key: cord-0904583-zes7b0j7 authors: Zhao, Hong‐Jin; Yang, Xiao‐Mei; Wang, Ai‐Hong; Li, Yan title: Pharmacological rationale for antihypertensive drug choice on COVID‐19–affected patients: ACEI/ARB might not increase their susceptibility date: 2020-09-17 journal: J Cell Mol Med DOI: 10.1111/jcmm.15850 sha: a0f2eac0f7540d9ab0649c3f8427a2671859ca30 doc_id: 904583 cord_uid: zes7b0j7 nan Dear Editor, The novel coronavirus outbreak is threatening human health globally mainly through causing severe acute respiratory syndrome (SARS), and this coronavirus is named as SARS-CoV-2 (severe acute respiratory coronavirus 2) to be differentiated from SARS-CoV in 2003. SARS-CoV-2 spreads mainly through the respiratory route and uses membrane-bound ACE2 (angiotensin-converting enzyme 2) as the receptor to enter into the cells for replication. 1 The receptor ACE2 is a single-pass membrane protein, and its extracellular enzymatic domain is classically known to convert Ang II (angiotensin II) to Ang1-7 in RAS (renin-angiotensin systems). 2 When cleaved from the cell membrane, ACE2 enters into the blood and this secreted ACE2 loses the ability to mediate the coronavirus infection. The membranebound ACE2-mediated SARS infection consumes a large proportion of ACE2 molecules, leading to the down-regulation of ACE2/Ang1-7 and up-regulation of Ang II. This imbalance of the RAS system eventually results in exacerbation of inflammation in lung tissues and cardiovascular dysfunction. 3 To avoid the adverse effects of Ang II on the cardiovascular system, ACEI/ARB (angiotensin-converting enzyme inhibitors/Ang II receptor blockers) is used as the first-line medicine in the treatment of hypertension and heart failure through inhibiting the production or function of Ang II. 4 Considering the large consumption of ACE2 due to the SARS infection and the subsequent increased Ang II accumulation, the drug choice ACEI/ARB should be more suitable for the treatment of hypertensive COVID-19 (coronavirus disease 2019) patients. This drug strategy will rebalance the RAS system and prevent the progression from pneumonia to severe ARDS in theory. Recently, Fang et al 5 have suggested the conversion of ACEI/ ARB to CCB (calcium channel blockers) for hypertensive patients based on studies reporting the up-regulatory effects of ACEI/ARB on ACE2 expression, which could contribute to increased sensitivity to SARS-CoV-2 infection. A study has shown the increased cardiac ACE2 mRNA levels by ACEI/ARB administration. 6 Moreover, ARB has been implicated in up-regulating the cardiac and renal ACE2 protein levels. 7, 8 However, Western blot data are lacking to experimentally distinguish ACE2 molecules in full-length membrane form from those in cleaved/secreted form due to their similar molecular weight. to other antihypertensive treatment at that time once COVID-19 was confirmed according to the initial guidelines in China, and the discontinuation of ACEI/ARB usually occurred at least one week before COVID-19 patients progressed to the severe cases. On the contrary, these data might hint the disadvantages of ACEI/ARB withdrawal from the treatment of hypertensive COVID-19 patients. In consistence, recent clinical research has implicated that the application of ACEI/ARB in hospitalized COVID-19 patients with hypertension has a lower risk of all-cause mortality in contrast to ACEI/ ARB non-users. 17 Currently, it is generally believed that SARS-CoV-2 infection exhausts a great number of ACE2 molecules, which leads to decreased ACE2 expression and increased angiotensin II levels, resulting in RAS imbalance. Such a RAS imbalance has been widely accepted to account for the exacerbation of inflammatory pneumonia and hypertension. Therefore, to achieve RAS system rebalance, most Chinese experts now recommend the administration of ACEI/ARB for the hypertensive treatment, especially in COVID-19 patients. The authors confirm that there are no conflicts of interest. The authors confirm that citations for available data have been included in References section. Xiao-Mei Yang 2 A new coronavirus associated with human respiratory disease in China Local renin-angiotensin II systems, angiotensin-converting enzyme and its homologue ACE2: their potential role in the pathogenesis of chronic obstructive pulmonary diseases, pulmonary hypertension and acute respiratory distress syndrome A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Blood pressure and the new ACC/AHA hypertension guidelines Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? 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