New Viral Diseases and New Possible Remedies by Means of the Pharmacology of the Renin-Angiotensin System

Abstract

All strains of SARS-CoV-2, as well as previously described SARS-CoV and MERS-CoV, bind to ACE2, the cell membrane receptor of β-coronaviruses. Monocarboxypeptidase ACE2 activity stops upon viral entry into cells, leading to inadequate tissue production of angiotensin 1-7 (Ang1-7). Acute lung injury due to the human respiratory syncytial virus (hRSV) or avian influenza A H7N9 and H5N1 viruses is also characterized by significant downregulation of lung ACE2 and increased systemic levels of angiotensin II (Ang II). Restoration of Ang1-7 anti-inflammatory, antifibrotic, vasodilating, and natriuretic properties was attempted at least in some COVID-19 patients through i.v. infusion of recombinant human ACE2 or intranasal administration of the modified ACE2 protein, with inconsistent clinical results. Conversely, use of ACE inhibitors (ACEis), which increase ACE2 cell expression, seemed to improve the prognosis of hypertensive patients with COVID-19. To restore Ang1-7 tissue levels in all these viral diseases and avoid the untoward effects frequently seen with ACE2 systemic administration, a different strategy may be hypothesized. Experimentally, when metallopeptidase inhibitors block ACE2, neprilysin (NEP), highly expressed in higher and lower airways, starts cleaving angiotensin I (Ang I) into Ang1-7. We suggest a discerning use of ACEis in normohypertensive patients with β-coronavirus disease as well as in atypical pneumonia caused by avian influenza viruses or hRSV to block the main ACE-dependent effects: Ang II synthesis and Ang1-7 degradation into angiotensin 1-5. At the same time, i.v.-infused Ang I, which is not hypertensive provided ACE is inhibited, may become the primary substrate for local Ang1-7 synthesis via ubiquitous NEP; i.e., NEP could replace inadequate ACE2 function if Ang I was freely available. Moreover, inhibitors of chymase, a serine endopeptidase responsible for 80% of Ang II-forming activity in tissues and vessel walls, could protect patients with atypical pneumonia from Ang II-mediated microvascular damage without reducing arterial blood pressure.