The renin-angiotensin system is pivotal in the regulation of blood pressure. One of its main components is ACE, which converts angiotensin I (Ang I) into angiotensin II (Ang II). Ang II exerts its hypertensive effects via AT1R activation. Apart from ACE, there are multiple other enzymes that metabolize angiotensin (the so-called “angiotensinases”), and one of these is the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). ACE2 converts the octapeptide Ang II (=Ang-(1–8)) into Ang-(1–7), and the decapeptide Ang I (=Ang-(1–10)) into Ang-(1–9) (Fig. 1). Yet, it additionally hydrolyzes multiple other peptides beyond the angiotensins. It is important to note that ACE2 does not convert Ang I into Ang II, and that its activity is not blocked by ACE inhibitors. This is not surprising, since ACE2 and ACE are different enzymes, and ACE inhibitors have been designed specifically for ACE only. ACE2 is a membrane-bound enzyme, with very low (soluble) levels in blood [8, 9]. The occurrence of sACE2 depends on cleavage of its membrane-anchor by A Disintegrin And Metalloprotease 17 (ADAM17) (Fig. 1). Interestingly, Ang II upregulates ADAM17. Yet, given that the vast majority of ACE2 is membrane-bound, fluctuations in the percentage of sACE by pathological conditions or drug use are unlikely to have major effects on the amount of membrane-bound ACE2. Obviously, SARS-CoV-2 entry relies exclusively on membrane-bound ACE2. sACE2 cannot mediate such entry, and, if anything, might even prevent it by keeping the virus in solution.
The concern related to the use of RAS blockers in COVID-19 patients is based on the idea that these drugs upregulate ACE2. Indeed, animal studies support such ACE2 upregulation after ARB treatment [10,11,12]. However, this generally required high doses, while effects differed per organ and per ARB. If true, this phenomenon should also be observed for ACE inhibitors. Yet, this has hardly been studied. Most importantly, we do not know whether the increase concerned membrane-bound ACE2 in pulmonary cells (relevant in SARS patients), nor whether a rise in membrane-bound ACE2, if occurring, truly facilitates virus entry. We do know that stopping RAS blocker treatment, particular in cardiovascular patients, has major serious consequences, including an increase in mortality.
Migraine patients using RAS blockers for the prevention of migraine often additionally suffer from hypertension. Normalizing increased blood pressure protects against cardiovascular disease, while migraine, especially in women, is associated with an increased cardiovascular risk . Hence, suddenly aborting preventive treatment with RAS blockers is likely to impose an increased cardiovascular risk in migraine patients, similar to that in hypertensive patients.