title: Implication of protein kinase A for a hepato-protective mechanism of milrinone pretreatment.
abstract: BACKGROUND
  We have previously reported that an increase of adenosine 3',5'-cyclic monophosphate (cAMP) in liver tissue after an administration of milrinone, a phosphodiesterase-3 inhibitor attenuates hepatic warm ischemia-reperfusion injury. The aim of this study was to determine whether cAMP-dependent protein kinase (protein kinase A) activation was involved in the milrinone-induced hepatoprotective effect on an ischemia-reperfusion injury in an in vivo model.
  
  
  METHODS
  Male Lewis rats were allocated into 3 groups. In Group M, milrinone was administrated before ischemia; in Group I, a protein kinase A inhibitor, adenosine 3',5'-cyclic monophosphorothioate, 8-bromo-, Rp-isomer, sodium salt (Rp-8-Br-cAMPS), was injected prior to the administration of milrinone; and in Group C, the control group, there was no pretreatment. After pretreatment, all rats were exposed to a 45-min total hepatic inflow occlusion.
  
  
  RESULTS
  After milrinone administration, liver cAMP concentrations and protein kinase A activity ratios were elevated. They protected the liver from ischemia-reperfusion injury. Rp-8-Br-cAMPS suppressed protein kinase A activation without affecting cAMP elevating responses to milrinone. Compared with Group C, hepatocellular necrosis, neutrophil infiltration, and congestion were ameliorated, and serum tumor necrosis factor-alpha, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were significantly suppressed in Group M. Rp-8-Br-cAMPS canceled this effect, showing histological damages in Group I as severe as in Group C. The levels of tumor necrosis factor-alpha, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were the same in Groups C and I.
  
  
  CONCLUSIONS
  Activation of protein kinase A might play an important role in the mechanism of milrinone-induced ischemic tolerance in the liver.
authors.affiliation: Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Satoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Kume
authors.forename: Yuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Siarhei V
authors.initials: SV
authors.lastname: Yakubouski
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006339:Heart Rate; D045022:Lactate Dehydrogenases / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020105:Milrinone / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011674:Pulse; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D045022:Lactate Dehydrogenases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017868:Cyclic AMP-Dependent Protein Kinases; D020105:Milrinone