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.
- NCT04335123: Study of Open Label Losartan in COVID-19. Phase-1 trial
to evaluate losartan safety in COVID-19; University of Kansas Medical
Center
- NCT04312009: Losartan for Patients With COVID-19 Requiring
Hospitalization; University of Minnesota
- NCT04335136: Recombinant Human Angiotensin-converting Enzyme 2
(rhACE2) as a Treatment for Patients With COVID-19
[APN01-COVID-19]; Apeiron Biologics and multiple academic
collaborators in Europe
- NCT04332666: Angiotensin-(1,7) Treatment in COVID-19: the ATCO Trial
(ATCO); Erasme University Hospital in Belgium