Angiotensin antihypertensives and COV... - Advanced Prostate...

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Angiotensin antihypertensives and COVID-19: No clear added risk nor protection.

MateoBeach profile image
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Yesterday in a reply I raised the possibility of whether angiotensin-related anti-hypertensive drugs, ACE inhibitors or ARBs would have any protective effect on COVID-19 infectivity, having heard that the virus uses "ACE2" as a receptor.

The current NEJM issue has an article summarizing this complex relationship.

nejm.org/doi/full/10.1056/N...

Bottom line first: "On the basis of the available evidence, we think that, despite the theoretical concerns and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which these drugs might affect the propensity for or severity of Covid-19, RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are being evaluated for, or have Covid-19."

"ACE2 is a key counterregulatory enzyme that degrades angiotensin II to angiotensin-(1–7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin-(1–9) and participates in the hydrolysis of other peptides.16 In studies in humans, tissue samples from 15 organs have shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells.17 Of interest, the circulating levels of soluble ACE2 are low and the functional role of ACE2 in the lungs appears to be relatively minimal under normal conditions18 but may be up-regulated in certain clinical states.

Because ACE inhibitors and ARBs have different effects on angiotensin II, the primary substrate of ACE2, the effects of these agents on ACE2 levels and activity may be anticipated to differ. Despite substantial structural homology between ACE and ACE2, their enzyme active sites are distinct. As a result, ACE inhibitors in clinical use do not directly affect ACE2 activity.19 Experimental animal models have shown mixed findings with respect to the effects of ACE inhibitors on ACE2 levels or activity in tissue.20-25 Similarly, animal models have had inconsistent findings with respect to the effects of ARBs on ACE2, with some showing that ARBs may increase messenger RNA expression or protein levels of ACE2 in tissue21,26-34 and others showing no effect.23

In contrast to available animal models, there are few studies in humans regarding the effects of RAAS inhibition on ACE2 expression. In one study, the intravenous administration of ACE inhibitors in patients with coronary artery disease did not influence angiotensin-(1–7) production, a finding that calls into question whether ACE inhibitors have any direct effects on ACE2-directed angiotensin II metabolism.35 Similarly, in another study, among patients with hypertension, angiotensin-(1–7) levels appeared to be unaffected after initial treatment with the ACE inhibitor captopril; however, with exposure to captopril monotherapy over a period of 6 months, angiotensin-(1–7) levels increased.36 Furthermore, few studies have examined plasma ACE2 activity or urinary ACE2 levels in patients who have received long-term treatment with RAAS inhibitors. In cross-sectional studies involving patients with heart failure,37 atrial fibrillation,38 aortic stenosis,39 and coronary artery disease,40 plasma ACE2 activity was not higher among patients who were taking ACE inhibitors or ARBs than among untreated patients. In a longitudinal cohort study involving Japanese patients with hypertension, urinary ACE2 levels were higher among patients who received long-term treatment with the ARB olmesartan than among untreated control patients, but that association was not observed with the ACE inhibitor enalapril or with other ARBs (losartan, candesartan, valsartan, and telmisartan).41 Previous treatment with ACE inhibitors was associated with increased intestinal messenger RNA levels of ACE2 in one study, but that association was not observed with ARBs25; data are lacking regarding the effects of RAAS inhibitors on lung-specific expression of ACE2."

Potential for Benefit Rather Than Harm of RAAS Blockers in Covid-19

"SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. It has been postulated but unproven that unabated angiotensin II activity may be in part responsible for organ injury in Covid-19.43,44 After the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation of ACE2 abundance on cell surfaces.45 Continued viral infection and replication contribute to reduced membrane ACE2 expression, at least in vitro in cultured cells.46 Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration in response to bacterial endotoxin47 and may result in unopposed angiotensin II accumulation and local RAAS activation."

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