title: Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.
abstract: BACKGROUND
  Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS).
  
  
  METHODS
  Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed.
  
  
  RESULTS
  Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects.
  
  
  CONCLUSIONS
  Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect.
authors.affiliation: Department of Anesthesiology, Nagasaki University, Nagasaki, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Shinya
authors.initials: S
authors.lastname: Tosaka
authors.forename: Reiko
authors.initials: R
authors.lastname: Tosaka
authors.forename: Takuji
authors.initials: T
authors.lastname: Maekawa
authors.forename: Sungsam
authors.initials: S
authors.lastname: Cho
authors.forename: Susumu
authors.initials: S
authors.lastname: Eguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Koji
authors.initials: K
authors.lastname: Sumikawa
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D057775:Ischemic Postconditioning; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D009569:Nitric Oxide; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D020105:Milrinone
keywords: Ischemia-reperfusion injury; Liver; Milrinone; Nitric oxide synthase; Phosphatidylinositol 3-kinase