Angiotensin-(1–7) treatment blocks lipopolysaccharide-induced organ damage, platelet dysfunction, and IL-6 and nitric oxide production in rats

Figures

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  Figure 1. Effects of angiotensin-(1–7) on haemodynamic parameters. We assessed the changes in mean arterial blood pressure (a) and heart rate (b) during the experimental period in rats infused with 0.9% NaCl (control, n = 6), angiotensin (Ang)-(1–7) (1 mg/kg for 3 h, n = 6), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 12), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 12). The data are expressed as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 2. Angiotensin-(1–7) improves liver and kidney dysfunction and ameliorates delayed hypoglycaemia in endotoxaemic rats. We assessed the changes in lactate dehydrogenase (LDH) (a), alanine aminotransferase (ALT) (b), blood urea nitrogen (BUN) (c), creatinine (d), and blood glucose (e) levels during the experimental period in rats infused with 0.9% NaCl (control, n = 6), angiotensin (Ang)-(1–7) (1 mg/kg for 3 h, n = 6), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 12), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 12). The data are shown as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 3. Effects of angiotensin-(1–7) on platelet counts and aggregation. We assessed the changes in platelet counts (a) during the experimental period in rats infused with 0.9% NaCl (control, n = 6), angiotensin (Ang)-(1–7) (1 mg/kg for 3 h, n = 6), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 12), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 12). Platelet aggregation was measured using various concentrations of collagen (b) and adenosine diphosphate (ADP) (c) to activate platelets from control (n = 4), Ang-(1–7) (n = 4), LPS (n = 9), or LPS + Ang-(1–7) (n = 9) rats at the end of the experiment (at 6 h). The data are shown as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 4. Angiotensin-(1–7) attenuates the elevated plasma levels of interleukin-6 and nitric oxide in endotoxaemic rats. We assessed the changes in interleukin (IL)-6 (a) in rats infused with 0.9% NaCl (control, n = 6), angiotensin (Ang)-(1–7) (1 mg/kg for 3 h, n = 6), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 6), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 6); or the changes in NO (b) during the experimental period in control (n = 6), Ang-(1–7) (n = 6), LPS (n = 12), or LPS + Ang-(1–7) (n = 12) rats. The data are shown as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 5. Effect of Angiotensin-(1–7) on tissue levels of nitric oxide (NO) and oxidative stress in endotoxaemic rats. We assessed the levels of NO (a,b), 4-hydroxynonenal (4-HNE) (c,d), and protein carbonyl (e,f) in lung and liver tissues in rats infused with 0.9% NaCl (control, n = 3), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 3), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 3). Lung and liver tissues were harvested 6 h after LPS administration. The data are shown as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control.

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  Figure 6. Angiotensin-(1–7) attenuated elevated tissue levels of CXCL1 and macrophage-inflammatory protein (MIP)-3α in endotoxaemic rats. We assessed the changes in lung CXCL1 (a), liver CXCL1 (b), lung MIP-3α (c), and liver MIP-3α levels in rats infused with 0.9% NaCl (control, n = 3), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min, n = 3), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, n = 3). Lung and liver tissues were harvested 6 h after LPS administration. The data are shown as the mean ± standard error of the mean. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 7. Ang-(1–7) attenuates the increased expression of inducible nitric oxide synthase and IκB, but not extracellular signal-regulated kinase 1/2, in endotoxaemic rats. We assessed the changes in inducible nitric oxide synthase (iNOS) (a), cytoplasmic IκB (b), and extracellular signal-regulated kinase (ERK) 1/2 (c) in the liver tissues of rats infused with 0.9% NaCl (control), angiotensin (Ang)-(1–7) (1 mg/kg for 3 h), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS). Liver tissues were harvested 24 h after LPS administration. Representative blots are shown in the upper panel of the figure. β-actin and total ERK1/2 served as loading controls for iNOS and IκB and for phosphorylated ERK1/2, respectively. The data are shown as the mean ± standard error of the mean from 4 rats per group. *, p < 0.05 for LPS vs. control. #, p < 0.05 for LPS + Ang-(1–7) vs. LPS.

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  Figure 8. Histological analysis of lung and liver. Haematoxylin and eosin staining on (a) lung and (b) liver sections from rats infused with 0.9% NaCl (control), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, LPS + Ang-(1–7)). Shown are representative micrographs from 3 independent experiments in which the same results were obtained. Magnification × 200.

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  Figure 9. Effect of Ang-(1–7) on NF-κB p65 activation in lung and liver tissues in endotoxaemic rats. Immunohistochemistry staining for phosphorylated- NF-κB p65 in lung (a) and liver (b) tissues in rats infused with 0.9% NaCl (control), E. coli lipopolysaccharide (LPS, 10 mg/kg for 15 min), or LPS plus Ang-(1–7) (1 mg/kg for 3 h at 0.5 h after LPS, LPS + Ang-(1–7)). Arrows indicate positive staining. Samples were obtained at 6 h after LPS. Shown are representative photographs from 3 independent experiments in which the same results were obtained. Magnification × 200.

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  Figure 10. Schematic diagram of the effects of angiotensin-(1–7) in rats with endotoxaemia. ERK: extracellular signal-regulated kinase; IL: interleukin; NF-κB; nuclear factor kappa B; NO: nitric oxide; p38 MAPK: p38 mitogen-activated protein kinase.