2021
DOI: 10.3389/fphar.2021.619524
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Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Angiotensin-Converting Enzyme 2 Levels: A Comprehensive Analysis Based on Animal Studies

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the pathogen of coronavirus disease 2019 (COVID‐19), caused the outbreak escalated to pandemic. Reports suggested that near 1–3% of COVID‐19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1–7), the main … Show more

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Cited by 30 publications
(22 citation statements)
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“…So far, clinical studies remain inconclusive regarding the relationship between RAAS inhibitors and outcomes in COVID-19 patients 6 . Animal studies aimed at determining how RAAS inhibitors might affect tissue ace2 levels have primarily used rodents and focused on restricted tissues (e.g., heart and kidney) 7 , leaving it unclear how these drugs may exert their effects in a broader set of organs and species. The impact of discontinuation of RAAS inhibitors on ace2 expression has not been evaluated.…”
Section: Introductionmentioning
confidence: 99%
“…So far, clinical studies remain inconclusive regarding the relationship between RAAS inhibitors and outcomes in COVID-19 patients 6 . Animal studies aimed at determining how RAAS inhibitors might affect tissue ace2 levels have primarily used rodents and focused on restricted tissues (e.g., heart and kidney) 7 , leaving it unclear how these drugs may exert their effects in a broader set of organs and species. The impact of discontinuation of RAAS inhibitors on ace2 expression has not been evaluated.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast, Sriram et al conducted a literature review of 12 different studies conducted using animal or human models and concluded that the data from these studies where inconsistent with the hypothesis of increased ACE2 expression in response to AECI or ARB treatment . Kriszta et al, published a comprehensive review of animal studies conducted since the early 2000's and found that the majority of studies observed that ACEI/ARB treatment can cause ACE2 upregulation in tissues (Kriszta et al, 2021), however, they also reviewed evidence from several studies supporting the hypothesis that ACE2 activity inhibits acute lung injury (Imai et al, 2008;Gopallawa and Uhal, 2014) through formation of Angiotensin (1-7), which through its interaction with the Mas receptor blocks detrimental effects of Angiotensin II induced oxidative stress, inflammation, and tissue injury by Angiotensin II mediated by the AT1 receptor, suggesting that these drugs could be protective against severe morbidity or mortality from COVID-19. However, Kriszta et al concluded that prospective well designed randomized trials are required to definitely answer whether ACEIs or ARBs increase or decrease the risk of morbidity and mortality in COVID-19 (Kriszta et al, 2021).…”
Section: Discussionmentioning
confidence: 99%
“…Kriszta et al, published a comprehensive review of animal studies conducted since the early 2000's and found that the majority of studies observed that ACEI/ARB treatment can cause ACE2 upregulation in tissues (Kriszta et al, 2021), however, they also reviewed evidence from several studies supporting the hypothesis that ACE2 activity inhibits acute lung injury (Imai et al, 2008;Gopallawa and Uhal, 2014) through formation of Angiotensin (1-7), which through its interaction with the Mas receptor blocks detrimental effects of Angiotensin II induced oxidative stress, inflammation, and tissue injury by Angiotensin II mediated by the AT1 receptor, suggesting that these drugs could be protective against severe morbidity or mortality from COVID-19. However, Kriszta et al concluded that prospective well designed randomized trials are required to definitely answer whether ACEIs or ARBs increase or decrease the risk of morbidity and mortality in COVID-19 (Kriszta et al, 2021). The lack of consensus regarding the impact of ACEI or ARB treatment on ACE2 levels on the cell surface has led to prolonged concerns about the safety of continued administration of these medications to COVID-19 patients.…”
Section: Discussionmentioning
confidence: 99%
“…ARBs inhibited the canonical RAS pathway through angiotensin /Ang II/ATR1 axis; increasing ACE2, TLR-2, and IL-1β; and causing accumulation of reactive oxygen species (ROS), while ACE2 upregulation activates Ang-(1-7)/Mas pathway and inhibits inflammatory signals [ 186 ]. Studies identified that ARB could rescue SARS-CoV-2 spike or influenza virus-mediated ALI [ 187 , 188 ]. However, other studies inferred that there could be adverse aspects of using ACEI/ARB [ 189 ].…”
Section: The Potential Therapeutic Role Of Ace2 In Covid-19mentioning
confidence: 99%