Neprilysin inhibitor angiotensin II receptor blocker combination (sacubitril/valsartan)

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Salient Points

On 11 March 2020, the WHO declared COVID-19 outbreak a pandemic.

No valid therapy for COVID-19 is actually available. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is empirically treated with antivirals, antimalarials, tocilizumab, etc.

The production of a vaccine for COVID-19 has been initiated, but the approval process requires time. The article describes a possible, alternative approach for treating COVID-19.

The lymphocyte count has been associated with a risk of increased disease severity. Patients who died from COVID-19 showed a significantly lower lymphocyte count than survivors, therefore this should be closely monitored.

A recent hypothesis suggests that the inhibition of the Angiotensin 1 receptor (AT1R) may provide benefits to COVID-19 patients. This is based on the observation that the

SARS-CoV-2 virus uses ACE2 as a receptor to bind to the bronchial cell membrane. These enzymes, ACE and ACE2 belong to the same peptidase family but have two very different

physiological functions. ACE cleaves angiotensin 1 to generate angiotensin 2, which binds to and activates AT1R, and thus promotes vasoconstriction. ACE2 cleaves Ang 2 and generates angiotensin 1, a powerful vasodilator acting through Mas receptors.

AT1R antagonists are widely used in hypertensive patients but they increase the ACE2 cardiac expression in rats and the urinary concentration of ACE2.

It has been demonstrated that the binding of virus to ACE2 leads to ACE2 down-regulation,

which increases the production of Ang 2 but reduces angiotensin 1.                                          This contributes to increased AT1-mediated pulmonary vascular permeability, thereby mediating increased lung pathology.

Therefore, higher ACE2 expression following chronic therapy with sartans may protect COVID-19 patients from acute lung injury rather than increasing the risk for SARS-CoV-2.

Detailed Summary

Two complementary mechanisms may explain such a hypothesis:

  • Sartans will continue to block excessive angiotensin-mediated AT1R activation due to the viral infection, and, in parallel, they will up-regulate ACE2, thus increasing angiotensin 1 production. In such a setting, the role of neprilysin (NEP) and its inhibitor sacubitril should also be revised. Recently, it was demonstrated that sacubitril/valsartan reduced the concentration of proinflammatory cytokines and neutrophil count, while increasing lymphocyte count more than valsartan alone or placebo. This finding might be related to the increase in plasma levels of atrial/brain/C-type natriuretic peptide, Ang I/II, substance P, bradykinin, and endothelin secondary to neprilysin inhibition by sacubitril.
  • It has recently been shown that early sacubitril/valsartan administration reduces high sensitivity C-reactive protein levels and increases lymphocyte count in patients with acute heart failure. These pieces of evidence support the biological plausibility of early administration of sacubitril/valsartan in COVID-19 patients, in order to maximize the anti-inflammatory effects of sacubitril and contain the effect of Ang I on the lungs.

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