Review Article

Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors and Coronavirus Disease 2019 (COVID-19)

Authors: Ahmed Abdalazim Dafallah Albashir, MBBS, MSc


Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. The angiotensin-converting enzyme 2 (ACE2) has been proven to be used by SARS-CoV-2 for host cell entry. Considering that angiotensin receptor blockers and ACE inhibitors (ACEIs) upregulate the expression of ACE2 in animal studies, there may be a concern about whether these drugs may increase COVID-19 susceptibility and severity. Recently, there has been a debate among clinicians about whether to continue or to stop ACEIs and angiotensin receptor blockers in the context of COVID-19. Also, some media outlets and health systems have called for the discontinuation of these drugs in the context of suspected COVID-19. This has necessitated an urgent release of guidance on the use of such medications in COVID-19 patients. To date, multiple theories relating to the pure effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on COVID-19 infections have been postulated. Favorable effects include blocking the ACE2 receptors, preventing viral entry into the heart and lungs, and protecting against lung injury in COVID-19. Adverse effects include a possible retrograde feedback mechanism that upregulates ACE2 receptors. This review provides greater insight into the role of the RAAS axis in acute lung injury and the effects of RAAS inhibitors on SARS-CoVs. The hypothesis that RAAS inhibitors facilitate viral insertion and the alternative hypothesis of the beneficial role of these drugs are discussed. Up-to-date published data concerning the RAAS inhibitors and COVID-19 are summarized.


This content is limited to qualifying members.

Existing members, please login first.

If you have an existing account please login now to access this article or view your purchase options.

Purchase only this article ($15)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.


1. Centers for Disease Control and Prevention. 2019 novel coronavirus, Wuhan, China. Published January 26, 2020. Accessed January 27, 2020. 2. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–1720. 3. Ramzy A, McNeil DG. W.H.O. declares global emergency as Wuhan coronavirus spreads. Published January 30, 2020. Accessed January 30, 2020. 4. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. JAMA 2020;323:1239–1242. 5. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506. 6. Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J Infect 2020;80:656–665. 7. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020;75:1730–1741. 8. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054–1062. 9. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–273. 10. Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004;383(Pt 1):45–51. 11. Santos RAS, Sampaio WO, Alzamora AC, et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol Rev 2018;98:505–553. 12. Guo J, Huang Z, Lin L, et al. Coronavirus disease 2019 (COVID-19) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection. J Am Heart Assoc 2020;9:e016219. 13. Serfozo P, Wysocki J, Gulua G, et al. Ang II (angiotensin II) conversion to angiotensin-(1–7) in the circulation is POP (prolyloligopeptidase)-dependent and ACE2 (angiotensin-converting enzyme 2)-independent. Hypertension 2020;75:173–182. 14. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:1. 15. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019;16:69. 16. Hofmann H, Geier M, Marzi A, et al. Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor. Biochem Biophys Res Commun 2004;319:1216–1221. 17. Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998;32:387–392. 18. Campbell DJ. Endogenous angiotensin II levels and the mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor type 1 antagonists. Clin Exp Pharmacol Physiol 1996;23(suppl 3):S125–S131. 19. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensinconverting enzyme 2. Circulation 2005;111:2605–2610. 20. Iwanami J, Mogi M, Tsukuda K, et al. Role of angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis in the hypotensive effect of azilsartan. Hypertens Res 2014;37:616–620. 21. Lakshmanan AP, Thandavarayan RA, Palaniyandi SS, et al. Modulation of AT-1R/CHOP-JNK-caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice. Eur J Pharm Sci 2011;44:627–634. 22. Zhong JC, Ye JY, Jin HY, et al. Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. Regul Pept 2011;166(1–3):90–97. 23. Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006;48:572–578. 24. Soler MJ, Ye M, Wysocki J, et al. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol 2009;296:F398–F405. 25. Burchill LJ, Velkoska E, Dean RG, et al. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. Clin Sci (Lond) 2012;123:649–658. 26. Campbell DJ, Zeitz CJ, Esler MD, et al. Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. J Hypertens 2004;22:1971–1976. 27. Luque M, Martin P, Martell N, et al. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1–7) in essential hypertension. J Hypertens 1996;14:799–805. 28. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACEinhibitors. Amino Acids 2015;47:693–705. 29. Epelman S, Shrestha K, Troughton RW, et al. Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes. J Card Fail 2009;15:565–571. 30. Ramchand J, Patel SK, Srivastava PM, et al. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLOS One 2018;13:e0198144. 31. Walters TE, Kalman JM, Patel SK, et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace 2017;19:1280–1287. 32. Ramchand J, Patel SK, Kearney LG, et al. Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis. JACC Cardiovasc Imaging 2020;13:655–664. 33. Furuhashi M, Moniwa N, Mita T, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens 2015;28:15–21. 34. Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 2005;280:30113–30119. 35. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875–879. 36. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care 2017;21:305. 37. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112–116. 38. Jia HP, Look DC, Shi L, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol 2005;79:14614–14621. 39. Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 2020;63:364–374. 40. Mancia G, Rea F, Ludergnani M, et al. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431–2440. 41. de Abajo FJ, Rodríguez-Martín S, Lerma V, et al. Use of renin-angiotensinaldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet 2020;395:1705–1714. 42. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020;382:e102. 43. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;382:2441–2448. 44. Fernández-Ruiz I. RAAS inhibitors do not increase the risk of COVID-19. Nat Rev Cardiol 2020;17:383. 45. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res 2020;126:1671–1681. 46. European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. Published March 13, 2020. Accessed March 20, 2020. 47. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Published March 17, 2020. Accessed March 20, 2020. 48. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA 2020;323:1769–1770.