Protection against isoproterenol-induced cardiac injury by sacubitril/valsartan is associated with upregulation of the alternative renin-angiotensin-aldosterone system pathway

Figures

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  Fig. 1. Schematic illustration of the experimental design. ACE angiotensin-converting enzyme, Ang angiotensin, ANP atrial natriuretic peptide, ARNI sacubitril/valsartan, BNP B-type natriuretic peptide, C Wistar controls, ISO isoproterenol, LV left ventricle, LVW left ventricular weight, RVW right ventricular weight.

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  Fig. 2. The effect of ARNI on systolic blood pressure (A) and heart rate (B), average systolic blood pressure (C) and average heart rate (D) in isoproterenol-induced myocardial injury. C Wistar controls (n: 15), ARNI sacubitril/valsartan (n: 15), ISO isoproterenol (n: 40), ISO+ARNI (n: 32); SBP systolic blood pressure, HR heart rate. Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO; α p < 0.05 vs. ARNI.

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  Fig. 3. The effect of ARNI on left (A) and right (C) ventricular weight and on the left (B) and right (D) ventricular weight to tibia length ratio in isoproterenol-induced myocardial injury. C Wistar controls (n: 15), ARNI sacubitril/valsartan (n: 15), ISO isoproterenol (n: 40); ISO+ARNI (n: 32); LVW left ventricular weight, RVW right ventricular weight, TL tibia length. Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 4. The effect of ARNI on left ventricular ejection fraction (LVEF) (A) and left ventricular fractional shortening (LVFS) (B) in isoproterenol-induced myocardial injury. C Wistar controls (n: 8), ARNI sacubitril/valsartan (n: 8), ISO isoproterenol (n: 13); ISO+ARNI (n: 13). Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 5. The effect of ARNI on ratio of the diastolic transmitral peak early and late filling velocities (E/A ratio) (A), the ratio of the diastolic transmitral peak early filling velocity and the maximal velocity of early diastolic wall movement wave at the level of mitral annulus (E/Em ratio) (B), the deceleration time (DecT) (C) and the isovolumic relaxation time (IVRT) (D) in isoproterenol-induced myocardial injury. Wistar controls (n: 8); ARNI, sacubitril/valsartan (n: 8); ISO, isoproterenol (n: 13); ISO+ARNI (n: 13). Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 6. The effect of ARNI on hydroxyproline concentration in soluble and insoluble collagenous proteins and on the total hydroxyproline concentration (A), and on hydroxyproline content in the soluble and insoluble collagenous proteins, and on the total hydroxyproline content (B) in the left ventricle in isoproterenol-induced myocardial injury. ARNI sacubitril/valsartan, C Wistar controls, ISO isoproterenol. N: 15 animals per group. Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 7. The effect of ARNI on angiotensins (A–F) and aldosterone serum concentrations (G) in isoproterenol-induced myocardial injury. ARNI sacubitril/valsartan, C Wistar controls, ISO isoproterenol, Ang angiotensin. N: 6 animals per group. Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 8. The effect of ARNI on markers of renin (A) and ACE (B) activities in isoproterenol-induced myocardial injury. ARNI sacubitril/valsartan, C Wistar controls, ISO isoproterenol, PRA-S renin activity, ACE-S angiotensin-converting enzyme activity. N: 6 animals per group. Results are presented as means ± SEM. One-way, two-tailed ANOVA followed by multiple comparisons with a Bonferroni post-hoc test; * p < 0.05 vs. C; # p < 0.05 vs. ISO.

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  Fig. 9. A schematic illustration presenting the mean serum levels of angiotensins and aldosterone in isoproterenol-induced myocardial injury. ACE angiotensin-converting enzyme, Aldo aldosterone, Ang angiotensin, AP aminopeptidase, ARNI sacubitril/valsartan, AT1R angiotensin II type 1 receptor, NEP neprilysin (neutral endopeptidase), C Wistar controls, ISO isoproterenol. N: 6 animals per group. Results are presented as means.