Fimasartan, an angiotensin II receptor antagonist, ameliorates an in vivo zebrafish model of heart failure

Abstract

Background/Aims: Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established a model of arrhythmia-induced heart failure (HF) in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasartan, through the assessment of cellular and physiologic responses, morbidity, and mortality. Methods: HF was induced in zebrafish larvae by exposure to 20 μM terfenadine.Morphologic, physiologic, and functional parameters were assessed in the presence or absence of fimasartan treatment. Results: Zebrafish exposed to terfenadine showed marked dilatation of the ventricle and reduced systolic function. Treatment with terfenadine was associated with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), increased p53 mRNA expression, and chromatin fragmentation in the TUNEL assay, all of which were significantly reduced by fimasartan treatment. Moreover, fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fimasartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001). Conclusions: Fimasartan effectively protected against the progression of HF in zebrafish by improving hemodynamic indices, which improved survival. A reduction in apoptotic cell death and an improvement in hemodynamics may be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in the treatment of HF.

An intestinal cell type in zebrafish is the nexus for the SARS-CoV-2 receptor and the Renin-Angiotensin-Aldosterone System that contributes to COVID-19 comorbidities

“…Expression of agtr2 was also detected in 5dpf mesenchyme (c135) and in 5dpf enteric smooth muscle cells (c197). Agtr antagonists taken to control hypertension also ameliorate zebrafish models of heart failure (Quan et al, 2020), showing conserved structure and function of angiotensin receptors.…”

“…The selective Agtr1 antagonist telmisartan blocks sodium uptake in zebrafish cultured in low ionic strength water as expected if Ang II acts on sodium retention by binding to Agtr1 (Kumai et al, 2014), even though fish lack aldosterone. The high blood pressure medication fimasartan, an Ang II receptor antagonist, also ameliorates zebrafish models of heart failure, normalizing the expression of atrial natriuretic peptide, reducing cell death around the heart, and improving blood flow (Quan et al, 2020). These results show that Agtr1 structure and function are conserved in human and zebrafish.…”

The SARS-CoV-2 receptor and other key components of the Renin-Angiotensin-Aldosterone System related to COVID-19 are expressed in enterocytes in larval zebrafish

“…S10J " type="url"/> ). Agtr antagonists that patients take to control hypertension also ameliorate zebrafish models of heart failure ( Quan et al, 2020 ), showing conserved structure and function of angiotensin receptors.…”

“…The selective Agtr1 antagonist telmisartan blocks sodium uptake in zebrafish cultured in low ionic strength water as expected if Ang II acts on sodium retention by binding to Agtr1 ( Kumai et al, 2014 ), even though fish lack aldosterone. The high blood pressure drug fimasartan, an Ang II receptor antagonist, also ameliorates zebrafish models of heart failure, normalizing the expression of atrial natriuretic peptide, reducing cell death around the heart, and improving blood flow ( Quan et al, 2020 ). These results show that Agtr1 structure and function are conserved in human and zebrafish.…”

Cardioluminescence in transgenic zebrafish embryos: a Ca2+imaging tool to study drug effects and pathological modeling

“…However, differences were observed in terfenadine-treated embryos (0.26 ± 0.05 for major vs. 0.44 ± 0.04 for minor diameter; p<0.0001) suggesting that contraction was altered (Fig. 7B) [40,41]. We therefore examined Ca 2+ levels by cardioluminescence.…”