4 ms·

Another interesting side effect could be other temporizing measures in the inpatient setting. My understanding from a brief skim of older research papers is tha

Another interesting side effect could be other temporizing measures in the inpatient setting. My understanding from a brief skim of older research papers is that the ACE inhibitors and angiotensin receptor blockers that we use today, like lisinopril or losartan, could upregulate the expression of ACE-2 receptors. If a patient is admitted with coronavirus, discontinuing blood pressure medications such as lisinopril and losartan could be worthwhile to decrease length of stay, morbidity, and mortality.

chroem- 7y ago
I suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.
- epmaybe 7y ago
  No, I think that's just the fact that most of the people who died were older with lots of comorbidities, like high blood pressure, diabetes, COPD, etc
- rolph 7y ago
  it doesnt explain it, but it is something worth chasing to its end for a possible therapeutic benefit. its does suggest that such comorbidities such as high blood pressure or existing lung disorder disease or other wellness impairment --- --- could contribute to mortality
rolph 7y ago
this is something of a bush to beat around. - when the virus docks with the ACE2 receptor there is a loss of the ACE2 receptor function as it is a destructive process. - when the virus inhabits the cell there is probably a cytoplasmic down regulation of ACE2 expression as the cell is now "claimed" as a place for replication so the question would be when would we administer or withdraw such an ACE2 blocker the loss of ACE2 functionality is devastating to the cell but the presence of functional ACE2 receptor makes a cell vulnerable to entry -and should we be using a blocker pe se or should we use some sort of hypothetical receptor inhibitor that is not displace by coronavirus spike protien, as in competetive inhibition?
- ptest1 7y ago
  I wrote a long comment and it got deleted, argh! Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well: https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-might-be-a-good-choice-for-the-therapy-of-covid-19-pneumonia/?from_single_result=Inhibitors+of+RAS+covid https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m... They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2. ACE2-fc being developed- will both stop AT1R activation and neutralize virus: https://twitter.com/robertlkruse/status/1233986542097567744?s=21 https://twitter.com/robertlkruse/status/1233986542097567744?... He is looking for funding if any funders are reading this. Comment here and I can connect.
  - rolph 7y ago
    there would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur. there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm. the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis
    - ptest1 7y ago
      I guess what I think could be possible is: ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s=21 https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point. Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal? Check out this paper: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Proportion of reduction of ACE2 correlates with disease severity. Check out figure 1 “Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.” Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease. So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity. Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen. Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2? If damage from increased loss, then I can see the ARB approach helping. If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.
pezo1919 7y ago
Can you please give me a pointer on these researches? Also its not clear to me: do blood pressure mediacations in general upregulate the expression of ACE-2, or is it possible that they downregulate it? (Not lisonopril or losartan)
- rolph 7y ago
  you can do both depending on the med and there are different mechanisms of action. Also : any sort of EXPERIMENTATION should be done in a clinical setting with qualified professionals, this discussion is about scientific research and is not even close to being acceptable for clinical trials. blood pressure medication is normally prescribed with physician monitoring the patient for desirable or undesirable effect
unsrsly 7y ago
Lisinopril and losartan are usually stopped in patients admitted to the hospital for an infection.

chroem- 7y ago

I suppose that explains why a lot (most?) of the people who died also suffered from high blood pressure.

epmaybe 7y ago
No, I think that's just the fact that most of the people who died were older with lots of comorbidities, like high blood pressure, diabetes, COPD, etc
rolph 7y ago
it doesnt explain it, but it is something worth chasing to its end for a possible therapeutic benefit. its does suggest that such comorbidities such as high blood pressure or existing lung disorder disease or other wellness impairment --- --- could contribute to mortality

rolph 7y ago

this is something of a bush to beat around. - when the virus docks with the ACE2 receptor there is a loss of the ACE2 receptor function as it is a destructive process. - when the virus inhabits the cell there is probably a cytoplasmic down regulation of ACE2 expression as the cell is now "claimed" as a place for replication so the question would be when would we administer or withdraw such an ACE2 blocker the loss of ACE2 functionality is devastating to the cell but the presence of functional ACE2 receptor makes a cell vulnerable to entry -and should we be using a blocker pe se or should we use some sort of hypothetical receptor inhibitor that is not displace by coronavirus spike protien, as in competetive inhibition?

ptest1 7y ago
I wrote a long comment and it got deleted, argh! Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well: https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-might-be-a-good-choice-for-the-therapy-of-covid-19-pneumonia/?from_single_result=Inhibitors+of+RAS+covid https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m... They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2. ACE2-fc being developed- will both stop AT1R activation and neutralize virus: https://twitter.com/robertlkruse/status/1233986542097567744?s=21 https://twitter.com/robertlkruse/status/1233986542097567744?... He is looking for funding if any funders are reading this. Comment here and I can connect.
- rolph 7y ago
  there would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur. there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm. the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis
  - ptest1 7y ago
    I guess what I think could be possible is: ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s=21 https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point. Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal? Check out this paper: https://twitter.com/__philipn__/status/1229568317167243264?s=21 https://twitter.com/__philipn__/status/1229568317167243264?s... Proportion of reduction of ACE2 correlates with disease severity. Check out figure 1 “Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.” Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease. So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity. Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen. Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2? If damage from increased loss, then I can see the ARB approach helping. If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.

pezo1919 7y ago

Can you please give me a pointer on these researches? Also its not clear to me: do blood pressure mediacations in general upregulate the expression of ACE-2, or is it possible that they downregulate it? (Not lisonopril or losartan)

rolph 7y ago
you can do both depending on the med and there are different mechanisms of action. Also : any sort of EXPERIMENTATION should be done in a clinical setting with qualified professionals, this discussion is about scientific research and is not even close to being acceptable for clinical trials. blood pressure medication is normally prescribed with physician monitoring the patient for desirable or undesirable effect

unsrsly 7y ago

Lisinopril and losartan are usually stopped in patients admitted to the hospital for an infection.