Hypothetical dysfunction of the epithelial sodium channel may justify neurohumoral blockade in coronavirus disease 2019

In general, increased cardiac stress due to hypoxaemia caused by respiratory failure as well as acute cardiac injury in response to the myocardial infection and systemic inflammation leading to massive cytokine release could all play an important role in disease progression. 1 However, it still remains elusive how SARS‐CoV‐2 is able to present such a negative impact on the CV system. [...]new insights into the molecular mechanisms in COVID‐19 may enhance the better understanding of the disease course, thereby enabling the development of further therapeutic approaches. [...]current data support the idea that the use of RAAS inhibitors in COVID‐19 seems to be safe without an apparent detrimental effect on the clinical outcome. 6 Moreover, a study‐level meta‐analysis from China even showed a mortality benefit of hypertensive patients treated with RAAS compared with non‐RAAS inhibitors. 7 The intricate balance between ACE2 down‐regulation by the viral infection and ACE2 up‐regulation due to RAAS inhibition could, in theory, explain the above findings. [...]the dysregulation of ENaC activity leads to lower intracellular sodium concentrations, followed by insufficient Na+/K+‐ATPase activity and, subsequently, an increase in serum potassium levels. Besides the epithelium, ENaC was also identified on non‐epithelial sites, such as vascular smooth muscle and endothelial cells, with implications for regulating vascular tone. Furthermore, the cleavage of both the virus and ENaC are carried out at the cell membrane level. [...]in cells where ENaC and ACE2 are both presented (such as the alveolar epithelial cell), a competition may be present for furin‐mediated cleavage upon SARS‐CoV‐2 infection. 14 Interestingly, the tissue distributions of ENaC and ACE2 share similar sites, including nephron tubules, the lungs, the colon epithelium, and the vascular endothelium.