title: Pharmacological preconditioning using intraportal infusion of L-arginine protects against hepatic ischemia reperfusion injury.
abstract: OBJECTIVE
  The present study examined the effects of intraportal infusion of L-arginine on ischemia/reperfusion injury (I/RI) in pig livers, by observing changes in the liver function, liver cell morphology, and changes in the mitochondrial ultrastructure.
  
  
  BACKGROUND
  The involvement of the nitric oxide (NO) pathway in the reperfusion-ischemic phenomenon is complex and not fully understood. Likewise, little is known about the possible benefit of intraportal infusion of L-arginine (substrate for the NO synthesis) on liver I/RI.
  
  
  METHODS
  A pig model consisting of 90 min of hepatic ischemia and 180 min of reperfusion was employed. Eighteen female hybrid pigs were randomly divided into three groups: sham-operated, non-preconditioned, and pharmacologically preconditioned group (intraportal infusion of L-arginine 400 mg/kg) 10 min before being subjected to ischemia and reperfusion. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and the bile flow were measured. Liver biopsies were taken 180 min after reperfusion for histology, caspase-3 immunohistochemistry, and ultrastructural examination of mitochondria.
  
  
  RESULTS
  In the pharmacologically preconditioned group, we observed increased bile flow (P < 0.01) and improved serum AST levels (P < 0.01) relative to the non-preconditioned group. Serum concentrations of TBARS did not differ between the groups. Sinusoidal congestion (P = 0.02) was more evident in the non-preconditioned group than in the sham operated group. Infiltrating PMNs (P = 0.01) were more evident in the non-preconditioned group than in the sham and pharmacologically preconditioned group. The pharmacologically preconditioned group showed an approximately 2.5-fold decrease in caspase-3 activity relative to the non-preconditioned group (P < 0.01). Notably, damage to the mitochondrial ultrastructure in the pharmacologically preconditioned group was reduced relative to the other groups (P < 0.01).
  
  
  CONCLUSIONS
  Pharmacological preconditioning with intraportal L-arginine provided protection against hepatic I/RI in early phases of the reperfusion period. The mechanisms underlying the protective effect may include preservation of the mitochondrial structure and inhibition of caspase-3 activity.
authors.affiliation: Graduate Program of Medical Sciences, University Federal do Rio Grande do Sul, Porto Alegre, Brazil. rafaelgiovanardi@hotmail.com
authors.forename: Rafael Omar
authors.initials: RO
authors.lastname: Giovanardi
authors.forename: Ernani Luis
authors.initials: EL
authors.lastname: Rhoden
authors.forename: Carlos Thadeu
authors.initials: CT
authors.lastname: Cerski
authors.forename: Miriam
authors.initials: M
authors.lastname: Salvador
authors.forename: Antonio Nocchi
authors.initials: AN
authors.lastname: Kalil
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007262:Infusions, Intravenous; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; D001120:Arginine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3