RAAS Blockade and COVID-19: Mechanistic Modeling of Mas and AT1 Receptor Occupancy as Indicators of Pro-Inflammatory and Anti-Inflammatory Balance.
Clin Pharmacol Ther
; 109(4): 1092-1103, 2021 04.
Article
in English
| MEDLINE | ID: covidwho-1051200
ABSTRACT
ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro-inflammatory and anti-inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS-CoV-2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro-inflammatory/anti-inflammatory balance. RAAS blockade prior to SARS-CoV-2 infection is predicted to increase the mas-AT1 receptor occupancy ratio up to 20-fold, indicating that in patients already taking an ACEi/ARB before infection, the anti-inflammatory arm is already elevated while the pro-inflammatory arm is suppressed. Predicted pro-inflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to anti-inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas-AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1-7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1-7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2-Ang(1-7)-mas arm may not be large enough to play a major role in COVID-19 pathophysiology.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Renin-Angiotensin System
/
Angiotensin-Converting Enzyme Inhibitors
/
Receptor, Angiotensin, Type 1
/
Angiotensin Receptor Antagonists
/
COVID-19
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Clin Pharmacol Ther
Year:
2021
Document Type:
Article
Affiliation country:
Cpt.2177
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