FIMASARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, AMELIORATES AN IN VIVO ZEBRAFISH MODEL OF HEART FAILURE

Abstract

Objective: 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 an arrhythmia-induced heart failure (HF) model in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation using an angiotensin II type 1 receptor blocker, fimasartan, by assessing cellular and physiologic responses as well as morbidity and mortality. Design and method: HF was induced by exposure to 20 μM terfenadine in zebrafish larvae. Morphologic, physiologic, and functional parameters were assessed with or without fimasartan pretreatment. Results: Zebrafish exposed to terfenadine showed marked dilation of the ventricle and reduction in systolic function. Treatment with terfenadine was associated with a ten-fold higher expression of atrial natriuretic peptide (p < 0.01 vs. vehicle), increased p53 mRNA expression and chromatin fragmentation by TUNEL assay, all of which were significantly reduced with fimasartan treatment. Moreover, fimasartan improved fractional shortening (FS) (terfenadine + fimasartan 21.7 ± 2.1 % vs. terfenadine + vehicle 8.4 ± 0.7 % vs. vehicle 37.3 ± 2.1 %, p < 0.01). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine 96.0%, p < 0.01). Conclusions: Fimasartan effectively prevented HF and improved survival in zebrafish. Reduction of apoptotic cell death and improved hemodynamics might be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in heart failure treatment.