Controlling common diseases could save the world from the SARS-CoV-2 pandemic.
By: Eliel Cruz
Tags: Health, Coronavirus, Co Vid 19, Science, Articles

Photo by the BBC.

By today, the “death toll from the COVID‐19 epidemic caused by coronavirus SARS‐CoV‐2, which emerged in late December 2019 in Wuhan, China (World Health Organization, 2019), has surpassed the combined death toll of the SARS (Severe Acute Respiratory Syndrome) epidemic of 2002–2003 and the MERS (Middle East Respiratory Syndrome) epidemic of 2013 combined (Mahase, 2020). This epidemic seems to be spreading at an exponential rate, with a doubling period of 1.8 days, and there are fears that it might progress to pandemic scales (Cheng & Shan, 2020). Yet, no SARS‐CoV‐2 therapeutics are presently available, albeit some treatment options which await validation have been published, including several broad spectrum antivirals such as favipiravir and remdesivir (Beigel et al., 2019, Li & De Clercq, 2020), the anti‐malaria drug chloroquine (Gao, Tian, & Yang, 2020), and a traditional Chinese herbal formula (Luo et al., 2020).” — (Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics)

The whole population, from the common citizen to the government members, wants a vaccine for the SARS-CoV-2 as soon as possible, but vaccines for the SARS‐CoV developed since its outbreak 18 years ago have not materialized to an approved product.

In addition, there have been concerns about vaccine‐mediated enhancement of disease, for example, due to pulmonary immunopathology upon challenge with SARS‐CoV. Moreover, even once a vaccine is approved for human use, high virus mutation rates mean that new vaccines may need to be developed for each outbreak, similarly to the situation with new annual influenza vaccines.

Could the Hypertension pills can fight the COVID-19?

Notably, angiotensin‐converting enzyme (ACE) and its close homologue ACE2, while both belonging to the ACE family of dipeptidyl carboxydipeptidases, serve two opposing physiological functions. ACE cleaves angiotensin I to generate angiotensin II, the peptide which binds to and activates AT1R to constrict blood vessels, thereby elevating blood pressure. By contract, ACE2 inactivates angiotensin II while generating angiotensin 1–7, a heptapeptide having a potent vasodilator function via activation of its Mas receptor (Santos et al., 2003), and thus serving as a negative regulator of the renin–angiotensin system. These opposing actions of ACE and ACE2 were recently reviewed by Smyth, Cañadas‐Garre, Cappa, Maxwell, & McKnight, 2019.

The AT1R antagonists losartan and olmesartan, commonly applied for reducing blood pressure in hypertensive patients, were shown to increase cardiac ACE2 expression about three‐fold following chronic treatment (28 days) after myocardial infarction induced by coronary artery ligation of rats (Ishiyama et al., 2004). Losartan was also shown to upregulate renal ACE2 expression in chronically treated rats (Klimas et al., 2015). In agreement with these observations, higher urinary ACE2 levels were observed in hypertensive patients treated with the AT1R antagonist olmesartan (Furuhashi et al., 2015). Taken together, these observations suggest that chronic AT1R blockade results in ACE2 upregulation in both rats and humans.

“ACE2 is the common binding site for both the SARS‐CoV of the 2002–2003 SARS epidemic and, most likely, also the SARS‐CoV‐2 strain underlying the current COVID‐19 epidemic. Hence, the suggestion to treat SARS patients with AT1R antagonists for increasing their ACE2 expression seems counter‐intuitive. However, several observations from studies on SARS‐CoV, which very likely are relevant also for SARS‐CoV‐2, seem to suggest otherwise. It has been demonstrated that the binding of the coronavirus spike protein to ACE2, its cellular binding site, leads to ACE2 downregulation, which in turn results in excessive production of angiotensin by the related enzyme ACE, while less ACE2 is capable of converting it to the vasodilator heptapeptide angiotensin 1–7. This in turn contributes to lung injury, as angiotensin‐stimulated AT1R results in increased pulmonary vascular permeability, thereby mediating increased lung pathology (Imai et al., 2005; Kuba et al., 2005). Therefore, higher ACE2 expression following chronically medicating SARS‐CoV‐2 infected patients with AT1R blockers, while seemingly paradoxical, may protect them against acute lung injury rather than putting them at higher risk to develop SARS. This may be accounted for by two complementary mechanisms: blocking the excessive angiotensin‐mediated AT1R activation caused by the viral infection, as well as upregulating ACE2, thereby reducing angiotensin production by ACE and increasing the production of the vasodilator angiotensin 1–7. These aspects on the role of dysregulated ACE2 in SARS‐CoV pathogenesis are reviewed in detail by de Wit et al., 2016. Incidentally, following the SARS‐CoV epidemic of 2002–2003, ACE2 inhibitors were suggested as SARS therapeutics (Huentelman et al., 2004; Turner et al., 2004); however, this proposal has not led to new drugs.” — (Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics)

Losartan, telmisartan, olmesartan (and additional AT1R antagonists) are widely applied in the clinic since the 1990s for control of hypertension and kidney disorders, and are known as safe drugs that are rarely implicated in adverse drugs events (Deppe, Böger, Weiss, & Benndorf, 2010; McIntyre, Caffe, Michalak, & Reid, 1997). However, it should be noted that around half of SARS‐CoV patients developed hypotension during their hospitalization (Yu et al., 2006). At time of writing this commentary, no comprehensive information is available on hypotension rates among hospitalized SARS‐CoV‐2 patients; it is thus premature to estimate what percentage of SARS patients of the currently ongoing epidemic can be safely treated with AT1R blockers without risking exacerbated hypotension.

The tentative suggestion to apply AT1R antagonists such as losartan and telmisartan as SARS‐CoV‐2 therapeutics for treating patients prior to the development of acute respiratory syndrome remains unproven until tried. Knowledge gained from such datamining of clinical records seems crucial for reducing the mortality and morbidity of SARS‐CoV‐2. At the same time, efforts must be made for developing a SARS‐CoV‐2 vaccine.