursors of calciferol (vitamin D3), which require activation by ultraviolet radiation and metabolic incorporation of 3 additional hydroxylic groups in the liver, the Ecd type of vitamin D6 (6 comes from the latin “Hexapoda” = insects) contains not only 3, but 6 or 7 prefabricated hydroxylic groups.

    There are sufficient data which show that Ecd (Vitamin D6) can stimulate regeneration and tissue growth or enhance metabolic rates in insects, mammals and also in humans. Unfortunately, due to the limited supply of pure Ecd compounds, there are still limited pharmacological data on avitaminosis due to the lack of the vitamin D6. It is difficult to cure avitaminosis if you do not know or do not have the responsible vitamin. I have a feeling, however, that the defficiency of vitamin D6 (Ecd) could be behind the hitherto incurable diseases, especially those related to impaired regeneration, aberrant cell growth or disturbed neuromuscular functions. Investigations along these lines have been persistently hindered by an errant belief in the moulting hormones of insects.
    Are Ecdysteroids insect hormones? – Atlas of Science

    ...

    The Neglected Vitamin D1 (Polyhydroxylated 6-Keto,7-Dehydrocholesterol, Ecdysteroid): Effects on Growth and Regeneration in Animal Tissue and Cells

    Karel Sláma
    * Laboratory of Insect Physiology, Evropska, Praha, Czech Republic Citation: Karel Sláma. “The Neglected Vitamin D1 (Polyhydroxylated 6-Keto,7-Dehydrocholesterol, Ecdysteroid): Effects on Growth and Regeneration in Animal Tissue and Cells”. EC Pharmacology and Toxicology 7.7 (2019): 678-690. *Corresponding Author: Karel Sláma, Laboratory of Insect Physiology, Evropska 674, Praha 6, Czech Republic.

    Abstract Unlike the biologically inactive vitamins D2 and D3, which need activation by UV-light and additional hydroxylation in liver, the polyhydroxylated derivatiives of 6-keto, 7-dehydrocholesterol (ecdysone, ecdysteroids; discovered accidentally in the search for an insect moulting hormone), support the mitotic divisions and somatic growth in all organisms. It has been found that these sterolic compounds are not insect hormones and do nor stimulate insect ecdysis. Due to their strong anabolic, growth stimulating effects in domestic animals and humans, the new biological status of these pharmacologically important natural compounds has been identified as the previously overlooked vitamin D1. The vitamin (20-hydroxyecdysone) supports cell proliferation and regeneration in animal tissues without a necessity of UV-irradiation or hydroxylation in the liver. Moreover, vitamin D1 shows strong anabolic, growth promoting activity not only in insects, but also in vertebrate animals and humans. The vitamin is biosynthesized and widely distributed in microorganisms, fungi, lower or higher plants and intestinal symbiotic flora. It enters human body with food and, unlike the vitamins D2 and D3, it represents a special group of vitamins that are partly soluble both in water as well as in the hydrophobic llipid solvents. Studies performed on various domestic animals and humans revealed a plethora of beneficial pharmacological effects. In insects, and probably in all animals and humans, the dietary supply of vitamin D1 is essential for the construction of bipolar, water/lipid permeable cytoplasmic and intracellular membranes. Deficiency of vitamin D1 in insect haemolymph or human blood prevented the obligatory arrest of mitotic divisions at the end of the regeneration process. The resulting, polynuclear syncytia of aberrant cells are characteristic for the malignant tumours. Possible application of vitamin D1 deficiency theory of malignant growth in oncologiccal therapy is discussed.

    https://www.ecronicon.com/ecpt/pdf/ECPT-07-00328.pdf
     
  12. GorillaHead

    GorillaHead Member

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    I believe in this.
    So perhaps Added progesterone could help get thyroid up and running.

    but are there any natural alternatives to Telmisartan ?
     
  13. GorillaHead

    GorillaHead Member

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    Actually this makes it seem like progesterone may be a bad idea?
     

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  14. Tristan Loscha

    Tristan Loscha Member

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    Effect of aldosterone and mineralocorticoid receptor blockade on vascular inflammation
    Hylton V Joffe, Gail K Adler
    Heart failure reviews 10 (1), 31-37, 2005
    Aldosterone, the final product of the renin-angiotensin-aldosterone system, is classically viewed as a regulator of renal sodium and potassium handling, blood volume, and blood pressure. Recent studies suggest that aldosterone can cause microvascular damage, vascular inflammation, oxidative stress and endothelial dysfunction. In animal models, aldosterone-mediated vascular injury in the brain, heart, and kidneys leads to stroke, myocardial injury, and proteinuria. These effects may be modified by dietary salt intake; aldosterone-mediated vascular damage is increased in susceptible animals fed a high-salt diet compared to a low-salt diet despite lower plasma aldosterone levels on the high-salt diet. In humans, there is a growing literature supporting the adverse effects of aldosterone in heart failure, hypertension, left ventricular hypertrophy, and renal disease. Aldosterone receptor antagonists are beneficial even in patients on angiotensin converting enzyme inhibitors and attenuate aldosterone-mediated vascular injury by mechanisms that appear to be independent of changes in systolic blood pressure. This review focuses on the adverse effects of aldosterone on the vascular system and describes our current understanding of the underlying mechanisms for this injury.





    "These effects may be modified by dietary salt intake; aldosterone-mediated vascular damage is increased in susceptible animals fed a high-salt diet compared to a low-salt diet despite lower plasma aldosterone levels on the high-salt diet."

    High-Salt Augments Aldosterone Toxicity Despite Lowered Plasma-Readings.
     
  15. Estradiol

    Estradiol Member

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    I have seen these too. Unlike Dr. Peat there are studies showing that progesterone actually increases aldosterone.
     
  16. wavelength123

    wavelength123 Member

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    11bHSD2 inhibition has shown to cause heart complications and they oftentimes go with hair loss. Nothing surprising here, excess cortisol is the enemy.

    good list of 11bHSD1 inhibitors.

    Anabolic Androgenic Steroid Fluoxymesterone Inhibits 11β-Hydroxysteroid Dehydrogenase 2–Dependent Glucocorticoid Inactivation

    Paper above is about the effect of steroids on the 11bHSD2 enzyme.... Dhea, proviron and primobolan are fine (table 1). Testosterone (probably by way of DHT), anadrol... not so much. Halotestin is terrible.
     
  17. mrchibbs

    mrchibbs Member

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    Yeah it is puzzling. Increased aldosterone levels in vivo, decreased aldosterone secretion in vitro...need to look into this.
     
  18. GorillaHead

    GorillaHead Member

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    Super puzzling but if aldosterone increases does it matter if progesterone is blocking the receptor?



    also according to this university, they state that the majority of Mr receptors are activated by aldosterone not Glucocorticoids.

    Mineralocorticoids


    Also they state that there are two reasons for aldosterone to increase here.

    Anyone care to help me understand what low vascular volume is?


    To me i am more focused on the receptor. Perhaps the reason for baldness is whatever in our diet increases the expression of MR in our scalp
     

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  19. GorillaHead

    GorillaHead Member

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  20. OP
    md_a

    md_a Member

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    Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo
    Abstract


    Whilst topical steroids represent one of the most frequently administered treatments for skin and hair diseases, predominantly based on their glucocorticoid receptor-mediated anti-inflammatory effects, the mineralocorticoid effects of topical steroids have received surprisingly little attention. However, the role of mineralocorticoid receptor (MR) signaling is now known to extend beyond the kidney, with human skin, including the hair follicle (HF), expressing the MR. Using microdissected female HFs treated ex vivo with MR agonists and antagonists, we sought to determine the effects of MR-mediated signaling in the cutaneous context. Indeed, not only did the skin and HF epithelium express the MR at both the gene and protein level, but its expression was hair cycle dependent. Moreover, the selective MR antagonist eplerenone promoted hair shaft elongation and hair matrix keratinocyte proliferation whilst delaying catagen (HF regression). These novel observations suggest that the female human HF is sensitive to the inhibition of MR signaling and provide the first evidence that sustained MR signaling may even be required to maintain the growth phase (anagen) of human scalp HFs. Indeed, these data encourage the systematic evaluation of MR agonists and antagonists in human hair growth control so as to identify much-needed, novel anti-hirsutism and/or hair growth-promoting agents, respectively.

    Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo - PubMed

    ...
    Eplerenone, sold under the brand name Inspra, is a steroidal antimineralocorticoid of the spirolactone group that is used as an adjunct in the management of chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. Classed as a selective aldosterone receptor antagonist (SARA),[5] it is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, glucocorticoid, or estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarction. Eplerenone is a potassium-sparing diuretic, meaning that it helps the body get rid of water but still keep potassium.

    It was patented in 1983 and approved for medical use in the United States in 2002.[6][7] Eplerenone is currently approved for sale in Canada, the US, EU, Netherlands and Japan.[7] Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[8]

    Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia.[8] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[3] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[3]

    Eplerenone - Wikipedia

    ...

    Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)

    ABSTRACT
    Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensinconverting enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels — a phenomenon termed “aldosterone synthesis escape.” Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone — the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) — is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

    CONCLUSION
    Eplerenone will be the first drug in a new class of SARAs. The ability to effectively block the MR while avoiding limiting side effects promises to be an important advancement in the chronic treatment of life-threatening cardiovascular disorders. Ongoing phase III trials in hypertension and heart failure will soon reveal if the promising preclinical and phase II clinical data can be extended to large patient populations and are likely to uncover additional benefits of this unique agent.

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