Figure-1: Active agents on the RAS system
These drugs have an extraordinary therapeutic efficacy, but can also cause side effects such as hyperkalaemia, hypotension, cough, angioedema. An increase in ACE-2 concentrations has already been documented both in murine models and in human patients treated with ACE-i and ARB. This is because by inhibiting the ACE pathway, angiotensin I is directed into the conversion pathway to angiotensin I-7, requiring a higher expression of ACE-2 to compensate for the greater amount to be converted. The same mechanism is if you use ARB by blocking the Ang II receptor, in fact the system counter-regulates increasing ACE and ACE-2, in addition both ACE-i and ARB cause an increase in the concentration of renin and all the upstream mediators of the enzyme cascade, and this compensatory mechanism may be favorable or unfavorable depending on which stage of the SARS-Cov-2 infection the patient is. With the use of ACE-i or ARB and therefore an increase in the level of expression of the viral receptor mentioned above, an increase in infectious power and colonization could plausibly be obtained. In phase I of the infection, therefore, the virus is penetrating the cell and is replicating, perhaps in this phase it could be useful to administer a direct renin inhibitor which, acting upstream, lowers the concentrations of ACE and especially ACE-2, decreasing the concentration of receptor protein for the virus. On the contrary, in phase two or three of the disease, where there is an hyperactive inflammatory state and where it seems that ACE-2 may have a protective role in particular on the respiratory tract, it may be appropriate to increase ACE-2 with ACE-i or blocking the inflammatory effects of Ang II using ARBs, which also increase the expression of ACE-2 itself. In recent observational studies the most frequent comorbidities reported in patients with SARS-Cov-2 are often treated with (ACE-i); however, the correlation between SARS-Cov-2 and treatment with ACE-i has not been evaluated and demonstrated in any of the studies. Based on PubMed research of 28 February 2020, there is no evidence suggested that direct renin inhibitors cause an increase in ACE2, this drug could therefore be used to manage the hypertension of patients which are in phase I of the infection, or in a preventive (non-virus positive patient) way to reduce the risk of contracting SARS-Cov-2. (14 –15-16-17-18-19-20-21-22-23-24-25-26)
Table 1: Active agents on the RAS system that modulate the concentration of ACE-2 and hypothetical their use in the various stages of SARS-Cov-2 infection.