Inhibition of AGTR1 (ARBs) and potentially post-AGTR1 signaling mechanisms
Antagonism of AGTR1, the primary mediator of Ang II-promoted tissue injury in SARS infections, is an attractive means to improve the course/outcome of patients with COVID-19 by preventing and/or decreasing such injury. This prediction is supported by data from studies of ventilator-induced lung injury and ARDS (Wang D et al., 2019) and other settings of tissue injury (e.g., Arumugam et al., 2016). A recent preprint reported less morbidity and mortality in elderly COVID-19 patients with hypertension treated with ARBs prior to hospitalization (Liu Y et al, 2020). Since numerous ARBs are approved drugs for other indications (e.g., hypertension, heart failure, renal disease), such ARBS could be rapidly tested as therapeutics on a compassionate use basis and in trials to assess their efficacy for COVID-19. Although the use of ARBs is potentially effective in decreasing lung and cardiac injury from COVID-19, possible side effects, including systemic hypotension, may occur in patients receiving those drugs.
Table 1 summarizes information (including the pros and cons) of each of those types of therapeutic approaches. Systemic administration of drugs will likely be the focus of therapies for COVID-19 but should administration by inhalation be considered for direct delivery to the lungs (albeit collapsed alveoli in COVID-19 patients might limit such delivery)? An important advantage of such an approach is to reduce effects/complications from systemic administration. Clinical studies have shown that inhaled NO or prostacyclin can improve oxygenation in ARDS, but without improvement in mortality (Attaway et al., 2017). We speculate that other inhaled agents might offer benefit in the lungs by increasing cellular cAMP (e.g., agonists of β-adrenoceptors or other Gs-linked GPCRs), cGMP (e.g., guanylyl cyclase activators) or both cyclic nucleotides (phosphodiesterase inhibitors). Given the importance of inflammation to COVID-19 pathobiology, as discussed above and in Pedersen & Ho, (2020), inhalational administration of other immunomodulatory/anti-inflammatory drugs may also have utility. Multiple ACEIs and ARBs are available in solution and thus are potential candidates for use with nebulizers. Such an approach might minimize complications from systemic administration of those agents, of particular importance in hypotensive patients or those at risk for hypotension. Of note, both ACEIs and ARBs have been administered experimentally via inhalational methods (Godugu et al., 2013; Suk et al., 2019; Kim et al., 2020).
Much recent debate has occurred regarding the use of ACEIs and ARBs in COVID-19 patients (Gurwitz, 2020; Danser et al., 2020; Diaz, 2020; Fang et al., 2020; Bozkurt et al., 2020; Phadke and Saunik, 2020; Lewis, 2020; Patel and Verma, 2020; Vaduganathan M et al., 2020). Some authors emphasize potential harms of these medications (e.g. Fang et al., 2020, Diaz, 2020) whilst others argue against this idea (e.g. Danser et al., 2020; Bozkurt et al., 2020) or hypothesize benefits of these drugs (e.g. Gurwitz 2020; Phadke and Saunik, 2020; Patel and Verma, 2020). Most of these articles are brief correspondences with limited supporting evidence. As a result, health providers and patients have been confused regarding the administration of ACEIs and ARBs to patients with COVID-19.
Articles with concern regarding the potential harms of ACEI/ARB use in COVID-19 generally cite articles that report administration of ACEI/ARBs may increase ACE2 expression, thereby possibly increasing the risk and spread of infection. We recently analyzed results from animal and human studies and concluded that no consistent, replicable data provide evidence of a relationship between ACEI/ARB use and ACE2 expression (Sriram and Insel, 2020), Here, we focus on the potential benefits of ACEI/ARB and other ways to target the RAS pathway in COVID-19, an idea that others share, e.g., Zhang et al., (2020), who suggested ACE2 as a target.
As listed below several clinical trials for COVID-19 have been initiated that target the RAS pathway. These studies are mostly of small size and are yet to begin enrollment. The targeting of the RAS for therapeutic benefit has thus as-yet not received the attention given to other approaches.