High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.

B Székács,S Várbíró,L Debreczeni

doi:10.1556/2060.2021.00007

B Székács, S Várbíró + Show 1 more

Open Access

https://doi.org/10.1556/2060.2021.00007

Copy DOI

Abstract

We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients. The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions. Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Highlights

The high mortality rate of elderly vulnerable hypertensive patients infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often associated with cytokine storm [1]
On the basis of earlier scientific findings, some researchers tried to prove the pathological importance of kallikrein-kinin systems (KKSs) in the inflammatory process by combined BKB1R and BKB2R blockade or kallikrein inhibition, assuming increased BK and DABK/LYDABK concentrations and higher BKB1R and BKB2R receptor activation in COVID-19 infection no approved inhibitors are available [6, 15]
Several pathological mechanisms in KKS-RAS inter-regulation can promote the development of the SARSCoV-2 related inflammation, resulting in increased production and suppressed degradation of bradykinin and its active metabolites leading to highly activated BKB2R and DABK/LYDA BKB1R axles

Summary

INTRODUCTION

The high mortality rate of elderly vulnerable hypertensive patients infected with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often associated with cytokine storm [1]. On the basis of earlier scientific findings, some researchers tried to prove the pathological importance of KKS in the inflammatory process by combined BKB1R and BKB2R blockade or kallikrein inhibition, assuming increased BK and DABK/LYDABK concentrations and higher BKB1R and BKB2R receptor activation in COVID-19 infection no approved inhibitors are available [6, 15] Some of these interventions improved pulmonary inflammation in experimental animals, supporting a role of KKS and BK in severe respiratory and systemic inflammation caused by SARS-CoV-2 infection [6, 15]. Another potential way to inhibit BKB1R activity is blocking innate cytokines (IL-1) that upregulates BKB1R on endothelial cells at the site of inflammation [6]

RAS DYSREGULATION

CONCLUSIONS