key: cord-0854207-jhogpa56 authors: Khalili, Azadeh; Karim, Hosein; Bayat, Gholamreza title: Theoretical Assessment of Therapeutic Effects of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors on COVID-19 date: 2021-07-03 journal: Iran J Med Sci DOI: 10.30476/ijms.2021.88753.1949 sha: 79a5131412e3c54118d5aab59df2b43f1c6bcb35 doc_id: 854207 cord_uid: jhogpa56 nan Iran J Med Sci July 2021; Vol 46 No 4 COVID-19-induced respiratory problems. Therefore, ACEI-induced accumulation of bradykinin could be a putative mechanism, which can intensify COVID-19-induced respiratory distress. Activation of AT1R is responsible for several physiological/pathological processes such as aldosterone secretion, tubular sodium reabsorption, blood pressure elevation, induction of fibrosis, and generation of free reactive radicals. 13 ARBs block RAAS by inhibiting Ang II-mediated AT1R activation, thus, effectively inhibiting the above-mentioned mechanisms. AT1R activation is also mediated through Ang II-independent pathways by conformational changes such as mechanical stress, 13 the situation that occurs during ventilator-induced respiratory distress by COVID-19. In this acute condition, activation of the counterregulatory arm of AT2R could be life-saving. Similar to ACEIs, ARBs also stimulate renin secretion by inhibiting Ang II negative feedback. Despite the elevation of Ang II level, blockade of AT1R by ARBs leads to the stimulation of AT2R whereby its activation effectively counteracts the pathophysiological effects of AT1R. AT2R activation is the main therapeutic advantage of ARBs over ACEIs. A higher level of Ang II also has a high potential of conversion into a higher level of protectant peptide of Ang (1-7), and consequently activation of MasR (figure 1B). ARBs activate Ang II/AT2R as well as Ang (1-7)/MasR, pathways involved in protective processes such as anti-inflammatory response, anti-fibrosis, and antihypertensive effect. 13 Secretion of aldosterone from the adrenal cortex is mediated through AT1R activation. 21 However, not all ARBs are successful in inhibiting aldosterone secretion. Aldosterone escape by administrating ARBs is dependent 22 Although aldosterone secretion continues during losartan and irbesartan treatment, it is more efficiently blocked with valsartan and candesartan. Aldosterone production via adrenocortical AT1R is mediated by two independent signaling pathways: the production of diacylglycerol/inositol trisphosphate and β-arrestin-1. Effective blockade of both pathways is needed to completely inhibit aldosterone production. While losartan is ineffective in inhibiting the β-arrestin-1 pathway of aldosterone production, valsartan and candesartan are the most potent β-arrestin-1 inhibitors in both in vitro and in vivo studies. 23, 24 Considering the role of aldosterone on the expression of ACE2, this could be another advantage of the therapeutic effect of ARBs, especially the aldosterone blocker types, over ACEIs on COVID-19. Unlike ACEIs, ARBs do not stimulate bradykinin accumulation. In theory, besides the lower risk of adverse effects, ARBs are not involved in bradykinin-induced respiratory distress, an acute complication of COVID-19. Some studies have compared the anti-inflammatory properties of ACEIs and ARBs in different medical conditions. As reported by Lai and colleagues, ARBs were associated with a lower risk of severe exacerbations, pneumonia, and mortality in COPD patients than ACEIs. 25 This could be explained theoretically by the activation of Ang II/AT2R as well as MasR and consequently amelioration of the inflammation. In addition, bradykinin-mediated pulmonary edema induced by ACEIs is not beneficial for extensive inflammation and acute cytokine storm involved in COVID-19. 26 Considering both the theoretical aspects and previous clinical and experimental results, attention should be paid to some important differences between the therapeutic effects of ARBs and ACEIs, especially on COVID-19-associated acute respiratory syndrome. Theoretical justifications are in favor of using ARBs over ACEIs in the case of COVID-19. Considering distinctive pharmacodynamic differences among ARBs, it seems that aldosterone blockers (e.g., candesartan and valsartan) have the preferred therapeutic benefit. This hypothesis requires further clarifications through preclinical and clinical studies. 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