Beneficial effects of adenosine triphosphate-sensitive K^+ channel opener on liver ischemia/reperfusion injury

AIM:To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury.METHODS:Wistar male rats underwent partial liver ischemia performed by clamping the pedicle from the medium and left anterior lateral segments for 1 h under mechanical ventilation.They were divided into 3 groups:Control Group,rats submitted to liver manipulation,Saline Group,rats received saline,and Diazoxide Group,rats received intravenous injection diazoxide(3.5 mg/kg) 15 min before liver reperfusion.4 h and 24 h after reperfusion,blood was collected for determination of aspartate transaminase(AST),alanine transaminase(ALT),tumor necrosis factor(TNF-α),interleukin-6(IL-6),interleukin-10(IL-10),nitrite/nitrate,creatinine and tumor growth factor-β1(TGF-β1).Liver tissues were assembled for mitochondrial oxidation and phosphorylation,malondialdehyde(MDA) content,and histologic analysis.Pulmonary vascular permeability and myeloperoxidase(MPO) were also determined.RESULTS:Four hours after reperfusion the diazoxide group presented with significant reduction of AST(2009 ± 257 U/L vs 3523 ± 424 U/L,P = 0.005); ALT(1794 ± 295 U/L vs 3316 ± 413 U/L,P = 0.005); TNF-α(17 ± 9 pg/mL vs 152 ± 43 pg/mL,P = 0.013; IL-6(62 ± 18 pg/mL vs 281 ± 92 pg/mL); IL-10(40 ± 9 pg/mL vs 78 ± 10 pg/mL P = 0.03),and nitrite/nitrate(3.8 ± 0.9 μmol/L vs 10.2 ± 2.4 μmol/L,P = 0.025) when compared to the saline group.A significant reduction in liver mitochondrial dysfunction was observed in the diazoxide group compared to the saline group(P < 0.05).No differences in liver MDA content,serum creatinine,pulmonary vascular permeability and MPO activity were observed between groups.Twenty four hours after reperfusion the diazoxide group showed a reduction of AST(495 ± 78 U/L vs 978 ± 192 U/L,P = 0.032); ALT(335 ± 59 U/L vs 742 ± 182 U/L,P = 0.048),and TGF-β1(11 ± 1 ng/mL vs 17 ± 0.5 ng/mL,P = 0.004) serum levels when compared to the saline group.The control group did not present alterations when compared to the diazoxide and saline groups.CONCLUSION:Diazoxide maintains liver mitochondrial function,increases liver tolerance to ischemia/reperfusion injury,and reduces the systemic inflammatory response.These effects require further evaluation for using in a clinical setting.

Pentoxifylline 通过 TNF- 合成和 TGF-1 基因表示的下面规定改进肝新生

AIM:To investigate the mechanism of pentoxifylline(PTX)improvement in liver regeneration.RESULTS:Rats were randomized into 4 groups:Control rats;Sham-sham-operation rats;Saline-70% hepatectomy plus saline solution;PTX-70%hepatectomy plus PTX.At 2 and 6 h after hepatectomy,aspartate aminotransferase,alanine aminotransferase,tumor necrosis factor(TNF)-α and interleukin-6(IL-6)serum and hepatic tissue levels were determined.Tumor growth factor(TGF)-β1 gene expression in liver tissue was evaluated 24 h after hepatectomy by quantitative reverse transcriptase polymerase chain reaction analysis.Proliferation was analyzed by mitotic index and proliferating cell nuclear antigen(PCNA)staining 48 h after hepatectomy.RESULTS:TNF-α and IL-6 serum levels increased at 2 and 6 h after hepatectomy.At 2 h after hepatectomy serum PTX was reduced but not hepatic levels of TNF-α and IL-6.A decrease in liver TGF-β1 gene expression and an increase in mitotic index and PCNA after hepatectomy were observed in the PTX treatment group in comparison to the saline group.CONCLUSION:PTX improves liver regeneration by a mechanism related to down regulation of TNF-α production and TGF-β1 gene expression.