ABSTRACT
Objective: Angiotensin converting enzyme 2 (ACE-2) has regained widespread attention as the cellular receptor of SARS-CoV-2 virus that caused the COVID-19 pandemic. It was contended that ACE inhibitors (ACEis) and angiotensin type 1 receptor (AT1R) antagonists (ARBs) increase ACE2 expression in lung cells and their administration in Covid-19 patients could be detrimental and/ or constitute a potential risk factor. As there were no evidences supporting this hypothesis we investigated the effect of ACEis/ARBs on ACE2 expression in lung cells. Design and method: Calu-3 cells, epithelial cells derived from lung adenocarcinoma, were treated with 10 μM irbesartan (ARB), or 10 μM ramipril (ACEi) alone or in the presence of 100 nM Angiotensin II (Ang II) for 12 hours in serum-free media. After 12 hrs ACE2 mRNA expression was evaluated by Digital droplet (dd)PCR. Results: We found that Ang II increased by two-fold ACE2 mRNA copies (vehicle 792.7 ± 161.3 vs Ang II 1475 ± 319.9;p<0.001), while both irbesartan and ramipril did not affect ACE2 expression levels (722.3 ± 170.2 and 747.8 ± 313.8, respectively). Moreover, pretreatment with irbesartan abolished Ang II-induced ACE2 expression (722.3 ± 170.2 copies irbesartan vs 1046 ± 182.4 copies Ang II + irbesartan;p<0.05), while pretreatment with rampiril had no such effect (1252 ± 246,4 copies Ang II + ramipril). Conclusions: ARBs and ACEis do not increase ACE2 expression at mRNA levels in human epithelial lung cells. Ang II increased ACE2 expression by acting via AT1R. Therefore, these results provided mechanistic support to a beneficial effect of both ACEi and ARB treatment in Covid19 patients with Sars-CoV-2 infection.
ABSTRACT
Objective: Recently, the influence of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) gained increasing attention, especially since concerns were raised regarding a potential influence of RAAS inhibitors on Corona Virus Disease 2019 (COVID-19). Our objective was to study the effect of recently initiated antihypertensive drugs on Angiotensin (Ang) II (1-8) and Ang (1-7) as markers of the pro-inflammatory ACE/Ang II/Ang Type 1 receptor (AT1R) axis and the counteractive ACE2/Ang (1-7)/Mas R axis in patients with newly diagnosed hypertension. Design and method: Randomized, open-label trial investigating RAAS peptide profiles after initiation of antihypertensive treatment with either perindopril, olmesartan, amlodipine, or hydrochlorothiazide. Ang II and Ang (1-7) concentrations were measured at 8am and 12am at day of treatment initiation and after four weeks of treatment. Results: 80 patients were randomized in a 1:1:1:1 fashion. Between the four substances, we found significant differences for the concentrations of Ang II (p<0.0005 for 8 and 12am) and Ang (1-7) (p=0.019 for 8am and <0.0005 for 12am) four weeks after treatment start. Ang II was decreased by perindopril (p=0.002), and increased by olmesartan (p<0.0005) and amlodipine (p=0.012), and hydrochlorothiazide (p=0.001) (Figure panel A). Ang (1-7) was increased by perindopril and olmesartan (p=0.008 and 0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p=0.317 and 0.109) (Figure panel B). Conclusions: Initiation of antihypertensive therapy causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptide shifts upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.