Dear Editor,
We read with great interest the article by Khashkhusha TR et al “ACE
inhibitors and COVID-19: We don’t know yet”.1 The
authors discuss whether the use of angiotensin-converting enzyme (ACE)
inhibitors (ACEIs) in novel coronavirus disease‐19 (COVID‐19) patients
is beneficial or harmful. ACEIs and angiotensin receptor antagonists
(ARBs) both upregulate ACE2 levels.2 We believe that
ARBs should be preferred since, unlike ARBs, ACEIs may increase
angiotensin II through the chymase pathway. We would like to discuss
potential harms ACEI may cause through secondary bradykinin-chymase
pathways.
ACEI and ARBs are extensively prescribed for their proven beneficial
effects. Their potential benefit or harm in COVID-19 patients is
controversial. In some trials, morbidity and mortality seem better among
users than non-users of these drugs but there is no head to head
comparison between the groups.3 ACEIs catalyze the
transformation of angiotensin I to angiotensin II. When this pathway is
inhibited angiotensin I is increasingly converted to angiotensin 1-9
which is an intermediate product and consequently converted to
angiotensin 1-7.4 Angiotensin 1-9 and angiotensin 1-7
both have vasodilator and anti-inflammatory
properties.4 Nevertheless, there is no concrete
evidence that angiotensin 1-7 prevents acute respiratory distress
syndrome.2 Continuous infusion of angiotensin 1-7 is
shown to have a vasodilating effect in female rats but not in
males.2 It is not clear whether the increase of ACE2
would have a beneficial effect through increased angiotensin 1-7. On the
other hand, angiotensin II is found in increased amounts in COVID-19
patients with lung injury.3 It is proposed that
blocking of ACE2 by COVID-19 decreases the conversion of angiotensin II
to angiotensin 1-7 with a resultant increase in angiotensin II
levels.3
ACE blocking of ACEIs up-regulates ACE2 while down-regulates
ACE.5 Angiotensin I is not the only substrate for ACE;
another among the others is bradykinin. Bradykinin is not a substrate
for ACE2, thus, ACE inhibition increases bradykinin
levels.6 Increased bradykinin, in turn, leads to mast
cell degranulation and chymase activation.6 Chymase
which converts angiotensinogen derived angiotensin 1-12 to angiotensin
II is very active in heart, lung, and blood and produces angiotensin II
independent of renin and ACE.6 Angiotensin II is
directly responsible for vascular endothelium, heart, and lung injury.
Increased synthesis of angiotensin II, levels of which has already been
increased by viral blockage of ACE2,3 by augmented
chymase activity may further damage heart and lung tissue. We propose
that ARBs should be chosen instead of ACEIs in COVID-19 patients.
Conflict of interests
The authors declare that there is no conflict of interests.