Dr. Peat Right Again: Losartan And Covid-19 Evidence For Efficacy

yoshiesque

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U
Peat can be wrong, there are any clinical proof on this, Others say that this can increase virus activity.
You need to make sure ur source has evidence behind it. Losartan can also increase ACE2, the very thing covid binds to. So that's likely their assumption. But it doesn't hold, because young ppl have high ACE2.
 

schultz

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Peat can be wrong, there are any clinical proof on this, Others say that this can increase virus activity.

U

You need to make sure ur source has evidence behind it. Losartan can also increase ACE2, the very thing covid binds to. So that's likely their assumption. But it doesn't hold, because young ppl have high ACE2.

Yes, I think people are getting confused because they hear that the virus binds to ACE2 and so think that more ACE2 means worse outcome because it means more virus. The virus itself is a bit irrelevant here, it has more to do with the idea that there is less ACE2 available because the virus has deactivated it by attaching to it. ACE2 counters ACE by reducing the effects of angiotensin. When you don't have as much ACE2, then ACE is free to cause problems as it able to increase angiotensin without interference from ACE2.

That's the gist of it, albeit incredibly over-simplified.

People are too focused on the virus itself and are not thinking about the systems in the body. Don't worry about "killing" the virus, worry about improving the state of the organism so that it can deal with cascade of inflammatory events initiated by the virus. Anything that kills the virus but harms the organism is not an optimal treatment. Sort of like chemotherapy. We kill cancer by irradiating a person.... When the body is healthy it can deal with this stuff on its own no problem. War mentality.

The study below shows what happens to lungs when ACE2 is downregulated.

Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury

"Influenza A (H7N9) virus-induced ALI [acute lung injury] results in the significant downregulation of ACE2, which regulates the RAS."

"The data presented here also demonstrated that ACE2 deficiency aggravated influenza A (H7N9) virus-induced ALI in mice."
 
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U

You need to make sure ur source has evidence behind it. Losartan can also increase ACE2, the very thing covid binds to. So that's likely their assumption. But it doesn't hold, because young ppl have high ACE2.
md_a 's writing explains it well. The virus binds to ACE2 effectively DECREASING its function, like an antagonist. So increasing ACE2 would be a good thing.
 

Beastmode

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Peat can be wrong, there are any clinical proof on this, Others say that this can increase virus activity.

He could be wrong, but many here would take his research and take on it compared to the supposed "experts" out there. The ones that are potentially increasing virus activities are ACE inhibitors. Share the links that the "others" are saying. Best to hear this from all perspectives.
 

GenericName86

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Are there any alternatives to Losartan? I know peat mentioned prog but any other supplements that have similar effects?
 

md_a

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Novel components of the renin–angiotensin system and its...
Interactions-between-renin-angiotensin-system-kinin-kallikrein-system-and-insulin.jpg
Novel-components-of-the-renin-angiotensin-system-and-its-interactions-Abbreviations.jpg
 
OP
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My theory is ACE inhibitors lower ACE2.

Can someone smarter than me help interpret this animal study on the subject:
Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. - PubMed - NCBI

BACKGROUND:
Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene.

METHODS AND RESULTS:
Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT1), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA.

CONCLUSIONS:
Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT1 antagonists may in part be due to increased Ang II metabolism by ACE2.
 
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I think the key is here:

ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity.

--

So ARBs can increase ACE2. ACE inhibitors increase ACE2 mRNA, which may cause a down regulation of ACE2 in some way.
 
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Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2,

in a gut study of ACE and ACE inhibitors. So again, what does it mean when mRNA levels are increased?
 

Beastmode

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Are there any alternatives to Losartan? I know peat mentioned prog but any other supplements that have similar effects?

I haven't heard of alternatives, but cyproheptadine and aspirin are "global" approaches to consider according to him. Keeping PTH very low (via high calcium intake) and vitamin D up are other general approaches that will help avoid "sickness!"
 

md_a

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Angiotensin-converting enzyme 2 protects from severe acute lung failure.
Imai Y1, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM.
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Abstract
Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.

Angiotensin-converting enzyme 2 protects from severe acute lung failure. - PubMed - NCBI
 

md_a

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[Lessons from SARS: a new potential therapy for acute respiratory distress syndrome (ARDS) with angiotensin converting enzyme 2 (ACE2)].
[Article in Japanese]
Imai Y1, Kuba K, Penninger JM.
Author information

Abstract
During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS). Interestingly, a novel homologue of angiotensin converting-enzyme (ACE), termed angiotensin converting enzyme 2 (ACE2) has been identified as a receptor for SARS-CoV. ACE and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II that is a key effector peptide of the system and exerts multiple biological functions, whereas ACE2 reduces angiotensin II levels and thus is a negative regulator of the system. Importantly, our recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway, suggesting the activation of pulmonary RAS influences the pathogenesis of ARDS and SARS.

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. - PubMed - NCBI
 

md_a

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Angiotensin II receptor 1 blocker (losartan) restores the ability of the lung to clear edema in rats
Reem Ismael-Badarneh, Julia Guetta, Niroz Abu-Saleh, Geula Klorin, Gidon Berger, Zaid Abassi, Zaher Azzam
European Respiratory Journal 2013 42: P3921; DOI:
Abstract
Alveolar fluid clearance (AFC) is important in keeping the airspaces free of edema, mainly due to alveolar epithelial Na,K-ATPase pump and Na channels (ENaC). Angiotensin II (AngII) stimulates a variety of physiologic responses that supports arterial blood pressure and renal function. We previously showed that AngII impairs AFC (AFC in control rats was 0.44±0.04 ml/h (Mean ± SEM) and decreased by 40% in AngII treated rats (P = 0.003)). AngII effects are mediated by two specific receptors; AT1 and AT2. The localization of these two receptors in the lung was recently discovered, specifically in alveolar epithelial cells type II (ATII), but no studies investigated whether they play a role in AFC. In order to understand AngII mechanism, we investigated the effect of AT1 specific blocker (Losartan) using the isolated perfused lung model. Losartan administration, followed by AngII restored the inhibitory effect of AngII, indicating an AT1 mediated effect of AngII on AFC.

Furthermore, Oubain (Na,K-ATPase ihhibitor) and Amiloride (ENaC ihibitor) reduced AFC to 5.9±0.4 ml/hr and 5.8±0.11 ml/hr respectively. The administration of either Oubain or Amiloride with AngII tended to have more inhibitory effect on AFC (4.41±0.2 ml/hr or 5.29±0.08ml/hr respectively), suggesting that AngII signaling may target more than one protein. In ATII cells treated with AngII the expression of AT1 levels was upregulated. Notably, there was no significant change in αNa,K-ATPase and αENaC abundance after AngII treatment.

We herein provide a new mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema.
Angiotensin II receptor 1 blocker (losartan) restores the ability of the lung to clear edema in rats
 
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I'm looking for harm from ACE inhibitors. My thesis is that they are causing a lot of deaths. ARBs would be helpful, ACEi are harmful.

That's a question for ya.
 

Lollipop2

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I do not know if it is correct, but I try to understand, apparently the acute accelerating lung fibrosis induced by COVID-19 infection can be justified through ACE – ACE2 - AT1 overactivation caused by the virus. Losartan is an AT1 antagonist with a selective, competitive function which decreases the end

organ responses to Angiotensin II. It is a common anti-hypertensive agent which is currently prescribed for high blood pressure patients, particularly those who are prone to diabetic nephropathies. Losartan may lead to protection of lung fibrosis through other molecular mechanisms such as downregulation of TGF-β1.

After entrance to the body, COVID-19 fuse their envelopes with membranes of the host cells, then transport their genetic material into the affected cells. This essential fusion is mediated by glycosylated spike proteins on the surface of the virion interacting with proper surface receptors on the membrane of host cells. Angiotensin-converting enzyme 2 (ACE2) receptor is a known surface human cell proteins on which COVID-19 spike proteins are specifically bound.

The activation of RAS is triggered by secreting of renin from kidney, through juxtaglomerular cells. Renin is a protease that cleaves angiotensinogen, the precursor of angiotensin, which is made by liver. It produces an inactive peptide: Angiotensin I (AngI).

Then, ACE mediate the conversion of AngI to AngII, a major RAS effector. ACE is a protein with high expression on membranes of vascular endothelial cells, predominantly in lung tissue. The most of the RAS associated physiologic effects are run by interacting of AngII with a G-protein coupled AngII type 1 (AT1) receptor. This activates a physiologic pathway in different tracts, such as kidney, liver, central nervous system, respiratory, and cardiovascular system. Some crucial events are regulated via active AT1 receptors including arterial pressure, fluid and sodium balance, fibrosis, and cellular growth and migration.

In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.

Some studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung. Altogether given the several studies, the ACE-AngII-AT1 axis in the RAS system shows a predominant role in the organ fibrosis, particularly in lung and liver.

According to some recent studies, ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.

The most common complication leading to the CoV-induced mortality is respiratory failure due to an extensive, accelerating lung fibrogenesis. Rather than PCRbased testing to detect CoV infection, a radiologic lung infiltration pattern in chest X ray could have a diagnostic value to screen the suspicious patients. It seems the cytopathic effects of virus resulted from its massive replication in infected cells need more time than what happens to cause acute manifestation of the disease. So, the acute accelerating lung fibrosis induced by COVID19 infection can be justified through ACE-AngII-AT1 overactivation caused by the virus.


Coronavirus is more severe and deadly in the aged, hypertensive, and diabetic.

It is also of note that ATR-1 Receptors increase with age and are increased in diabetes, hypertension, COPD. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children. As the SARS-COV2 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher AngII and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19. Another factor playing a role is that hypoxia causes cells to produce more AT-1. So the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.


Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.

If young people have higher ACE2, and that was the factor allowing faster viral inoculation, then it would be worse in the young, but it is not.

Cancer, hypertension, diabetes, chronic obstructive pulmonary disease are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.

In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.

ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.

Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.

Angiotensin-converting enzyme or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II

ACE is also part of the kinin-kallikrein system where it degrades bradykinin, a potent vasodilator, and other vasoactive peptides.

Other less known functions of ACE are degradation of bradykinin and amyloid beta-protein.

Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.

Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.

During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically, in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.

Bradykinin is also thought to be the cause of the dry cough in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.

ACE inhibitors - lower your blood pressure by reducing Angiotensin II in the body.

I understand that, the large number of deaths in Italy are old people with hypertension, heart disease and diabetes and probably have used ACE inhibitors drugs.

ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.

Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.

Angiotensin converting enzyme 2 (ACE2) - is a protein that sits on the lining cells within alveoli of the lung. It acts as an enzyme, being an exopeptidase that catalyses the conversion of Angiotensin II to angiotensin 1–7, which acts as a vasodilator. It also converts angiotensin I to nanopeptide angiotensin[1–9] It is a single-pass type I membrane protein expressed on the surface of epithelial cells of the pulmonary alveolus, and on small intestine enterocytes and other cell types.

ACE2 has been shown to be the entry point into human cells for some coronaviruses, including SARS-CoV, the virus that causes SARS. A number of studies have identified that the entry point is the same for SARS-CoV-2, the virus that causes COVID-19.

This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.

In fact, the interaction of the spike protein of the virus with the ACE2 induces a drop in the levels of ACE2 in cells. ( A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury - PubMed )


Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disorder that is frequently associated with multiple organ dysfunction leading to high mortality. The mechanisms underlying ARDS are multi-factorial, and are thought to include the renin-angiotensin system (RAS).


The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensin-converting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE. Thus, the ACE2 axis negatively regulates the ACE axis.


Conversion of Ang I to Ang II can readily occur in the lung by abundant ACE in pulmonary vessels. This may contribute to rapid responses of vasoconstriction in the pulmonary circulation and low blood flow, leading to ventilation/perfusion mismatch in conditions such as tissue hypoxia. On the other hand, ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells and epithelial injury is a critical event in the development of ARDS in humans; thus, the ability to produce ACE2 is severely impaired, resulting in dominant ACE activities during ARDS and/or ventilator-induced lung injury.

The RAS—specifically Ang II via AT1 and AT2 receptors—has a number of effects: induction of pulmonary vasoconstriction and vascular permeability in response to hypoxia resulting in pulmonary edema; stimulation of the lung production of inflammatory cytokines directly and indirectly by targeting bradykinin; acceleration of the Fas-induced apoptosis in alveolar epithelial cells; and promotion of extracellular matrix synthesis and human lung fibroproliferation. These effects of the RAS highlight the crucial role of Ang II in ACE/ACE2-regulated ARDS. Indeed, enhanced ACE activity and decreased ACE2 activity contribute to lung injury during cyclic stretch of human lung epithelial cells and to VILI in animal models. In models of ARDS, the use of ACE2 gene knockout mice demonstrated that ACE2 and Ang 1-7 are protective.

The use of Ang II receptor blockers or ACE inhibitors has been effective in decreasing lung injury in animal models, but this approach could have potential side effects, including systemic hypotension in humans. Since ACE2 protected the lung from developing ARDS and functioned as a coronavirus receptor for severe acute respiratory syndrome, the recombinant ACE2 (rACE2) protein may have an important place in protecting ARDS patients and as a potential therapeutic approach in the management of emerging lung diseases such as avian influenza A infections. (A Crucial Role of Angiotensin Converting Enzyme 2 (ACE2) in SARS Coronavirus-Induced Lung Injury - PubMed). Acute respiratory distress syndrome, also known as ARDS, is a common killer among critically ill patients hospitalized with COVID-19.
What a fantastic post - clear and explanatory! Very helpful. Thank you for taking the time.
 

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