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


CONCLUSIONS
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.
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Mateus Antunes
MA
Nogueira
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Ana Maria Mendonça
AM
Coelho
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Sandra Nassa
SN
Sampietre
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Rosely Antunes
RA
Patzina
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Fabiano
F
Pinheiro da Silva
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Luiz Augusto Carneiro
LA
D'Albuquerque
Mateus Antunes Nogueira, Ana Maria Mendonça Coelho, Sandra Nassa Sampietre, Rosely Antunes Patzina, Fabiano Pinheiro da Silva, Luiz Augusto Carneiro D'Albuquerque, Marcel Cerqueira Cesar Machado, Department of Gastroenterology (LIM/37), Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil.
Marcel Cerqueira Cesar
MC
Machado
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003981:Diazoxide / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015221:Potassium Channels / Q000819:agonists* / Q000378:metabolism; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D015415:Biomarkers; D018836:Inflammation Mediators; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide
Diazoxide; K+ channel opener; Liver ischemia/reperfusion; Liver mitochondria; Mitochondrial ATP-sensitive potassium channel